The Biology of Interleukin-2: Thomas R. Malek

ANRV338-IY26-15 ARI 16 February 2008 12:45
The Biology
of Interleukin-2
Thomas R. Malek
Annu. Rev. Immunol. 2008.26:453-479. Downloaded from www.annualreviews.org
Department of Microbiology and Immunology and the Diabetes Research Institute,

by University of Massachusetts - Amherst on 08/03/12. For personal use only.
Miller School of Medicine, University of Miami, Miami, Florida 33101;

email: [email protected]
Annu. Rev. Immunol. 2008. 26:453–79 Key Words

First published online as a Review in Advance on IL-2, immune tolerance, T regulatory cell, T effector cell, immune
December 6, 2007
memory
The Annual Review of Immunology is online at
immunol.annualreviews.org Abstract
This article’s doi: Much data support an essential role for interleukin (IL)-2 in immune
10.1146/annurev.immunol.26.021607.090357
tolerance. This idea is much different from the early paradigm in
Copyright c 2008 by Annual Reviews. which IL-2 is central for protective immune responses. This change
All rights reserved
in thinking occurred when a T regulatory cell defect was shown to be
0732-0582/08/0423-0453$20.00 responsible for the lethal autoimmunity associated with IL-2/IL-2R
deficiency. This realization allowed investigators to explore immune
responses in IL-2-nonresponsive mice rendered autoimmune-free.
Such studies established that IL-2 sometimes contributes to optimal
primary immune responses, but it is not mandatory. Emerging find-
ings, however, suggest an essential role for IL-2 in immune memory.
Here, the current understanding of the dual role of IL-2 in maintain-
ing tolerance and contributing to immunity in vivo is reviewed with
some emphasis on T regulatory cell production and homeostasis.
Also discussed are implications of this new appreciation concern-
ing the immunobiology of IL-2 with respect to targeting IL-2 or its
receptor in immunotherapy.
453
INTRODUCTION cell production is the main reason for au-

toimmunity associated with IL-2/IL-2R de-
More than 30 years ago, Doris Morgan,
ficiency. This cell population suppresses po-
Treg cell: T Francis Ruscetti, and Robert Gallo (1) and
regulatory cell tentially autoreactive peripheral T cells that
Steven Gillis and Kendall Smith (2) estab-
escape thymic negative selection (8). Initially,
WT: wild-type lished that culture fluids of activated T cells
before it was appreciated that CD25 was a
contain mediators that induce the prolifera-
good marker for Treg cells, IL-2- and lL-
tion of antigen-activated T cells. In the en-
2Rα-deficient mice were shown to contain a
suing years, the protein responsible for this
greatly reduced number of IL-10-producing
T cell growth factor activity was purified and
CD4+ CD25+ T cells, suggesting that the ab-
its gene cloned to establish that this activity
sence of these cells is related to their au-
is due to a single molecular species (3). T cell
toimmune disease (9). A regulatory cell defect
growth factor was assigned the more generic
rather than a cell intrinsic abnormality was
nomenclature of interleukin (IL)-2, as lym-
suspected in IL-2-deficient mice because as-

phokines typically mediate diverse biological
pects of this autoimmune syndrome or experi-

functions.
mental autoimmune encephalomyelitis (EAE)
Work during the 1980s, which largely re-
are contained by wild-type (WT) populations
lied on in vitro systems, showed that T cell re-
of T cells or IL-2-treated IL-2−/− T cells
sponses require IL-2, leading to a widely ac-
in various adoptive transfer settings (10–13).
cepted model. Activation of T cells through
The demonstration that highly purified WT
the T cell receptor (TCR) and costimula-
CD4+ CD25+ T cells are sufficient to prevent
tory molecules such as CD28 causes produc-
all the abnormalities associated with the lack
tion of IL-2 and expression of the IL-2 re-
of IL-2R signaling provides direct data that
ceptor (IL-2R). The IL-2/IL-2R interaction
the main problem in IL-2/IL-2R-deficient
then drives extensive clonal expansion and ef-
mice is the inability to produce Treg cells (14,
fector development. This model places IL-
15).
2 as a central player for T cell–dependent
The issue concerning the importance for
immune responses. It was quite surprising,
IL-2 during T cell–dependent immune re-
therefore, that after the genes for IL-2 or
sponses in vivo still remains. Early on, IL-2-
two subunits of the IL-2R, IL-2Rα (CD25)
deficient mice were shown to develop protec-
and IL-2Rβ (CD122), were individually in-
tive immunity upon challenge with a variety of
activated in mice by gene targeting, the re-
infectious agents (16–18). A major caveat with
sulting phenotype is not immunodeficiency, as
these experiments is that the rapid autoim-
predicted, but rather a very serious lympho-
munity might bypass a requirement for IL-2.
proliferative and autoimmune disorder (4–7).
This complication, however, does not account
The progression of this disease in IL-2Rβ−/−
for these findings because more recent stud-
mice is shown in Table 1.
ies show that IL-2- or IL-2R-deficient mice
There is now much evidence that a defect
develop effective immunity in settings where
in CD4+ CD25+ Foxp3+ T regulatory (Treg)
Table 1 Autoimmune disease in C57BL/6 IL-2Rβ (CD122)-deficient mice

Birth No symptoms
2 weeks old Enlarged lymph nodes; increased proportion of activated T cells
3–8 weeks old Lymphadenopathy; splenomegaly; considerable proportion of activated T cells, especially CD4 T cells;
increased granulocytes in the bone marrow and spleen; hemolytic anemia; anti-DNA auto-antibodies;
multi-organ inflammatory infiltrates; wasting disease
8–12 weeks old Many symptoms above continue; thymic aplasia; sometimes decreased lymph node and spleen cellularity;
impaired B cell development and cellularity; death
454 Malek
the associated autoimmunity is greatly abated the high DNA sequence conservation in the
or completely prevented (19). Thus, although human and the mouse IL-2 genes. TCR sig-
IL-2 is essential for many T cell responses naling induces AP-1, increases the levels of
GFP: green
in vitro, it is dispensable for induction of T active NF-κB p65/rel, and causes calcineurin- fluorescent protein
cell–dependent immunity in vivo. Neverthe- mediated dephosphorylation of NFAT (nu-
Auto-regulatory
less, there remains one aspect of long-lasting clear factor of activated T cells), promoting loop: a gene
T cell immunity that may strictly require IL- its translocation into the nucleus. These tran- product that
2, i.e., recall responses by CD8+ memory T scription factors, in conjunction with consti- promotes or inhibits
cells (20, 21). tutive factors such as OCT-1, bind to spe- its own production
There are several past reviews that pro- cific sites in a cooperative fashion within Stat: signal
vide detailed information concerning the role the first 300 base pairs of the minimal pro- transducer and
activator of
of IL-2 in vitro and its signaling pathways, as moter, contributing to IL-2 gene transcrip-
transcription
well as detailed discussion concerning initial tion. HMGI(Y) and Ets factors bind to reg-
studies implicating IL-2 in Treg cell produc- ulatory sites just upstream. AML1/Runx1 is
tion (19, 22–24). This review primarily deals another positive regulator that binds to sites
with our current understanding of IL-2 in approximately 1.4 kb upstream of the tran-
the production of Treg cells and in T cell– scriptional start site (35). Although the min-
dependent immune responses in vivo where imal IL-2 promoter is very active in vitro,
autoimmunity is not a confounding factor. To this region or a larger 2.8 kb upstream
start, I introduce the basics of the IL-2/IL-2R IL-2 gene fragment does not give tissue-
system. specific and copy number–dependent activa-
tion in vivo that recapitulates the endogenous
IL-2 gene (36–38). Thus, other regulatory el-
IL-2 ements must lie further 5 downstream, con-
IL-2 is a 15,000-kDa α-helical cytokine pro- trolling IL-2 gene expression in vivo. Consis-
duced predominately by activated CD4+ and tent with this notion, the expression of green
CD8+ T cells, the latter to a lesser extent. fluorescent protein (GFP) under the control
Activated dendritic cells (DCs), natural killer of 8.4 kb of the IL-2 5 upstream sequence in
(NK) cells, and NKT cells also produce IL-2 mice more closely resembles the expression of
(25–29), but the biological relevance of IL- the endogenous IL-2 gene (27, 28).
2 from these cells remains unclear. IL-2 is The mechanism that dictates IL-2 gene si-
rapidly and transiently produced upon en- lencing after T cell activation is less well un-
gaging the TCR and costimulatory molecules derstood, but it represents another critical as-
such as CD28 on naive T cells. The transient pect controlling IL-2’s transient expression.
nature of IL-2 secretion depends on transcrip- Zfxla (ZEB, TCF8) and CREM (Icer) bind
tional induction by TCR signals and stabi- to the IL-2 minimal promoter and inhibit re-
lization of IL-2 mRNA by costimulatory sig- porter gene transcription, but their mecha-
nals, followed by transcriptional silencing of nism of action is undefined (39–43). More re-
the IL-2 gene and rapid degradation of IL-2 cently, T-bet (Tbx21) has been implicated in
mRNA (30–34). repressing IL-2 production through interac-
As described in more detail elsewhere tion with Rel-A within the proximal IL-2 pro-
(see 30–32), much is known concerning moter (44).
the stringent transcriptional induction of A classical auto-regulatory feedback loop
the IL-2 gene. A minimal proximal pro- has recently been described in which IL-2 in-
moter/enhancer region extends approxi- hibits its own production (45, 46). This auto-
mately 500 base pairs upstream of the tran- regulatory loop depends on activation of sig-
scriptional start site of the IL-2 gene. The nal transducer and activator of transcription-5
importance of this region is highlighted by (Stat5) and IL-2-dependent induction of the
www.annualreviews.org • The Function of IL-2 455

Activated T cell
APC Naive
T cell
TCR IL-2R IL-2R
Blimp-1
MHC 1
pSTAT5 p-
Il2 im
B7
Il2 Bl Il2
Il2
CD28
IL-2
TCR signaling IL-2 secretion IL-2 repression

IL-2R signaling
IL-2 transcription IL-2R expression IL-2R upregulation
Figure 1
The autocrine IL-2 auto-inhibitory loop.
transcriptional repressor B lymphocyte matu- subunits are required for formation of the
ration protein-1 (Blimp-1) (Figure 1). Thus, high-affinity IL-2R (Kd ∼10−11 M). The IL-
after antigen-activation of a naive T cell, IL- 2R does not exist as a preformed heterotrimer,
2 is produced; the high-affinity IL-2R is ex- but rather CD25 on its own initially binds IL-
pressed; secreted IL-2 binds to the IL-2R, 2 (Kd ∼ 10−8 M), which promotes association
leading to Stat5 activation and Blimp-1 in- with CD122 and γc. The crystal structure of
duction; and ultimately the IL-2 gene is re- IL-2 bound to the IL-2R reveals that each re-
pressed. Blimp-1 is a key downstream medi- ceptor subunit contacts IL-2, with most con-
ator of IL-2 repression because ectopic ex- tacts at the IL-2/CD25 interface, and that sig-
pression of Blimp-1 in activated T cells in- nificant interactions occur between CD122
hibits IL-2 production and the 8.4 kb IL- and γc, leading to a stable quaternary com-
2/GFP reporter (46), and Blimp-1-deficient plex of IL-2, CD25, CD122, and γc (49, 50).
T cells produce increased IL-2 (47, 48). Nev- This quaternary complex induces IL-2 sig-
ertheless, it remains to be determined whether naling that depends on the cytoplasmic tails
IL-2-dependent Stat5 activation directly tar- of CD122 and γc. When in close proxim-
gets Blimp-1 induction and whether Blimp- ity, Jak-3 via γc and Jak-1 via CD122 phos-
1 directly represses IL-2. Interestingly, mice phorylate key tyrosine residues on CD122,
with T cell conditional knockout of Blimp- leading to association of the adapter Shc and
Blimp-1: B 1 exhibit severe inflammatory bowel disease either Stat5 or Stat3, the latter to a lesser
lymphocyte leading to early death (47, 48). The basis extent. Shc provides a platform to activate
maturation protein-1 for this autoimmunity, including whether it the mitogen-activated protein kinase (MAPK)
High-affinity is due to improper production of IL-2, is not and the phosphatidylinositol 3-kinase (PI3K)
IL-2R: the known. pathways, important for cell growth and sur-
functional IL-2R, vival (22, 24). The associated Stats are fur-
composed of
IL-2Rα (CD25),
ther phosphorylated, allowing their dimeriza-
IL-2R tion and translocation into the nucleus, where
IL-2Rβ (CD122),
and γc (CD132) The IL-2R consists of three subunits, IL-2Rα Stat5 is the main IL-2-induced Stat in acti-
Jak: Janus kinase (CD25), IL-2Rβ (CD122), and the common vated T cells that regulates genes important
MAPK:
gamma chain or γc (CD132). CD122 and for effector function and T cell growth. Al-
mitogen-activated γc are primarily folded into β-sheet struc- though activation of the MAPK, PI3K, and
protein kinase tures and are related to members of the class Stat5 pathways are important for conven-
PI3K: I cytokine receptor superfamily. In contrast, tional activated T cells, Stat5 is the main path-
phosphatidylinositol CD25 and IL-15Rα contain “sushi” modules way by which IL-2R contributes to Treg cell
3-kinase in their extracellular region (22). All three production and maintenance.
456 Malek
IL-2 bound to the high-affinity IL-2R is effector cells readily, but transiently, express
short-lived on the cell surface as this com- CD25. The activation of naive T cells in vitro
plex is rapidly internalized (t1/2 10–20 min). leads to very high levels of CD25 expression
IL-2, CD122, and γc are targeted for lyso- through a two-step process (Figure 1). First,
somal degradation that is regulated by the moderate levels of CD25 are rapidly induced
proteasome and that depends on the cyto- by TCR and costimulatory signals, in part
plasmic tail of γc, whereas CD25 recycles to by activation of NF-κB, NFAT, AP-1, and
the cell surface (51–54). Importantly, driving CREB/AFT (58). Subsequently, IL-2 binds
IL-2-dependent T cells into S-phase of the to the IL-2R and increases the initial level
cell cycle requires sustained IL-2R signaling of CD25 through a Stat5-dependent positive
for several hours (55). Thus, IL-2-dependent feedback loop. Such a mechanism increases
T cell clonal expansion requires a somewhat IL-2 binding and hence signaling by activated
prolonged source of IL-2 and a continued ex- T cells through enhanced capture of IL-2 by
pression of all subunits of the IL-2R. How- CD25.

ever, some key downstream targets of the IL- CD25 is also found on natural
2R may be properly activated by the initial CD4+ Foxp3+ Treg cells. Like activated
IL-2/IL-2R interaction. effector T cells, CD25 expression by Treg
The γc subunit is expressed on virtually cells is influenced by TCR activation and
all hematopoeitic cells and is shared by the re- IL-2 upregulation. Another means for CD25
ceptors for IL-4, IL-7, IL-9, IL-15, and IL-21 expression is based on TCR activation and
(22, 56). CD122 is a subunit of both the IL- transforming growth factor (TGF)-β1 sig-
2R and the IL-15R. CD122 is constitutively naling (59). Treg cells may also express CD25
expressed on a subset of early lymphoid pro- in part based on this mechanism through
genitors, NK cells, NKT cells, memory phe- their production of TGF-β1.
notypic CD8 T cells, and Foxp3+ Treg cells,
whereas its expression is induced on virtu-
ally all antigen-activated T cells. IL-2 weakly EXPRESSION OF IL-2
binds to cells expressing only CD122 and γc, AND IL-2R IN VIVO
but this is unlikely to be biologically relevant, Although individual IL-2R subunits are
as the phenotype of IL-2- and CD25-deficient widely distributed on many different cell types
mice is very similar (6, 7). Besides binding sol- in the lymphoid compartment when directly
uble IL-15, CD122 and γc also readily bind examined ex vivo, only two major cell sub-
IL-15 through a process of trans-presentation sets readily coexpress CD25, CD122, and γc,
in which IL-15 bound to IL-15Rα on one cell which are required for the high-affinity IL-
presents IL-15 and engages CD122 and γc on 2R, i.e., CD4+ Foxp3+ Treg cells and activated
another cell (57). Accordingly, IL-15- or IL- conventional CD4+ and CD8+ T cells. Thus,
15Rα-deficient mice show defects in produc- Treg cells and antigen-activated T cells rep-
tion of NK and NKT cells and in the home- resent the main population of cells poised to
ostasis of CD8 memory cells (57). respond to IL-2 in vivo. CD25 is very tran-
Most lymphoid cells do not express CD25 siently expressed at a high level by activated
when directly examined ex vivo. However, T cells in vivo (60). Treg cells, rather than con-
CD25 is readily found on subsets of develop- ventional activated T cells, consistently ex-
ing pre-T and pre-B cells, but these cells lack press the highest level of CD25 in vivo (61).
CD122 and cannot respond to IL-2. Thus, This is somewhat surprising given the ability
mainstream T and B cell development is nor- to drive very high levels of CD25 on activated
mal in young CD25-deficient mice before T cells in vitro. CD25 has proven to be a use-
their accompanying severe autoimmunity dis- ful marker, albeit not a perfect one, for isolat-
rupts lymphocyte development (6). Activated ing natural Treg cells, especially in the mouse,

where most of the CD25+ CD4+ T cells are NKT cells, and direct enumeration of IL-2-
also Foxp3+ Treg cells (61). In human, con- producing thymic T cells supports a contribu-
ventional activated CD25+ T cells are more tion by both TCRαβ+ and TCRγδ+ T cells.
prevalent and the isolation of Treg cells based One limitation with this reporter is that it
on CD25 is more problematic. may overstate IL-2 expression by TCRγδ+
An important issue with respect to IL-2- and NKT cells, as GFP mRNA is substan-
dependent control of Treg cells and activated tially proportionally higher than IL-2 mRNA
T cells in vivo is an understanding of how IL- in these T cell subsets (28).
2 is made available to these cell populations. Peripheral immune tissues also contain a
One issue is what proportion of cells produce resident population of IL-2-producing cells.
IL-2 spontaneously or in response to endoge- Using the same IL-2/GFP reporter, the
nous immune stimuli. Without direct im- spleen contains approximately 2% GFP+ T
munological challenge, IL-2-producing cells, cells, the majority of which were TCRαβ+
cells (27, 28). For CD4+ GFP+ T cells,
all of T cell origin, are readily detected by in

situ hybridization and immunohistochemistry most express an effector/memory phenotype,

within the thymus from day 14 of gestation suggesting that these cells are recently ac-
until at least 5 weeks of age, in the epidermis tivated. Real-time PCR revealed that the
of the skin in neonates with a clusters of IL-2+ CD4+ CD25low splenic T cell subset, which
cells near hair follicles from 3–5 weeks of age, primarily corresponds to activated conven-
and from day 16 of gestation through adult tional T cells, expresses the highest levels of
life within the intestine (62). The significance IL-2 mRNA. NK and NKT cells also express
of the IL-2-producing cells in the skin and in- IL-2 mRNA but at strikingly lower levels,
testine is not clear, but their embryonic and whereas DCs lack this mRNA (26). As IL-2
early neonatal appearance suggests some de- dominantly controls the homeostasis of Treg
velopmental role. Along this line, production cells in peripheral immune tissue, one expects
of Vγ3Vδ1+ T cells in CD122−/− mice and a source of IL-2 for these cells in the spleen
CD8αα intraepithelial lymphocytes in IL-2- and lymph nodes, and these findings are con-
or CD122-deficient mice is impaired, consis- sistent with activated T cells as a source of
tent with a requirement for IL-2 or IL-15 for IL-2. Whether endogenous antigens or auto-
the development and/or maintenance of these antigens provide the immune stimulus for this
T cells, respectively (63–66). IL-2 production remains to be determined.
IL-2-producing T cells in the thymus may With respect to antigen-specific induction
reflect T cells undergoing positive and nega- of IL-2 by naive CD4+ T cells in vivo, early
tive selection as T cell activation accompanies studies indicate that IL-2 mRNA and protein
these processes, including IL-2 production. peak 6–12 h after antigen challenge, with less
IL-2-secreting thymocytes are readily found than 50% of the antigen-activated cells IL-2+ ,
at the cortical medullary junction and within and are then undetectable 24 h post-challenge
the medulla and are surrounded by a halo of (60, 69). The use of a more sensitive IL-2 se-
IL-2 protein, suggesting that IL-2 is available cretion assay refined this analysis and reveals
only to T cells within close proximity (62). that IL-2 protein is secreted by 1 h after anti-
This thymic IL-2 may promote the devel- gen challenge of naive T cells, and by 5–6 h
opment of Treg cells, which are also found later nearly 80% of antigen-specific T cells
within the inner thymus (67, 68). The use of produce maximal IL-2 (70). After this time,
GFP transgenic reporter mice under control IL-2 secretion declines and is undetectable by
of 8.4 kb of 5 IL-2 regulatory sequence reveals 16 h after the initial stimulation. IL-2 produc-
approximately 1% GFP+ cells in the thymus tion by memory T cells is similarly transient,
(27). These GPF+ cells are distributed be- with a peak response as rapid as 1–2 h after
tween conventional TCRαβ+ , TCRγδ+ , and antigen challenge. A similar high frequency of
458 Malek
IL-2-producing CD8+ T cells is detected af- tain mutations within the Foxp3 gene exhibit
ter viral infection of mice (71). IL-2 is secreted a very severe systemic autoimmune disease
directionally at the immune synapse favoring that parallels the autoimmunity seen in IL-
Autocrine:
use by IL-2R-bearing T cells in close proxim- 2/IL-2R-deficient mice, although the tempo production and use
ity to antigen-presenting cells in either an au- of the disease in Foxp3-deficient mice is of a cytokine by the
tocrine or paracrine manner (72). In vivo IL-2 quicker. same cell
production is somewhat more rapid and tran- One difference between Foxp3−/− ani- Paracrine: a cell
sient than seen in vitro and is consistent with mals and IL-2-, CD25-, and CD122-deficient that responds to a
the recently described IL-2 auto-inhibitory mice is that only the former completely lacks cytokine produced
by a neighboring cell
loop (45, 46). Importantly, this time course Foxp3+ T cells. In comparison with WT
indicates that IL-2 is available primarily dur- mice, the Foxp3+ CD4+ T cells within IL-
ing the initial programming phase of antigen- 2/IL-2R-deficient mice contain an approxi-
activated T cells that precedes T cell prolif- mately twofold reduced level of Foxp3, es-
eration. This implies a role for IL-2 during sentially lack expression of CD25, and are
an immune response independent of driving found in markedly reduced proportions, es-

extensive clonal expansion. The considerable pecially within peripheral immune tissues (75,
T cell expansion after immune challenge of 77, 78). Investigators have argued that the
IL-2- or IL-2R-deficient mice is consistent CD4+ Foxp3low CD25neg cells in IL-2/IL-2R-
with an IL-2-independent mechanism for T deficient mice are functional Treg cells, but
cell growth. they cannot keep up with the autoreactive T
cells, accounting for the slower pace of au-
toimmunity (61). In support of this idea, the
IL-2 AND THE GENETIC BASIS Foxp3+ T cells within IL-2-deficient mice
OF AUTOIMMUNITY show some capacity to inhibit T cell prolif-
Mice deficient in IL-2, CD25, or CD122 ex- eration in a Treg cell–dependent suppression
hibit lethal autoimmunity (4–7) and are im- assay in vitro (61, 79). The overall relevance
paired in Treg cell production (14, 15, 61). of this in vitro suppression has been ques-
These findings and the related phenotype of tioned because, in tumor-bearing vaccine-
Foxp3-deficient mice, which lack Treg cells, treated CD25−/− mice, the resident Foxp3+
are consistent with the genetic basis for IL- T cells do not suppress antitumor immu-
2/IL-2R in immune tolerance at the level nity (78). Alternatively, less rapid autoim-
of Treg cells. Even though IL-2 and IL-15 munity in IL-2/IL-2R-deficient mice may
share common receptor signaling subunits, be due to impaired autoimmune effector T
i.e., CD122 and γc, IL-15- and IL-15Rα- cells that delay disease. In support of this
deficient mice are autoimmune-free and con- idea and discussed more fully below, IL-2/IL-
tain a normal number of Foxp3+ Treg cells 2R-deficient mice are immunocompetent but
(57, 73), firmly establishing that IL-2 is the show variable abnormalities in clonal expan-
critical cytokine for Treg cells. sion and effector function. Similarly, acute
Foxp3 is a transcriptional regulator that is disease by autoreactive effector CD4+ T cells
essential for Treg cell production (74, 75) and was shown to be milder when induced by IL-
is currently the best marker for Treg cells. In 2−/− effector cells (80). Furthermore, when
WT mice, Foxp3 is uniformly expressed at a autoimmunity in CD122-deficient mice is
high level in only natural Treg cells and is not prevented by the adoptive transfer of WT
induced in activated effector T cells (61). In Treg cells, a normal proportion and num-
humans, high levels of Foxp3 are also found in ber of donor WT CD4+ CD25+ Foxp3+ Treg
Treg cells, but some activated effector T cells cells are found in the peripheral immune com-
also transiently express Foxp3 at a low level partment while the number of endogenous
(76). Foxp3-deficient or scurfy mice that con- Foxp3low CD25neg CD122−/− T cells remains

very low (81). This finding implies that these sis of the phenotype of mice deficient in this
Foxp3low cells are largely nonfunctional and transcriptional activator (92–95). A patient
perhaps analogous to the Foxp3low phenotype with a homozygous missense mutation in the
associated with effector rather than regulatory Stat5b gene has also been identified with im-
human T cells (82–84). Thus, the problem mune dysregulation and impaired expression
with Treg cells in IL-2/IL-2R-deficient mice of Foxp3 and Treg cell function (96), impli-
is more complex than simply a failure to keep cating Stat5 activation with human Treg cell
up with autoreactive cells. production.
In autoimmune-prone NOD mice, one of
the autoimmune susceptibility genes, Idd3,
spans 650 kb of genomic DNA and con- IL-2 IN Treg CELL
tains the IL-2 gene (85, 86). Molecular and DEVELOPMENT
functional studies indicate that Idd3 regulates Natural CD4+ CD25+ Foxp3+ T cells de-
IL-2 transcription such that mice containing velop within the thymus and require TCR-
the NOD Idd3 gene segment express twofold mediated selection on self-antigens (97).
lower IL-2 (86). Importantly, by specifically Foxp3 expression is primarily restricted to
targeting the IL-2 gene within the Idd3 lo- CD4+ “single positive” thymocytes. How-
cus, autoimmune diabetes is accelerated by ever, a few CD4+ CD8low thymocytes are also
this lower IL-2 production. Thus, a mouse Foxp3+ (61). This expression pattern is con-
IL-2 gene polymorphism contributes to au- sistent with commitment to a Treg lineage
toimmune susceptibility owing to fewer Treg at a somewhat late phase of T cell develop-
cells with less suppressive activity. ment. Besides TCR engagement, Treg devel-
With respect to IL-2R and human dis- opment also requires costimulation through
ease, several patients have been reported with CD28 (98, 99). One role of CD28 signaling
mutations in the CD25 gene (87–90). Anal- is cell intrinsic for Treg cell development, i.e.,
ogous to CD25-deficient mice, such patients induction of Foxp3 expression (100), and this
exhibit a wide spectrum of abnormalities, in- may explain the detection of Foxp3+ T cells in
cluding severe autoimmunity, lymphadenopa- the absence of IL-2/IL-2R. A second role is to
thy, and persistent viral infections. Problems induce IL-2 production by T cells undergo-
with Treg cells are suspected but not defini- ing selection to provide a potential source of
tively established. In one case, Foxp3+ CD4+ paracrine IL-2 to developing Treg cells (100).
T cells were detected, analogous to IL-2/IL- Some have argued that IL-2 is dispens-
2R-deficient mice (88). Activation of their T able for thymic Treg cell development be-
cells shows impaired production of IL-10. In cause Foxp3+ thymocytes are detected in IL-
another case, myeloablative conditioning fol- 2- and IL-2R-deficient mice (61, 79, 101).
lowed by an allogeneic bone marrow trans- This is most striking for the 6.5 TCR trans-
plant completely resolved the symptoms (89), gene selected upon its cognate antigen, vi-
consistent with reconstitution of Treg cells. ral hemagglutinin that is widely expressed
In addition, genome-wide association studies within the thymus, where the frequency of
that evaluated approximately 2000 patients, Foxp3+ thymocytes is similar in IL-2+/+ and
each with rheumatoid arthritis or type 1 di- IL-2−/− mice (79). However, the develop-
abetes, associate SNPs mapping to CD25 or ment of Foxp3+ thymocytes is nearly fivefold
CD122 genes, further relating possible poly- lower in IL-2−/− mice that expressed the 3.9
morphisms of the IL-2R with autoimmune TCR transgene, specific for hen egg lysozyme
diseases (91). (HEL), when selected upon HEL under con-
Stat5 activation is a main outcome of IL- trol of the insulin promoter (101). A major dif-
2R signaling, and Stat5 is known to be crit- ference in this setting is that HEL expression
ical for production of Treg cells on the ba- is not ubiquitous but dependent on expression
460 Malek
by Aire. Thus, under more physiological ex- veals a similar lack of CD4+ Foxp3+ T cells
pression of a model self-antigen, development (106). Collectively, these data indicate a re-
of Foxp3+ thymocytes is highly dependent quirement for one or more γc-dependent cy-
Model self-antigen:
on IL-2. Similarly, when compared with WT tokines that activate Stat5 for Foxp3 expres- germ-line expression
mice, there is a consistent twofold reduction sion and Treg cell development. IL-2, IL- of a defined foreign
in Foxp3+ thymocytes in IL-2- or IL-2R- 7, and IL-15 are the most likely possibilities antigen, usually as a
deficient mice containing a polyclonal TCR as they readily activate Stat5. IL-7−/− , IL- transgene, resulting
in its immune
repertoire (61, 73, 77). The reduction is even 7Rα (CD127)−/− , IL-15−/− , and IL-15Rα−/−
tolerance
greater when WT and CD25−/− thymocytes mice, however, contain a normal propor-
γc-dependent
develop in competition with each other (61). tion of CD4+ CD25+ Foxp3+ T cells (73,
cytokines:
In these settings, the level of Foxp3 protein 95), and IL-2/IL-2R-deficient mice contain cytokines whose
is also twofold lower (61, 77). These findings CD4+ Foxp3low CD25neg T cells, demonstrat- receptor contains the
also support a role for IL-2 in thymic Treg ing that these cytokines do not solely control γc subunit, i.e., the
the development of Foxp3+ T cells. Alter- receptors for IL-2,
cell development.
IL-4, IL-7, IL-9,

In addition to the observations men- natively, another γc-dependent cytokine con-
IL-15, and IL-21
tioned above, three additional lines of ev- tributes to the Foxp3low phenotype associated
idence directly implicate IL-2 for thymic with IL-2/IL-2R-deficient mice. In one study,
Treg cells. First, thymic-directed expression the thymus of CD122−/− mice was shown to
of WT CD122 in CD122−/− mice restores contain fewer CD4+ Foxp3+ thymocytes than
Treg cell production and prevents the as- do IL-2−/− mice (73), implying a contribu-
sociated autoimmunity (14, 102). More re- tion by IL-15. The decrease reported, how-
cent studies show that this transgenic IL- ever, is not as severe as in γc-deficient mice,
2R is functionally active within the thymus and this impairment was not observed in an-
by increasing to normal levels the number other study (61), indicating that IL-15 is not
of CD4+ Foxp3+ thymocytes and the expres- an essential cytokine for Treg cells. IL-7 and
sion of Foxp3 and CD25 (77). The increase IL-2 appear to be the relevant cytokines be-
in Foxp3 expression may be particularly im- cause, in the absence of both IL-7R and IL-
portant because lower expression of Foxp3 is 2R, CD4+ Foxp3+ T cells are not detected
directly related to development of autoim- (A.L. Bayer & T.R. Malek, unpublished data).
munity (103). Second, treatment of normal The TSLPR (thymic stromal-derived lym-
mice with anti-IL-2 reduces the number of phopoietin receptor) also utilizes IL-7Rα, but
thymic CD4+ CD25+ GITR+ Treg cells (104). not γc, as subunits. As Treg development de-
Third, thymic development of CD4+ Foxp3+ pends on multiple γc-dependent cytokines, as
T cells is restored in Rag2−/− mice recon- mentioned above, IL-7 is favored over TSLP
stituted with CD122−/− bone marrow trans- as the key cytokine that functions in tandem
duced with WT CD122 or a variant of CD122 with IL-2.
designed to selectively activate Stat5 (73). An important question is whether the ac-
This latter study shows an important role for tion of the IL-7R and IL-2R largely overlap at
IL-2-induced Stat5 in thymic Treg develop- the same stage of Treg cell development. One
ment. This regulation may be direct, as IL-2 possibility is that the Foxp3low phenotype in
activation of human Treg cells leads to Stat5 IL-2/IL-2R-deficient mice is due to minimal
and Stat3 binding to a conserved Stat-binding signaling by the IL-7R at the same develop-
site in the first exon of the Foxp3 gene (105). mental step. This scenario seems unlikely be-
Interestingly, although T cell development cause when IL-7R is increased on Treg cells
is severely blocked in γc−/− mice, the few by expressing CD127 as a transgene through-
CD4 T cells that are present contain a negligi- out most thymocytes in CD122−/− mice,
ble proportion of Foxp3-bearing T cells (61). Treg cell development is not rescued, and the
Analysis of Stat5- and Jak-3-deficient mice re- mice exhibit autoimmunity indistinguishable

from nontransgenic CD122−/− mice (107). compete with the IL-2-responsive WT donor
However, it was informative to observe the Treg cells.
activity of chimeric CD127/CD122, link- A key observation implicating IL-2 in pe-
ing IL-7 binding to IL-2R signaling, or re- ripheral Treg cell production is the demon-
ciprocally chimeric CD122/CD127, linking stration that adoptively transferred CD4+ T
IL-2 binding to IL-7R signaling, when ex- cells from IL-2−/− , but not CD25−/− , mice
pressed as transgenes in all T lineage cells in protect IL-2-sufficient recipient mice from
CD122-deficient mice (107). Only chimeric spontaneous EAE (13). This leads to an in-
CD122/CD127 increases the number of crease in donor CD4+ CD25+ T cells that de-
Foxp3+ thymocytes, upregulates Foxp3 and pends on host-derived IL-2. Besides provid-
CD25, and provides robust protection from ing data consistent with the rescue of IL-2−/−
autoimmunity. These results indicate that IL- Treg cells by paracrine IL-2 in the periph-
7R signaling promotes Treg cell development ery, this finding suggests that the requirement
in the absence of a functional IL-2R, but IL- for IL-2 can also be delivered extrathymically.
2 must trigger this signaling. The complete Subsequently, anti-IL-2 treatment of normal
failure of the chimeric CD127/CD122 or the mice was shown to block Treg cells in the
WT transgenic CD127 to rescue Treg cell de- periphery of neonatal and adult mice and to
velopment strongly suggests that IL-7 is un- cause autoimmunity in several disease-prone
available in the niche that is normally depen- strains (26, 104). Gene expression profiling
dent on IL-2. These data are consistent with of peripheral CD4+ Foxp3+ T cells derived
a model in which signaling by CD127 and from IL-2−/− mice after treatment with IL-2
CD122 occurs at distinct stages of Treg devel- revealed upregulation of growth-related mR-
opment and indicate that there is not a strict NAs rather than mRNAs important for im-
requirement for signal transduction through mune function (61). Furthermore, peripheral
the cytoplasmic tail of CD122. Treg cells with impaired expression of IL-2R
exhibit markedly lower homeostatic prolifer-
ation as assessed by BrdU uptake (14, 77).
IL-2 IN Treg CELL Thus, these data are consistent with IL-2 pro-
HOMEOSTASIS viding key signals in shaping the numbers
In addition to contributing to thymic Treg of peripheral Treg cells. Nevertheless, home-
development, considerable data indicate that ostasis of Treg cells also depends on other
IL-2 also functions to maintain Treg cells signals, including TCR recognition of self-
in the peripheral immune compartment. antigen in the context of MHC class II and
Peripheral immune tissues of IL-2- and costimulation through CD28 (98, 99, 108).
IL-2R-deficient mice contain an approxi- In competitive environments when enu-
mate tenfold reduction in the proportion merating CD4+ Foxp3+ T cells in peripheral
of CD4+ Foxp3+ T cells when enumerated immune tissue, WT Treg cells strongly out-
as a fraction in all CD4+ T lymphocytes compete the Foxp3+ cells of IL-2R nonre-
(61, 77). These cells are also Foxp3low and sponding origin, even after correcting IL-2R
largely CD25neg , analogous to their thymic signaling within the thymus (61, 77, 79, 81).
counterparts. This reduction in peripheral These data further support a critical role for
CD4+ Foxp3+ CD122−/− T cells remains at IL-2 in the periphery. A potentially impor-
least tenfold in absolute number upon cor- tant issue, however, is the extent that IL-2
recting autoimmunity by adoptive transfer of shapes the pool of peripheral Treg cells af-
WT Treg cells into lL-2Rβ−/− mice (81). ter exiting the thymus, particularly in neona-
This finding illustrates the striking inability tal or irradiated adult mice, as these set-
of these Foxp3low CD122−/− T cells, which tings readily support proliferation owing to
are continually produced by the thymus, to their lymphopenic environment (109). In this
462 Malek
regard, when WT Treg cells are transferred to the effect on Treg cell numbers. Furthermore,
1- to 2-day-old CD122-deficient mice, they anti-CD25 monoclonal antibody (mAb) or
undergo extensive IL-2-dependent prolifera- daclizumab immunotherapy is used in a va-
Peripheral
tion, expanding six- to eightfold in one week riety of clinical settings without obvious au- homeostasis:
(104). Furthermore, 10- to 20-day-old mice toimmune complications or dysregulation of constant number of a
were administered anti-IL-2 to induce au- the Treg cell compartment (111–113). lymphocyte subset in
toimmunity that was observed later in life Although Treg cells are one of the most peripheral immune
tissues through
(26). These experiments indicate that the Treg highly proliferating lymphocyte populations
regulated cell growth
cells present in the neonatal peripheral im- in vivo (14, 114), these cells are characterized and death
mune compartment are especially dependent as anergic and hyporesponsive to TCR and
on IL-2. Thus, one caveat concerning con- IL-2 signaling in vitro. Nevertheless, Treg
clusions about the requirement for IL-2 for cells efficiently suppress TCR-induced pro-
peripheral homeostasis of Treg cells is that it liferation when mixed with conventional T
is difficult to distinguish this early develop- cells in vitro by targeting inhibition of IL-
mental requirement versus subsequent main- 2 production (70, 115, 116). IL-2 initially
tenance in adult peripheral immune tissue. In produced from activated conventional T cells
any case, the available data indicate that, under acts on Treg cells to promote their survival,
physiological conditions, IL-2 begins to shape growth, and suppressor activity that in turn
the number of Treg cells and levels of Foxp3 cause inhibition of IL-2 production and sub-
during thymic development and continues to sequent proliferation by conventional T cells
function importantly in the periphery during (117–119). Treg cells may not have a strict
neonatal and adult life. requirement for IL-2 for suppressor function
Treg cells with defective IL-2R restricted in vitro because Foxp3+ T cells from IL-2-
to peripheral immune tissues are of some in- nonresponsive mice are suppressive in vitro
terest because they suppress autoimmunity (14, 61, 79, 120). Thus, there is some redun-
and are maintained at normal numbers even dancy for Treg cell inhibition in this assay, and
after adult thymectomy, probably because of other factors, such as IL-4, produced by ac-
slower death rate (14, 77). IL-2 induces very tivated T cells may substitute for IL-2 (121).
weak and transient Stat5 activation in these This in vitro assay, therefore, may model some
IL-2R-defective Treg cells. Correspondingly, aspects of IL-2-dependent Treg cell home-
downstream IL-2R-dependent responses are ostasis in vivo where autoreactive or antigen-
markedly impaired in vitro and in vivo. Thus, activated T cells likely provide IL-2 in close
this very minimal IL-2 signal is sufficient for proximity to Treg cells. This IL-2 is expected
peripheral Treg cell homeostasis, or there are to promote Treg cell homeostasis and may en-
IL-2-independent mechanisms in the periph- hance their functional activity. The finding
ery once Treg cells receive a productive IL-2 that the number of IL-2-producing effector
signal in the thymus. In either case, this re- cells is indexed to the number of Treg cells in
sult has an important implication, i.e., that vivo is consistent with this view (122).
peripheral Treg cells may be relatively resis-
tant to anti-IL-2 or IL-2R blockade. Indeed,
peripheral Foxp3+ T cells were transiently re- IL-2 AND INDUCED
duced by <50% after anti-IL-2 treatment of Treg CELLS
adult mice (61, 110). Another report showed Besides thymic-derived natural Treg cells, ac-
a greater reduction of peripheral adult Treg cumulating data indicate that conventional
cells by anti-IL-2, but investigators measured T cells can develop in the periphery to
CD25, not Foxp3 (26). As anti-IL-2 also in- become Foxp3+ -induced Treg (iTreg) cells
hibits CD25 expression on Treg cells in vivo (123). Naive T cells become iTreg cells in
(61, 110), this latter study likely overstated vitro upon activation through the TCR when

cultured with TGF-β and IL-2 (124–126). opment is inhibited by IL-2 through activa-
These cells exhibit potent suppressive activity tion of Stat5. Blocking IL-2R signaling, on
in vitro and are easily grown, representing the other hand, increased production of Th17
Adoptive
immunotherapy: another possible source of cells for adoptive cells (132). These investigators propose two
the transfer of in immunotherapy. The role of IL-2 for these mechanisms by which IL-2 limits antigen- or
vitro–derived cells is twofold: induction of Foxp3 and T auto-antigen-induced inflammation: produc-
effector or cell growth (127, 128). TGF-β-induced ex- tion of Treg cells and inhibition of effector cell
regulatory cells into
pression of Foxp3 is strictly dependent on differentiation into Th17 cells. Thus, altering
diseased individuals
to enhance or IL-2, whereas once Foxp3 is induced, other IL-2 levels, perhaps even in a narrow range,
suppress immunity cytokines, including γc-dependent cytokines, may have important pathogenic or therapeu-
Regulatory maintain this expression. These findings are tic consequences. For example, a seemingly
program: consistent with a role for IL-2 in Treg lineage modest twofold reduction of IL-2 results in
expression of a key commitment and are similar to IL-2 signaling a genetic predisposition to type 1 diabetes in
set of genes required
in vivo, where high levels of Foxp3 depend on NOD mice (86). In addition, the ready detec-
for functional Treg

IL-2 signaling (61, 77). tion of IL-2-producing cells in the intestine
cells
Recent evidence suggests that develop- (62) may function in part to prevent develop-
ment into auto-aggressive pathogenic Th17 ment of Th17 cells.
cells and development into Treg cells
are reciprocally regulated cell fate choices
(Figure 2) (129–131). Another interesting as- IL-2 AND THE Treg CELL
pect of IL-2 signaling is that it prevents gen- PROGRAM
eration of Th17 cells in vitro and within the Most T cells have the potential to secrete IL-
tumor microenvironment in vivo (132, 133). 2. Treg cells, however, do not produce IL-
Thus, IL-17-producing T cells develop after 2, and this represents one of their defining
stimulation through TCR and CD28 when features. In contrast to naive T cells, the IL-
TGF-β and IL-6 are present. This devel- 2 proximal promoter in Treg cells does not
undergo chromatin remodeling upon TCR
activation (134). Moreover, Foxp3 directly
Tnaive
binds to the minimal IL-2 promoter in asso-
ciation with NFAT and further downstream
Anti-CD3
Anti-CD28
in association with AML1/Runx1, contribut-
ing to active transcriptional repression of IL-
2 (35, 135). Blimp-1 is another candidate
Tact
to silence IL-2 (46), as its mRNA (47, 48)
and protein (D. Gong & T.R. Malek, un-
TGF-β published data) are also highly expressed in
Treg cells. Foxp3 cooperation with NFAT
and AML1/Runx1 has a broader role in Treg
Th17 iTreg cells than just repressing IL-2. Rather, these
also act to establish aspects of the regula-
IL-2 tory program of Treg cells. Thus, they pos-
IL-6
itively regulate expression of CD25, cytotoxic
Relative cytokine levels T lymphocyte-associated antigen-4 (CTLA-
Figure 2 4), and glucocorticoid-induced tumor necro-
IL-2 and the interrelationship between Th17 and
sis factor (TNF) receptor (GITR) by binding
induced Treg (iTreg) cells. IL-6 and IL-2 refer to to their promoters, and they thereby con-
their levels during T cell priming in the presence tribute to other important characteristics of
of TGF-β the Treg cell phenotype (35, 135).
464 Malek
Recent studies indicate that Treg lineage Table 2 IL-2/IL-2R-deficient mice develop effective immunity
commitment ensues without expression of Deficiency Immune response to References
Foxp3 (130, 136). An important function of IL-2 Vaccinia virus, LCMV, VSV 16
Foxp3 is to amplify and fix these pre-existing Islet allografts 18
features required for the suppressive program. Superantigen (SEA and SEB) 182
Moreover, paracrine IL-2 was suggested as
Cardiac allografts 183
essential for establishing this program (130).
IL-2 and IL-4 Vaccinia virus, LCMV 17
As the Treg cell suppressive program de-
Islet allografts 184
pends on consistent high levels of Foxp3 (103,
IL-2Rα (CD25) HSV-2 185
130, 137), a fundamental role of IL-2 likely
IL-2Rβ (CD122) Superantigen (SEB) 186
lies in its ability to increase Foxp3. Another
Salmonella entericia 187
link between IL-2R signaling and expression
of important molecules for Treg function is
HSV, herpes simplex virus; LCMV, lymphocytic choriomeningitis virus; SEA,
the fact that enforced expression of Foxp3, SEB, staphylococcal enterotoxin A or B; VSV, vesicular stomatitis virus.
TGF-β, or CTLA-4 into IL-2- or CD122-

deficient T cells controls many aspects of au- T lymphocyte (CTL) activity and interferon
toimmunity when such cells are present in IL- (IFN)-γ production (143, 144). Neverthe-
2- or CD122-deficient mice (120, 138, 139). less, the simplest interpretation of these find-
Collectively, these findings, especially the in- ings is that immune responses are largely IL-
crease in Foxp3 after IL-2R signaling (77), 2-independent. An important consideration
raise the possibility of a more fundamental with these studies, however, is that autoim-
role for this cytokine in Treg lineage com- munity associated with these mice may have
mitment, along with a role in maintenance bypassed normal physiological mechanisms.
and homeostasis. Thus, an important question A number of more recent studies use a
that remains to be fully defined is the precise variety of approaches either to inhibit or to
role for IL-2 in the production of Treg cells. prevent completely this autoimmune disease.
One approach is breeding a TCR transgene
onto IL-2−/− , CD25−/− , or CD122−/− ge-
IL-2 IN PRIMARY IMMUNE netic backgrounds. This tactic substantially
RESPONSES delays autoimmune disease, or, if these mice
Depending on how and when IL-2R signaling are further crossed to Rag1−/− or Rag2−/−
is enhanced during viral infections, the ini- mice, T cells bearing autoreactive TCRs do
tial response, the number of persistent mem- not develop, preventing autoimmunity. The
ory T cells, and recall proliferation have all use of T cells from such TCR transgenic
been reported to increase (140–142). Such mice also permits quantification of prolifera-
studies reveal the potential of cells to re- tive and functional responses. One common
spond to IL-2 but do not establish whether result from all such studies is that there is
IL-2 is required. Nevertheless, given these substantial T cell proliferation by CD4 (145,
results and the dominant role of IL-2 for T 146) or CD8 (147–151) T cells without IL-
cell expansion and effector cell development 2/IL-2R. Sometimes, these proliferative re-
in vitro, surprisingly, effective immune responses are comparable to that developed by
sponses occur in most studies in which IL- WT T cells, and at other times expansion by
2-, CD25-, or CD122-deficient mice were the IL-2/IL-2R-deficient cells is reduced two-
directly challenged (Table 2), although im- to threefold in lymphoid or nonlymphoid tis-
mune deficits are sometimes noted. For ex- sues. Alternatively, CD25−/− or CD122−/−
ample, the magnitude of the response to lym- mice are rendered autoimmune-free by cor-
phocytic choriomeningitis virus (LCMV) in recting the Treg cell defect through preparing
IL-2−/− mice is lower with impaired cytotoxic mixed bone marrow chimeras, by adoptively

transferring Treg cells during neonatal 4 in the cultures (153, 155). There are two
life, or by selectively reconstituting the observations, however, that suggest that γc-
IL-2R in the thymus of CD122−/− mice. dependent cytokines may not readily account
Again, substantial and generally normal pro- for IL-2-independent expansion in vivo. First,
liferative responses are noted by the IL- TCR transgenic CD4+ T cells from γc−/−
2R-deficient T cells after challenging with mice undergo normal antigen-driven expan-
LCMV, Listeria monocytogenes, vaccinia virus, sion when transferred into immunodeficient
or superantigen (20, 21, 152, 153). Notably, in hosts (156). Second, superantigen-mediated
these settings, which depend on the endoge- expansion and contraction by autoimmune-
nous TCR repertoire, effective primary im- free CD122-deficient CD4+ and CD8+ T
mune responses are elicited to the infectious cells are not impaired by blocking mAbs to γc
agent. (153). Co-stimulation by CD27 has emerged
Besides functioning as a T cell growth fac- as a possible candidate for IL-2-independent
clonal expansion by CD8+ T cells (157).
tor, IL-2 also sensitizes activated T cells to un-

dergo apoptosis upon restimulation through

the TCR (154) and promotes development of
effector function in vitro (155). IL-2, there- IL-2 AND T CELL MEMORY
fore, might contribute to the contraction Several recent studies raise the possibility that
phase of an immune response and/or pro- IL-2 is essential to develop efficient memory
mote effector cell differentiation. In this re- responses. CD4+ IL-2−/− TCR transgenic T
gard, CD25−/− and IL-2−/− TCR transgenic cells readily expand and contract after in vivo
CD4 T cells readily contract after prolifer- activation with peptide-pulsed DCs, but these
ation to antigenic peptide (145, 146). For IL-2−/− T cells poorly survive and yield a low
CD8 T cells without IL-2 or IL-2R signal- number of memory cells (146, 158). This is
ing, their contraction and subsequent devel- due to failed expression of the IL-7R, which
opment into memory cells is relatively normal is known to be critical for CD4 T cell memory
(20, 21, 148, 149, 152, 153). Functional re- (159–161). Particularly informative are stud-
sponses (i.e., CTL activity or IFN-γ or TNF- ies of immune responses by donor T cells af-
α secretion) by the activated CD8 T cells are ter preparing mixed bone chimeras that re-
also often readily detected (20, 21, 151, 152). ceive a mixture of WT and CD25-deficient
Sometimes, a particular effector activity is im- bone marrow. This approach prevents au-
paired without IL-2R signaling, e.g., direct toimmunity by Treg cells that develop from
ex vivo CTL activity during rejection of allo- WT precursor cells and permits an assessment
geneic skin grafts or IFN-γ secretion during of the requirement for IL-2 in a competitive
vaccinia virus infection (152). environment. Although some preference for
These studies demonstrate considerable WT T cells is noted, these experiments con-
IL-2-independent T cell proliferation and firm that the primary CD8 T cell response
effector cell development leading to effec- and memory cell generation after infection by
tive primary immune responses. However, in LCMV or Listeria monocytogenes is largely IL-
some model systems, specific responses are 2-independent (20, 21). However, the recall
lower and not comparable to those in WT response to these agents is severely impaired.
mice, indicating that IL-2 contributes to im- Interestingly, the requirement for IL-2 is not
mune responses. IL-2-independent immunity for expansion of the primed T cells in the sec-
likely depends on inflammatory or other γc- ondary response, but rather for IL-2 early dur-
dependent cytokines produced during the im- ing the primary response.
mune response. In this regard, the near strict Two mechanistic issues emerge from these
dependency on IL-2 for in vitro effector re- latter experiments. First, past studies by sev-
sponses is bypassed by including IL-12 or IL- eral laboratories indicate that CD4 T cell help
466 Malek
during the primary response is essential for tral for immune responses by promoting T
CD8 memory expansion (162). There is much cell growth and effector differentiation that
debate about this helper requirement, and has driven most therapeutic interventions tar-
the CD40/CD40L interaction between the geting IL-2 or its receptor. Accordingly, clin-
antigen-presenting DC and antigen-specific ical outcomes not predicted by this model are
CD4+ T cells is considered one necessary expected and have been reported. For exam-
signal for a CD8 T cell response. However, ple, IL-2 is used in immunotherapy with the
IL-2 production by CD4+ T cells during the intention to boost immunity in HIV/AIDS
very early activation of an immune response and cancer patients. In both cases, there are
might also represent a form of T cell help. reports of expansion of Treg cells (165–168).
Second, the ability to temporally dissociate For HIV/AIDS, increasing Treg cells might
the requirement for IL-2 from when recall re- have some benefit in restoring T cell home-
sponses are elicited suggests a programming ostasis and controlling T cell activation asso-
function for IL-2. This notion is in line with ciated with this disease. For cancer patients,
the role for IL-2 programming autonomous increasing Treg cells is likely to be detrimental
antigen-independent expansion and effector by preventing induction of tumor-specific T
cell development of CD8 T cells, although cell responses and may explain the limited effi-
these activities are also provided by redundant cacy of IL-2 in antitumor therapy. Anti-CD25
signals in vivo (155, 163, 164). Collectively, immunotherapy is widely used with some suc-
all this work with IL-2/IL-2R-deficient mice cess to inhibit unwanted immune responses in
raises the possibility that memory recall re- patients with autoimmune disease or recipi-
sponses, rather than primary responses, may ents of allogeneic transplants. On face value,
be a more important target when immune re- this success fits with the model that block-
sponses are inhibited after anti-IL-2 or anti- ing IL-2 prevents immune responses. How-
IL-2R immunotherapy. ever, for patients with multiple sclerosis and
autoimmune uveitis, the mechanism of im-
CONSIDERATIONS FOR mune inhibition is the induction of a regu-
IL-2-TARGETED latory CD56bright NK cell population, rather
IMMUNOTHERAPY than inhibition of effector cells (169, 170).
Newly revealed functions of IL-2 need
Based on the foregoing discussion, the re-
to be carefully considered in future use of
quirements for IL-2 are quite distinctive for
IL-2-directed therapies. Besides promoting
the T regulatory and T effector arms of the
Treg cells, two other important issues are the
immune system (Table 3). Much data now
auto-inhibitory loop where IL-2 inhibits its
support a dominant role for IL-2 for Treg cell
own production (Figure 1) and the capacity
production and homeostasis. Emerging find-
of IL-2 to antagonize development of auto-
ings also suggest an essential function for IL-2
aggressive Th17 cells (Figure 2). Whether
during immune responses at the level of mem-
these mechanisms are functional within the
ory responses. These ideas are much different
human system remains to be determined, as
from the early paradigm in which IL-2 is cen-
they have just been recently described for the
Table 3 In vivo dependency on IL-2 mouse. Given this caveat, one likely conse-
quence not previously considered when IL-2
Treg cell development High
is blocked in vivo may be increased IL-2 pro-
Treg cell homeostasis High
duction through impaired auto-inhibition. As
T effector cell expansion Low
low-dose IL-2 in humans selectively increases
T effector cell function Low/Intermediate CD56bright NK cells (171), it is tempting to
T effector contraction Low speculate that the increase in regulatory NKT
T memory recall responses High cells in autoimmune patients undergoing

anti-CD25 therapy may be the result of When targeting IL-2 in immunotherapy,

preventing the IL-2 auto-inhibitory loop, new strategies are needed to selectively en-
leading to increased IL-2. Another conse- hance or inhibit the regulatory versus the ef-
quence of blocking IL-2 may be increased fector components of the immune response.
development of auto-aggressive Th17 cells. Blocking particular pathways of IL-2R sig-
However, increased IL-2, through failed auto- nal transduction holds promise because IL-
repression, may counteract this greater poten- 2R signaling appears more diverse in effector
tial for Th17 cells by preventing Th17 devel- than in Treg cells, the latter of which domi-
opment and/or by promoting Treg cells. nantly require Stat5. In this regard, inhibit-
There remains much hope that adoptive ing downstream targets of the PI3K path-
immunotherapy with Treg cells will provide way with rapamycin aids selective expansion
therapeutic benefit to patients with severe au- of Treg cells in vitro and in type 1 diabetes pa-
toimmunity or that receive allogeneic trans- tients by preventing IL-2-dependent growth
plants. Another very important property of and promoting depletion of T effector cells,
IL-2, therefore, is its ability to support the respectively (178, 179). Another approach is
growth of Treg cells in vitro. Indeed, in the to independently block the effector arm while
most successful reports of Treg cell expansion, enhancing Treg cells. Indeed, the combined
IL-2 is a key ingredient in the growth pro- application of the immunosuppressant dex-
tocol in which activation through the TCR amethasone with IL-2 is more effective than
and CD28 is also required (172, 173). Some- IL-2 alone to expand Treg cells in periph-
what paradoxically and in stark contrast to eral tissues in normal mice and to inhibit EAE
antigen-activated effector cells, Treg cells do (180).
not directly proliferate to exogenous IL-2 Agonists that selectively target the IL-2R
even though they constitutively express the on distinct cell types may also be of value. The
high-affinity IL-2R (174, 175). One reason finding that anti-IL-2/IL-2 preformed com-
for the poor direct response by IL-2 is that plexes function as IL-2R agonists in vivo in
Treg cells contain increased levels of SOCS2 the mouse is an unanticipated example (181).
(suppressor of cytokine signaling 2), which One mAb/IL-2 complex activates cells bear-
generally dampens IL-2 signaling (175, 176). ing the high-affinity IL-2R (CD25, CD122,
Another reason is that IL-2 signal transduc- and γc), whereas another activates cells bear-
tion differs in Treg cells versus activated effec- ing only CD122 and γc, and hence does not
tor cells. IL-2 readily activates MAPK, PI3K, activate Treg cells. These agonists are used at
and Stat5 pathways in conventionally acti- much lower concentrations than is direct IL-2
vated T cells, whereas IL-2 activates Stat5, infusion, with less expected toxicity, but per-
but not downstream targets of the PI3K path- sist longer, leading to prolonged IL-2R sig-
way, in Treg cells (175). The poor activation naling. Although it may not be feasible to de-
of the PI3K pathway in Treg cells is due to in- velop an IL-2R agonist that distinguishes the
creased activity of phosphatase and tensin ho- high-affinity IL-2R on regulatory versus ef-
molog (PTEN) (174, 175). This may be par- fector T cells, these types of agonists alone or
ticularly relevant, as efficient IL-2-driven T in conjunction with IL-2R pathway antago-
cell growth normally requires prolonged ac- nists may represent an approach to improved
tivation of the PI3K pathway (177). Accord- IL-2-based immunotherapy. Ultimately, fur-
ingly, Treg cells directly proliferate to IL-2 af- ther defining quantitative and qualitative dif-
ter deletion of PTEN (174). Moreover, TCR ferences in IL-2R signaling between Treg and
activation of Treg cells in vitro downregulates T effector cells and downstream targets rep-
PTEN, which may be permissive for their resents a key step in devising more selective
subsequent IL-2-dependent growth. therapeutics.
468 Malek
DISCLOSURE STATEMENT
The author is not aware of any biases that might be perceived as affecting the objectivity of
this review.
ACKNOWLEDGMENTS
My research is supported by the National Institutes of Health and by the Juvenile Diabetes
Research Foundation.
LITERATURE CITED
1. Morgan DA, Ruscetti FW, Gallo R. 1976. Selective in vitro growth of T lymphocytes
from normal human bone marrows. Science 193:1007–8
2. Gillis S, Smith KA. 1977. Long-term culture of tumour-specific cytotoxic T cells. Nature
268:154–56
3. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, et al. 1983. Structure and
expression of a cloned cDNA for human interleukin-2. Nature 302:305–10
4. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. 1993. Ulcerative colitis-
like disease in mice with a disrupted interleukin-2 gene. Cell 75:253–61
5. Sadlack B, Lohler J, Schorle H, Klebb G, Haber H, et al. 1995. Generalized autoimmune
disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and
proliferation of CD4+ T cells. Eur. J. Immunol. 25:3053–59
6. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. 1995. Interleukin-2
receptor α chain regulates the size and content of the peripheral lymphoid compartment.
Immunity 3:521–30
7. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, et al. 1995. Deregulated
T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science
268:1472–76
8. Sakaguchi S. 2004. Naturally arising CD4+ regulatory T cells for immunologic self-
tolerance and negative control of immune responses. Annu. Rev. Immunol. 22:531–62
9. Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C. 1997. Regulatory CD4 T
cells: expression of IL-2Rα chain, resistance to clonal deletion and IL-2 dependency. Int.
Immunol. 10:371–78
10. Suzuki H, Zhou YW, Kato M, Mak TW, Nakashima I. 1999. Normal regulatory α/β T
cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor
β in vivo. J. Exp. Med. 190:1561–72
11. Wolf M, Schimpl A, Hunig T. 2001. Control of T cell hyperactivation in IL-2-deficient
mice by CD4+ CD25− and CD4+ CD25+ T cells: evidence for two distinct regulatory
mechanisms. Eur. J. Immunol. 31:1637–45
12. Klebb G, Autenrieth IB, Haber H, Gillert E, Sadlack B, et al. 1996. Interleukin-2 is indis-
pensable for development of immunological self-tolerance. Clin. Immunol. Immunopathol.
81:282–86
13. Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ. 2002. Interleukin 2
signaling is required for CD4+ regulatory T cell function. J. Exp. Med. 196:851–57
14. Malek TR, Yu A, Vincek V, Scibelli P, Kong L. 2002. CD4 regulatory T cells prevent lethal
autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of
IL-2. Immunity 17:167–78

15. Almeida AR, Legrand N, Papiernik M, Freitas AA. 2002. Homeostasis of peripheral
CD4+ T cells: IL-2Rα and IL-2 shape a population of regulatory cells that controls
CD4+ T cell numbers. J. Immunol. 169:4850–60
16. Kundig TM, Schorle H, Bachmann MF, Hengartner H, Zinkernagel RM, Horak I. 1993.
Immune responses in interleukin-2-deficient mice. Science 262:1059–61
17. Bachmann MF, Schorle H, Kuhn R, Muller W, Hengartner H, et al. 1995. Antiviral
immune responses in mice deficient for both interleukin-2 and interleukin-4. J. Virol.
69:4842–46
18. Steiger J, Nickerson PW, Steurer W, Moscovitch-Lopatin M, Strom TB. 1995. IL-2
knockout recipient mice reject islet cell allografts. J. Immunol. 155:489–98
19. Malek TR, Bayer AL. 2004. Tolerance, not immunity, crucially depends on IL-2. Nat.
Rev. Immunol. 4:665–74
20. Williams MA, Tyznik AJ, Bevan MJ. 2006. Interleukin-2 signals during priming are
required for secondary expansion of CD8+ memory T cells. Nature 441:890–93
21. Bachmann MF, Wolint P, Walton S, Schwarz K, Oxenius A. 2007. Differential role of
IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur. J.
Immunol. 37:1502–12
22. Nelson BH, Willerford DM. 1998. Biology of the interleukin-2 receptor. Adv. Immunol.
70:1–81
23. Waldmann TA, Dubois S, Tagaya Y. 2001. Contrasting roles of IL-2 and IL-15 in the
life and death of lymphocytes: implications for immunotherapy. Immunity 14:105–10
24. Gaffen SL. 2001. Signaling domains of the interleukin 2 receptor. Cytokine 14:63–77
25. Granucci F, Vizzardelli C, Pavelka N, Feau S, Persico M, et al. 2001. Inducible IL-2
production by dendritic cells revealed by global gene expression analysis. Nat. Immunol.
2:882–88
26. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. 2005. Homeostatic maintenance of
natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of
autoimmune disease by IL-2 neutralization. J. Exp. Med. 201:723–35
27. Yui MA, Hernandez-Hoyos G, Rothenberg EV. 2001. A new regulatory region of the IL-2
locus that confers position-independent transgene expression. J. Immunol. 166:1730–39
28. Yui MA, Sharp LL, Havran WL, Rothenberg EV. 2004. Preferential activation of an IL-2
regulatory sequence transgene in TCR γδ and NKT cells: subset-specific differences in
IL-2 regulation. J. Immunol. 172:4691–99
29. Jiang S, Game DS, Davies D, Lombardi G, Lechler RI. 2005. Activated CD1d-restricted
natural killer T cells secrete IL-2: innate help for CD4+ CD25+ regulatory T cells? Eur.
J. Immunol. 35:1193–200
30. Serfling E, Avots A, Neumann M. 1995. The architecture of the interleukin-2 promoter:
a reflection of T lymphocyte activation. Biochim. Biophys. Acta 1263:181–200
31. Jain J, Loh C, Rao A. 1995. Transcriptional regulation of the IL-2 gene. Curr. Opin.
Immunol. 7:333–42
32. Shaw J, Meerovitch K, Bleackley RC, Paetkau V. 1988. Mechanisms regulating the level
of IL-2 mRNA in T lymphocytes. J. Immunol. 140:2243–48
33. Lindstein T, June CH, Ledbetter JA, Stella G, Thompson CB. 1989. Regulation of
lymphokine messenger RNA stability by a surface-mediated T cell activation pathway.
Science 244:339–43
34. Fraser JD, Irving BA, Crabtree GR, Weiss A. 1991. Regulation of interleukin-2 gene
enhancer activity by the T cell accessory molecule CD28. Science 251:313–16
35. Ono M, Yaguchi H, Ohkura N, Kitabayashi I, Nagamura Y, et al. 2007. Foxp3 controls
regulatory T-cell function by interacting with AML1/Runx1. Nature 446:685–89
470 Malek
36. Brombacher F, Schafer T, Weissenstein U, Tschopp C, Andersen E, et al. 1994. IL-2

promoter-driven lacZ expression as a monitoring tool for IL-2 expression in primary T
cells of transgenic mice. Int. Immunol. 6:189–97
37. Reed WA, Elzer PH, Enright FM, Jaynes JM, Morrey JD, White KL. 1997. Interleukin
2 promoter/enhancer controlled expression of a synthetic cecropin-class lytic peptide in
transgenic mice and subsequent resistance to Brucella abortus. Transgenic Res. 6:337–47
38. Minasi LE, Kamogawa Y, Carding S, Bottomly K, Flavell RA. 1993. The selective ablation
of interleukin 2-producing cells isolated from transgenic mice. J. Exp. Med. 177:1451–59
39. Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden JM. 1996.
Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a
dominant-negative form of CREB. Nature 379:81–85
40. Juang YT, Wang Y, Solomou EE, Li Y, Mawrin C, et al. 2005. Systemic lupus erythe-
matosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2
production through CaMKIV. J. Clin. Invest. 115:996–1005
41. Bodor J, Bodorova J, Gress RE. 2000. Suppression of T cell function: a potential role for
transcriptional repressor ICER. J. Leukoc. Biol. 67:774–79
42. Yasui DH, Genetta T, Kadesch T, Williams TM, Swain SL, et al. 1998. Transcriptional
repression of the IL-2 gene in Th cells by ZEB. J. Immunol. 160:4433–40
43. Williams TM, Moolten D, Burlein J, Romano J, Bhaerman R, et al. 1991. Identification
of a zinc finger protein that inhibits IL-2 gene expression. Science 254:1791–94
44. Hwang ES, Hong JH, Glimcher LH. 2005. IL-2 production in developing Th1 cells is
regulated by heterodimerization of RelA and T-bet and requires T-bet serine residue 508.
J. Exp. Med. 202:1289–300
45. Villarino AV, Tato CM, Stumhofer JS, Yao Z, Cui YK, et al. 2007. Helper T cell IL-2
production is limited by negative feedback and STAT-dependent cytokine signals. J. Exp.
Med. 204:65–71
46. Gong D, Malek TR. 2007. Cytokine-dependent Blimp-1 expression in activated T cells
inhibits IL-2 production. J. Immunol. 178:242–52
47. Martins GA, Cimmino L, Shapiro-Shelef M, Szabolcs M, Herron A, et al. 2006. Tran-
scriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat. Immunol.
7:457–65
48. Kallies A, Hawkins ED, Belz GT, Metcalf D, Hommel M, et al. 2006. Transcriptional
repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat. Immunol.
7:466–74
49. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. 2006. Crystal structure of
the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. Proc. Natl.
Acad. Sci. USA 103:2788–93
50. Rickert M, Wang X, Boulanger MJ, Goriatcheva N, Garcia KC. 2005. The structure of
interleukin-2 complexed with its α receptor. Science 308:1477–80
51. Yu A, Olosz F, Choi C, Malek T. 2000. Efficient internalization of IL-2 depends upon
the distal portion of the cytoplasmic tail of the IL-2R γc subunit and a lymphoid cell
environment. J. Immunol. 165:2556–62
52. Yu CL, Burakoff SJ. 1997. Involvement of proteasomes in regulating Jak-STAT pathways
upon interleukin-2 stimulation. J. Biol. Chem. 272:14017–20
53. Hemar A, Subtil A, Lieb M, Morelon E, Hellio R. 1995. Endocytosis of interleukin
2 receptors in human T lymphocytes: distinct intracellular localization and fate of the
receptor α, β, and γ chains. J. Cell Biol. 129:55–64
54. Yu A, Malek TR. 2001. The proteasome regulates receptor-mediated endocytosis of
interleukin-2. J. Biol. Chem. 276:381–85

55. Cantrell DA, Smith KA. 1984. The interleukin-2 T-cell system: a new cell growth model.
Science 224:1312–16
56. Leonard WJ. 2001. Cytokines and immunodeficiency diseases. Nat. Rev. Immunol. 1:200–
8
57. Ma A, Koka R, Burkett P. 2006. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid
homeostasis. Annu. Rev. Immunol. 24:657–79
58. Kim HP, Imbert J, Leonard WJ. 2006. Both integrated and differential regulation of
components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 17:349–66
59. Kim HP, Kim BG, Letterio J, Leonard WJ. 2005. Smad-dependent cooperative regula-
tion of interleukin 2 receptor α chain gene expression by T cell receptor and transforming
growth factor-β. J. Biol. Chem. 280:34042–47
60. Rogers WO, Weaver CT, Kraus LA, Li J, Li L, Bucy RP. 1997. Visualization of antigen-
specific T cell activation and cytokine expression in vivo. J. Immunol. 158:649–57
61. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. 2005. A function for interleukin
2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:1142–51

62. Yang-Snyder JA, Rothenberg EV. 1998. Spontaneous expression of interleukin-2 in vivo
in specific tissues of young mice. Dev. Immunol. 5:223–45
63. De Creus A, Van Beneden K, Stevenaert F, Debacker V, Plum J, Leclercq G. 2002. De-
velopmental and functional defects of thymic and epidermal Vγ3 cells in IL-15-deficient
and IFN regulatory factor-1-deficient mice. J. Immunol. 168:6486–93
64. Ye SK, Maki K, Lee HC, Ito A, Kawai K, et al. 2001. Differential roles of cytokine
receptors in the development of epidermal γδ T cells. J. Immunol. 167:1929–34
65. Kawai K, Suzuki H, Tomiyama K, Minagawa M, Mak TW, Ohashi PS. 1998. Requirement
of the IL-2 receptor β chain for the development of Vγ3 dendritic epidermal T cells. J.
Invest. Dermatol. 110:961–65
66. Porter BO, Malek TR. 1999. IL-2Rβ/IL-7Rα doubly deficient mice recapitulate the
thymic and intraepithelial lymphocyte (IEL) developmental defects of γc−/− mice: roles
for both IL-2 and IL-15 in CD8αα IEL development. J. Immunol. 163:5906–12
67. Fontenot JD, Dooley JL, Farr AG, Rudensky AY. 2005. Developmental regulation of
Foxp3 expression during ontogeny. J. Exp. Med. 202:901–6
68. Watanabe N, Wang YH, Lee HK, Ito T, Cao W, Liu YJ. 2005. Hassall’s corpuscles
instruct dendritic cells to induce CD4+ CD25+ regulatory T cells in human thymus.
Nature 436:1181–85
69. Khoruts A, Mondino A, Pape KA, Reiner SL, Jenkins MK. 1998. A natural immunological
adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-
2-independent mechanism. J. Exp. Med. 187:225–36
70. Sojka DK, Bruniquel D, Schwartz RH, Singh NJ. 2004. IL-2 secretion by CD4+ T
cells in vivo is rapid, transient, and influenced by TCR-specific competition. J. Immunol.
172:6136–43
71. D’Souza WN, Lefrancois L. 2004. Frontline: an in-depth evaluation of the production
of IL-2 by antigen-specific CD8 T cells in vivo. Eur. J. Immunol. 34:2977–85
72. Huse M, Lillemeier BF, Kuhns MS, Chen DS, Davis MM. 2006. T cells use two direc-
tionally distinct pathways for cytokine secretion. Nat. Immunol. 7:247–55
73. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. 2007. IL-2 receptor β-
dependent STAT5 activation is required for the development of Foxp3+ regulatory T
cells. J. Immunol. 178:280–90
74. Hori S, Nomura T, Sakaguchi S. 2003. Control of regulatory T cell development by the
transcription factor Foxp3. Science 299:1057–61
472 Malek
75. Fontenot JD, Gavin MA, Rudensky AY. 2003. Foxp3 programs the development and
function of CD4+ CD25+ regulatory T cells. Nat. Immunol. 4:330–36
76. Roncador G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, et al. 2005.
Analysis of FOXP3 protein expression in human CD4+ CD25+ regulatory T cells at the
single-cell level. Eur. J. Immunol. 35:1681–91
77. Bayer AL, Yu A, Malek TR. 2007. Function of the IL-2R for thymic and peripheral
CD4+ CD25+ Foxp3+ T regulatory cells. J. Immunol. 178:4062–71
78. Antony PA, Paulos CM, Ahmadzadeh M, Akpinarli A, Palmer DC, et al. 2006. Interleukin-
2-dependent mechanisms of tolerance and immunity in vivo. J. Immunol. 176:5255–66
79. D’Cruz LM, Klein L. 2005. Development and function of agonist-induced
CD25+ Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol.
6:1152–59
80. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. 2005. Sequential development
of interleukin 2-dependent effector and regulatory T cells in response to endogenous

systemic antigen. J. Exp. Med. 202:1375–86

81. Adeegbe D, Bayer AL, Levy RB, Malek TR. 2006. Cutting edge: allogeneic
CD4+ CD25+ Foxp3+ T regulatory cells suppress autoimmunity while establishing trans-
plantation tolerance. J. Immunol. 176:7149–53
82. Gavin MA, Torgerson TR, Houston E, DeRoos P, Ho WY, et al. 2006. Single-cell analysis
of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T
cell development. Proc. Natl. Acad. Sci. USA 103:6659–64
83. Mantel PY, Ouaked N, Ruckert B, Karagiannidis C, Welz R, et al. 2006. Molecular
mechanisms underlying FOXP3 induction in human T cells. J. Immunol. 176:3593–602
84. Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. 2007. Transient
expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol.
37:129–38
85. Lyons PA, Armitage N, Argentina F, Denny P, Hill NJ, et al. 2000. Congenic mapping of
the type 1 diabetes locus, Idd3, to a 780-kb region of mouse chromosome 3: identification
of a candidate segment of ancestral DNA by haplotype mapping. Genome Res. 10:446–53
86. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, et al. 2007. Interleukin-2
gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet.
39:329–37
87. Sharfe N, Dadi HK, Shahar M, Roifman CM. 1997. Human immune disorder arising
from mutation of the α chain of the interleukin-2 receptor. Proc. Natl. Acad. Sci. USA
94:3168–71
88. Caudy AA, Reddy ST, Chatila T, Atkinson JP, Verbsky JW. 2007. CD25 deficiency causes
an immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome,
and defective IL-10 expression from CD4 lymphocytes. J. Allergy Clin. Immunol. 119:482–
87
89. Aoki CA, Roifman CM, Lian ZX, Bowlus CL, Norman GL, et al. 2006. IL-2 receptor α
deficiency and features of primary biliary cirrhosis. J. Autoimmun. 27:50–53
90. Roifman CM. 2000. Human IL-2 receptor α chain deficiency. Pediatr. Res. 48:6–11
91. Wellcome Trust Case Control Consortium. 2007. Genome-wide association study of
14,000 cases of seven common diseases and 3000 shared controls. Nature 447:661–78
92. Snow JW, Abraham N, Ma MC, Herndier BG, Pastuszak AW, Goldsmith MA. 2003.
Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient
mice. J. Immunol. 171:5042–50

93. Burchill MA, Goetz CA, Prlic M, O’Neil JJ, Harmon IR, et al. 2003. Distinct effects of
STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+ CD25+
regulatory T cells vs CD8+ memory T cells. J. Immunol. 171:5853–64
94. Antov A, Yang L, Vig M, Baltimore D, Van Parijs L. 2003. Essential role for STAT5
signaling in CD25+ CD4+ regulatory T cell homeostasis and the maintenance of self-
tolerance. J. Immunol. 171:3435–41
95. Peffault de Latour R, Dujardin HC, Mishellany F, Burlen-Defranoux O, Zuber J, et al.
2006. Ontogeny, function, and peripheral homeostasis of regulatory T cells in the absence
of interleukin-7. Blood 108:2300–6
96. Cohen AC, Nadeau KC, Tu W, Hwa V, Dionis K, et al. 2006. Cutting edge: decreased
accumulation and regulatory function of CD4+ CD25high T cells in human STAT5b
deficiency. J. Immunol. 177:2770–74
97. Liston A, Rudensky AY. 2007. Thymic development and peripheral homeostasis of reg-
ulatory T cells. Curr. Opin. Immunol. 19:176–85

98. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, et al. 2000. B7/CD28 costim-
ulation is essential for the homeostasis of the CD4+ CD25+ immunoregulatory T cells
that control autoimmune diabetes. Immunity 12:431–40
99. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, et al. 2003. Cutting edge: CD28 con-
trols peripheral homeostasis of CD4+ CD25+ regulatory T cells. J. Immunol. 171:3348–52
100. Tai X, Cowan M, Feigenbaum L, Singer A. 2005. CD28 costimulation of developing
thymocytes induces Foxp3 expression and regulatory T cell differentiation independently
of interleukin 2. Nat. Immunol. 6:152–62
101. Liston A, Siggs OM, Goodnow CC. 2007. Tracing the action of IL-2 in tolerance to
islet-specific antigen. Immunol. Cell Biol. 85:338–42
102. Malek TR, Porter BO, Codias EK, Scibelli P, Yu A. 2000. Normal lymphoid homeostasis
and lack of lethal autoimmunity in mice containing mature T cells with severely impaired
IL-2 receptors. J. Immunol. 164:2905–14
103. Wan YY, Flavell RA. 2007. Regulatory T-cell functions are subverted and converted
owing to attenuated Foxp3 expression. Nature 445:766–70
104. Bayer AL, Yu A, Adeegbe D, Malek TR. 2005. Essential role for interleukin-2 for
CD4+ CD25+ T regulatory cell development during the neonatal period. J. Exp. Med.
201:769–77
105. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, et al. 2006. IL-2 regulates FOXP3
expression in human CD4+ CD25+ regulatory T cells through a STAT-dependent mech-
anism and induces the expansion of these cells in vivo. Blood 108:1571–79
106. Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L, et al. 2007. Nonredundant roles for
Stat5a/b in directly regulating Foxp3. Blood 109:4368–75
107. Yu A, Malek TR. 2006. Selective availability of IL-2 is a major determinant controlling
the production of CD4+ CD25+ Foxp3+ T regulatory cells. J. Immunol. 177:5115–21
108. Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A. 2002. Homeostasis and anergy
of CD4+ CD25+ suppressor T cells in vivo. Nat. Immunol. 3:33–41
109. Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE. 2003. Neonates
support lymphopenia-induced proliferation. Immunity 18:131–40
110. Bayer AL, Malek TR. 2007. The role of IL-2 in the development and peripheral home-
ostasis of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. In Regulatory T
Cells and Clinical Applications, ed. S Jiang, RI Lechler. New York: Springer. In press
111. Vlad G, Ho EK, Vasilescu ER, Fan J, Liu Z, et al. 2007. Anti-CD25 treatment and
FOXP3-positive regulatory T cells in heart transplantation. Transpl. Immunol. 18:13–21
474 Malek
112. Kreijveld E, Koenen HJ, Klasen IS, Hilbrands LB, Joosten I. 2007. Following anti-CD25
treatment, a functional CD4+ CD25+ regulatory T-cell pool is present in renal transplant
recipients. Am. J. Transplant. 7:249–55
113. Waldmann TA. 2007. Daclizumab (anti-Tac, Zenapax) in the treatment of
leukemia/lymphoma. Oncogene 26:3699–703
114. Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira
A. 2001. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through
the production of IL-10. J. Immunol. 166:3008–18
115. Thornton AM, Shevach EM. 1998. CD4+ CD25+ immunoregulatory T cells suppress
polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med.
188:287–96
116. Duthoit CT, Mekala DJ, Alli RS, Geiger TL. 2005. Uncoupling of IL-2 signaling from
cell cycle progression in naive CD4+ T cells by regulatory CD4+ CD25+ T lymphocytes.
J. Immunol. 174:155–63
117. Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J, et al. 2005. CD25+
CD4+ T cells compete with naive CD4+ T cells for IL-2 and exploit it for the induction
of IL-10 production. Int. Immunol. 17:279–88
118. Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. 2004. Cutting edge: IL-2 is
critically required for the in vitro activation of CD4+ CD25+ T cell suppressor function.
J. Immunol. 172:6519–23
119. de la Rosa M, Rutz S, Dorninger H, Scheffold A. 2004. Interleukin-2 is essential for
CD4+ CD25+ regulatory T cell function. Eur. J. Immunol. 34:2480–88
120. Soper DM, Kasprowicz DJ, Ziegler SF. 2007. IL-2Rβ links IL-2R signaling with Foxp3
expression. Eur. J. Immunol. 37:1817–26
121. Thornton AM, Piccirillo CA, Shevach EM. 2004. Activation requirements for the induc-
tion of CD4+ CD25+ T cell suppressor function. Eur. J. Immunol. 34:366–76
122. Almeida AR, Zaragoza B, Freitas AA. 2006. Indexation as a novel mechanism of lym-
phocyte homeostasis: the number of CD4+ CD25+ regulatory T cells is indexed to the
number of IL-2-producing cells. J. Immunol. 177:192–200
123. Jaeckel E, Kretschmer K, Apostolou I, von Boehmer H. 2006. Instruction of Treg com-
mitment in peripheral T cells is suited to reverse autoimmunity. Semin. Immunol. 18:89–92
124. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. 2004. Cutting
edge: TGFβ induces a regulatory phenotype in CD4+ CD25− T cells through Foxp3
induction and down-regulation of Smad7. J. Immunol. 172:5149–53
125. Chen W, Jin W, Hardegen N, Lei KJ, Li L, et al. 2003. Conversion of peripheral
CD4+ CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGFβ induction
of transcription factor Foxp3. J. Exp. Med. 198:1875–86
126. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. 2004. Natural and induced
CD4+ CD25+ cells educate CD4+ CD25− cells to develop suppressive activity: the role
of IL-2, TGFβ, and IL-10. J. Immunol. 172:5213–21
127. Davidson TS, DiPaolo RJ, Andersson J, Shevach EM. 2007. Cutting edge: IL-2 is essential
for TGFβ-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178:4022–26
128. Zheng SG, Wang J, Wang P, Gray JD, Horwitz DA. 2007. IL-2 is essential for TGFβ to
convert naive CD4+ CD25− cells to CD25+ Foxp3+ regulatory T cells and for expansion
of these cells. J. Immunol. 178:2018–27
129. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, et al. 2006. Reciprocal developmental
pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature
441:235–38

130. Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, et al. 2007. Foxp3-
dependent programme of regulatory T-cell differentiation. Nature 445:771–75
131. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. 2006. TGFβ in the
context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-
producing T cells. Immunity 24:179–89
132. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, et al. 2007. Interleukin-2 sig-
naling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–81
133. Kryczek I, Wei S, Zou L, Altuwaijri S, Szeliga W, et al. 2007. Cutting edge: Th17 and
regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment.
J. Immunol. 178:6730–33
134. Su L, Creusot RJ, Gallo EM, Chan SM, Utz PJ, et al. 2004. Murine CD4+ CD25+
regulatory T cells fail to undergo chromatin remodeling across the proximal promoter
region of the IL-2 gene. J. Immunol. 173:4994–5001
135. Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, et al. 2006. FOXP3 controls
regulatory T cell function through cooperation with NFAT. Cell 126:375–87

136. Lin W, Haribhai D, Relland LM, Truong N, Carlson MR, et al. 2007. Regulatory T cell
development in the absence of functional Foxp3. Nat. Immunol. 8:359–68
137. Williams LM, Rudensky AY. 2007. Maintenance of the Foxp3-dependent developmen-
tal program in mature regulatory T cells requires continued expression of Foxp3. Nat.
Immunol. 8:277–84
138. Hwang KW, Sweatt WB, Mashayekhi M, Palucki DA, Sattar H, et al. 2004. Transgenic
expression of CTLA-4 controls lymphoproliferation in IL-2-deficient mice. J. Immunol.
173:5415–24
139. Carrier Y, Yuan J, Kuchroo VK, Weiner HL. 2007. Th3 cells in peripheral tolerance. II.
TGF-β-transgenic Th3 cells rescue IL-2-deficient mice from autoimmunity. J. Immunol.
178:172–78
140. Blattman JN, Grayson JM, Wherry EJ, Kaech SM, Smith KA, Ahmed R. 2003. Thera-
peutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9:540–47
141. Cheng LE, Ohlen C, Nelson BH, Greenberg PD. 2002. Enhanced signaling through the
IL-2 receptor in CD8+ T cells regulated by antigen recognition results in preferential
proliferation and expansion of responding CD8+ T cells rather than promotion of cell
death. Proc. Natl. Acad. Sci. USA 99:3001–6
142. Cheng LE, Greenberg PD. 2002. Selective delivery of augmented IL-2 receptor signals
to responding CD8+ T cells increases the size of the acute antiviral response and of the
resulting memory T cell pool. J. Immunol. 169:4990–97
143. Cousens LP, Orange JS, Biron CA. 1995. Endogenous IL-2 contributes to T cell ex-
pansion and IFN-γ production during lymphocytic choriomeningitis virus infection. J.
Immunol. 155:5690–99
144. Su HC, Cousens LP, Fast LD, Slifka MK, Bungiro RD, et al. 1998. CD4+ and CD8+ T
cell interactions in IFN-γ and IL-4 responses to viral infections: requirements for IL-2.
J. Immunol. 160:5007–17
145. Leung DT, Morefield S, Willerford DM. 2000. Regulation of lymphoid homeostasis by
IL-2 receptor signals in vivo. J. Immunol. 164:3527–34
146. Dooms H, Wolslegel K, Lin P, Abbas AK. 2007. Interleukin-2 enhances CD4+ T cell
memory by promoting the generation of IL-7Rα-expressing cells. J. Exp. Med. 204:547–
57
147. Krämer S, Mamalaki C, Schimpl A, Kioussis D, Hünig T. 1994. Thymic selection and
peptide-induced activation of T cell receptor-transgenic CD8 T cells in interleukin-2-
deficient mice. Eur. J. Immunol. 24:2317–22
476 Malek
148. Dai Z, Konieczny BT, Lakkis FG. 2000. The dual role of IL-2 in the generation and
maintenance of CD8+ memory T cells. J. Immunol. 165:3031–36
149. D’Souza WN, Schluns KS, Masopust D, Lefrancois L. 2002. Essential role for IL-2 in
the regulation of antiviral extralymphoid CD8 T cell responses. J. Immunol. 168:5566–72
150. D’Souza WN, Lefrancois L. 2003. IL-2 is not required for the initiation of CD8 T cell
cycling but sustains expansion. J. Immunol. 171:5727–35
151. Teague RM, Tempero RM, Thomas S, Murali-Krishna K, Nelson BH. 2004. Proliferation
and differentiation of CD8+ T cells in the absence of IL-2/15 receptor β-chain expression
or STAT5 activation. J. Immunol. 173:3131–39
152. Yu A, Zhou J, Marten N, Bergmann CC, Mammolenti M, et al. 2003. Efficient induction
of primary and secondary T cell-dependent immune responses in vivo in the absence of
functional IL-2 and IL-15 receptors. J. Immunol. 170:236–42
153. Jin H, Gong D, Adeegbe D, Bayer AL, Rolle C, et al. 2006. Quantitative assessment
concerning the contribution of IL-2Rβ for superantigen-mediated T cell responses in
vivo. Int. Immunol. 18:565–72

154. Lenardo MJ. 1991. Interleukin-2 programs αβ T lymphocytes for apoptosis. Nature
353:858–61
155. Malek TR, Yu A, Scibelli P, Lichtenheld MG, Codias EK. 2001. Broad programming
by IL-2 receptor signaling for extended growth to multiple cytokines and functional
maturation of antigen-activated T cells. J. Immunol. 166:1675–83
156. Lantz O, Grandjean I, Matzinger P, Di Santo J. 2000. γ chain required for naive CD4+
T cell survival but not antigen proliferation. Nat. Immunol. 1:54–58
157. Carr JM, Carrasco MJ, Thaventhiran JE, Bambrough PJ, Kraman M, et al. 2006. CD27
mediates interleukin-2-independent clonal expansion of the CD8+ T cell without effector
differentiation. Proc. Natl. Acad. Sci. USA 103:19454–59
158. Dooms H, Kahn E, Knoechel B, Abbas AK. 2004. IL-2 induces a competitive survival
advantage in T lymphocytes. J. Immunol. 172:5973–79
159. Seddon B, Tomlinson P, Zamoyska R. 2003. Interleukin 7 and T cell receptor signals
regulate homeostasis of CD4 memory cells. Nat. Immunol. 4:680–86
160. Li J, Huston G, Swain SL. 2003. IL-7 promotes the transition of CD4 effectors to
persistent memory cells. J. Exp. Med. 198:1807–15
161. Kondrack RM, Harbertson J, Tan JT, McBreen ME, Surh CD, Bradley LM. 2003. In-
terleukin 7 regulates the survival and generation of memory CD4 cells. J. Exp. Med.
198:1797–806
162. Williams MA, Bevan MJ. 2007. Effector and memory CTL differentiation. Annu. Rev.
Immunol. 25:171–92
163. Wong P, Pamer EG. 2004. Disparate in vitro and in vivo requirements for IL-2 during
antigen-independent CD8 T cell expansion. J. Immunol. 172:2171–76
164. Spierings DC, Lemmens EE, Grewal K, Schoenberger SP, Green DR. 2006. Duration
of CTL activation regulates IL-2 production required for autonomous clonal expansion.
Eur. J. Immunol. 36:1707–17
165. Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, et al. 2005. Lymphopenia and
interleukin-2 therapy alter homeostasis of CD4+ CD25+ regulatory T cells. Nat. Med.
11:1238–43
166. Ahmadzadeh M, Rosenberg SA. 2006. IL-2 administration increases CD4+ CD25hi
Foxp3+ regulatory T cells in cancer patients. Blood 107:2409–14
167. Cesana GC, DeRaffele G, Cohen S, Moroziewicz D, Mitcham J, et al. 2006. Characteri-
zation of CD4+ CD25+ regulatory T cells in patients treated with high-dose interleukin-2
for metastatic melanoma or renal cell carcinoma. J. Clin. Oncol. 24:1169–77

168. van Dervliet HJ, Koon HB, Yue SC, Uzunparmak B, Seery V, et al. 2007. Effects of the
administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients
with advanced melanoma and renal cell cancer. Clin. Cancer Res. 13:2100–8
169. Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, et al. 2006. Reg-
ulatory CD56bright natural killer cells mediate immunomodulatory effects of IL-2Rα-
targeted therapy (daclizumab) in multiple sclerosis. Proc. Natl. Acad. Sci. USA 103:5941–
46
170. Li Z, Lim WK, Mahesh SP, Liu B, Nussenblatt RB. 2005. Cutting edge: in vivo blockade
of human IL-2 receptor induces expansion of CD56bright regulatory NK cells in patients
with active uveitis. J. Immunol. 174:5187–91
171. Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, et al. 1993. Selective
modulation of human natural killer cells in vivo after prolonged infusion of low dose
recombinant interleukin 2. J. Clin. Invest. 91:123–32
172. Tang Q, Bluestone JA. 2006. Regulatory T-cell physiology and application to treat au-
toimmunity. Immunol. Rev. 212:217–37

173. June CH, Blazar BR. 2006. Clinical application of expanded CD4+ 25+ cells. Semin.
Immunol. 18:78–88
174. Walsh PT, Buckler JL, Zhang J, Gelman AE, Dalton NM, et al. 2006. PTEN inhibits
IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J. Clin. Invest. 116:2521–31
175. Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R, et al. 2004. Distinct IL-2
receptor signaling pattern in CD4+ CD25+ regulatory T cells. J. Immunol. 172:5287–96
176. Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, et al. 2006. Foxp3-dependent
and -independent molecules specific for CD25+ CD4+ natural regulatory T cells revealed
by DNA microarray analysis. Int. Immunol. 18:1197–209
177. Lali FV, Crawley J, McCulloch DA, Foxwell BM. 2004. A late, prolonged activation of
the phosphatidylinositol 3-kinase pathway is required for T cell proliferation. J. Immunol.
172:3527–34
178. Battaglia M, Stabilini A, Roncarolo MG. 2005. Rapamycin selectively expands
CD4+ CD25+ FoxP3+ regulatory T cells. Blood 105:4743–48
179. Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG.
2006. Rapamycin promotes expansion of functional CD4+ CD25+ FOXP3+ regulatory T
cells of both healthy subjects and type 1 diabetic patients. J. Immunol. 177:8338–47
180. Chen X, Oppenheim JJ, Winkler-Pickett RT, Ortaldo JR, Howard OM. 2006. Glu-
cocorticoid amplifies IL-2-dependent expansion of functional FoxP3+ CD4+ CD25+ T
regulatory cells in vivo and enhances their capacity to suppress EAE. Eur. J. Immunol.
36:2139–49
181. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. 2006. Selective stimulation of
T cell subsets with antibody-cytokine immune complexes. Science 311:1924–27
182. Kneitz B, Herrmann T, Yonehara S, Schimpl A. 1995. Normal clonal expansion but
impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice.
Eur. J. Immunol. 25:2572–77
183. Dai Z, Konieczny BT, Baddoura FK, Lakkis FG. 1998. Impaired alloantigen-mediated
T cell apoptosis and failure to induce long-term allograft survival in IL-2-deficient mice.
J. Immunol. 161:1659–63
184. Li XC, Roy-Chaudhury P, Hancock WW, Manfro R, Zand MS, et al. 1998. IL-2 and
IL-4 double knockout mice reject islet allografts: a role for novel T cell growth factors
in allograft rejection. J. Immunol. 161:890–96
478 Malek
185. Tsunobuchi H, Nishimura H, Goshima F, Daikoku T, Nishiyama Y, Yoshikai Y. 2000.

Memory-type CD8+ T cells protect IL-2 receptor α-deficient mice from systemic infec-
tion with herpes simplex virus type 2. J. Immunol. 165:4552–60
186. Suzuki H, Hayakawa A, Bouchard D, Nakashima I, Mak TW. 1997. Normal thymic
selection, superantigen-induced deletion and Fas-mediated apoptosis of T cells in IL-2
receptor β-chain deficient mice. Int. Immmunol. 9:1367–74
187. Nishimura H, Tagaya M, Tsunobuchi H, Suzuki H, Nakashima I, Yoshikai Y. 2001. Mice
lacking interleukin-2 (IL-2)/IL-15 receptor β chain are susceptible to infection with
avirulent Salmonella enterica subsp. enterica serovar choleraesuis but mice lacking IL-2 are
resistant. Infect. Immun. 69:1226–29

AR338-FM ARI 12 January 2008 18:11
Annual Review of
Immunology
Contents Volume 26, 2008
Frontispiece
K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Doing What I Like

K. Frank Austen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
Protein Tyrosine Phosphatases in Autoimmunity
Torkel Vang, Ana V. Miletic, Yutaka Arimura, Lutz Tautz, Robert C. Rickert,
and Tomas Mustelin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 29
Interleukin-21: Basic Biology and Implications for Cancer
and Autoimmunity
Rosanne Spolski and Warren J. Leonard p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 57
Forward Genetic Dissection of Immunity to Infection in the Mouse
S.M. Vidal, D. Malo, J.-F. Marquis, and P. Gros p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 81
Regulation and Functions of Blimp-1 in T and B Lymphocytes
Gislâine Martins and Kathryn Calame p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p133
Evolutionarily Conserved Amino Acids That Control TCR-MHC
Interaction
Philippa Marrack, James P. Scott-Browne, Shaodong Dai, Laurent Gapin,
and John W. Kappler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171
T Cell Trafficking in Allergic Asthma: The Ins and Outs
Benjamin D. Medoff, Seddon Y. Thomas, and Andrew D. Luster p p p p p p p p p p p p p p p p p p p p p205
The Actin Cytoskeleton in T Cell Activation
Janis K. Burkhardt, Esteban Carrizosa, and Meredith H. Shaffer p p p p p p p p p p p p p p p p p p p p233
Mechanism and Regulation of Class Switch Recombination
Janet Stavnezer, Jeroen E.J. Guikema, and Carol E. Schrader p p p p p p p p p p p p p p p p p p p p p p p261
Migration of Dendritic Cell Subsets and their Precursors
Gwendalyn J. Randolph, Jordi Ochando, and Santiago Partida-Sánchez p p p p p p p p p p p p p293
v
AR338-FM ARI 12 January 2008 18:11
The APOBEC3 Cytidine Deaminases: An Innate Defensive Network

Opposing Exogenous Retroviruses and Endogenous Retroelements
Ya-Lin Chiu and Warner C. Greene p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p317
Thymus Organogenesis
Hans-Reimer Rodewald p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p355
Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell
Death
Dipanjan Chowdhury and Judy Lieberman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p389
Monocyte-Mediated Defense Against Microbial Pathogens
Natalya V. Serbina, Ting Jia, Tobias M. Hohl, and Eric G. Pamer p p p p p p p p p p p p p p p p p p p421
The Biology of Interleukin-2

Thomas R. Malek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p453
The Biochemistry of Somatic Hypermutation
Jonathan U. Peled, Fei Li Kuang, Maria D. Iglesias-Ussel, Sergio Roa,
Susan L. Kalis, Myron F. Goodman, and Matthew D. Scharff p p p p p p p p p p p p p p p p p p p p p481
Anti-Inflammatory Actions of Intravenous Immunoglobulin
Falk Nimmerjahn and Jeffrey V. Ravetch p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p513
The IRF Family Transcription Factors in Immunity and Oncogenesis
Tomohiko Tamura, Hideyuki Yanai, David Savitsky, and Tadatsugu Taniguchi p p p p p535
Choreography of Cell Motility and Interaction Dynamics Imaged
by Two-Photon Microscopy in Lymphoid Organs
Michael D. Cahalan and Ian Parker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p585
Development of Secondary Lymphoid Organs
Troy D. Randall, Damian M. Carragher, and Javier Rangel-Moreno p p p p p p p p p p p p p p p p627
Immunity to Citrullinated Proteins in Rheumatoid Arthritis
Lars Klareskog, Johan Rönnelid, Karin Lundberg, Leonid Padyukov,
and Lars Alfredsson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p651
PD-1 and Its Ligands in Tolerance and Immunity
Mary E. Keir, Manish J. Butte, Gordon J. Freeman, and Arlene H. Sharpe p p p p p p p p677
The Master Switch: The Role of Mast Cells in Autoimmunity
and Tolerance
Blayne A. Sayed, Alison Christy, Mary R. Quirion, and Melissa A. Brown p p p p p p p p p p705
T Follicular Helper (TFH ) Cells in Normal and Dysregulated Immune
Responses
Cecile King, Stuart G. Tangye, and Charles R. Mackay p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p741
vi Contents

The Biology of Interleukin-2: Thomas R. Malek

Uploaded by

The Biology of Interleukin-2: Thomas R. Malek

Uploaded by

ANRV338-IY26-15 ARI 16 February 2008 12:45

Department of Microbiology and Immunology and the Diabetes Research Institute,

Miller School of Medicine, University of Miami, Miami, Florida 33101;

Annu. Rev. Immunol. 2008. 26:453–79 Key Words

INTRODUCTION cell production is the main reason for au-

suspected in IL-2-deﬁcient mice because as-

pects of this autoimmune syndrome or experi-

Table 1 Autoimmune disease in C57BL/6 IL-2Rβ (CD122)-deficient mice

www.annualreviews.org • The Function of IL-2 455

TCR signaling IL-2 secretion IL-2 repression

pression of all subunits of the IL-2R. How- CD25.

www.annualreviews.org • The Function of IL-2 457

all of T cell origin, are readily detected by in

situ hybridization and immunohistochemistry most express an effector/memory phenotype,

an immune response independent of driving found in markedly reduced proportions, es-

www.annualreviews.org • The Function of IL-2 459

IL-4, IL-7, IL-9,

www.annualreviews.org • The Function of IL-2 461

www.annualreviews.org • The Function of IL-2 463

for functional Treg

TGF-β, or CTLA-4 into IL-2- or CD122-

www.annualreviews.org • The Function of IL-2 465

tor, IL-2 also sensitizes activated T cells to un-

dergo apoptosis upon restimulation through

www.annualreviews.org • The Function of IL-2 467

anti-CD25 therapy may be the result of When targeting IL-2 in immunotherapy,

www.annualreviews.org • The Function of IL-2 469

36. Brombacher F, Schafer T, Weissenstein U, Tschopp C, Andersen E, et al. 1994. IL-2

www.annualreviews.org • The Function of IL-2 471

2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:1142–51

of interleukin 2-dependent effector and regulatory T cells in response to endogenous

systemic antigen. J. Exp. Med. 202:1375–86

www.annualreviews.org • The Function of IL-2 473

ulatory T cells. Curr. Opin. Immunol. 19:176–85

www.annualreviews.org • The Function of IL-2 475

regulatory T cell function through cooperation with NFAT. Cell 126:375–87

vivo. Int. Immunol. 18:565–72

www.annualreviews.org • The Function of IL-2 477

toimmunity. Immunol. Rev. 212:217–37

185. Tsunobuchi H, Nishimura H, Goshima F, Daikoku T, Nishiyama Y, Yoshikai Y. 2000.

www.annualreviews.org • The Function of IL-2 479

Contents Volume 26, 2008

Doing What I Like

The APOBEC3 Cytidine Deaminases: An Innate Defensive Network

The Biology of Interleukin-2

You might also like