T Helper

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T Helper Cell Differentiation, Heterogeneity,

and Plasticity
Jinfang Zhu
Molecular and Cellular Immunoregulation Section, Laboratory of Immunology, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892
Correspondence: [email protected]
Naïve CD4 T cells, on activation, differentiate into distinct T helper (Th) subsets that produce
lineage-specific cytokines. By producing unique sets of cytokines, effector Th subsets play
critical roles in orchestrating immune responses to a variety of infections and are involved in
the pathogenesis of many inflammatory diseases including autoimmunity, allergy, and
asthma. The differentiation of Th cells relies on the strength of T-cell receptor (TCR) signaling
and signals triggered by polarizing cytokines that activate and/or up-regulate particular tran-
scription factors. Several lineage-specific master transcription factors dictate Th cell fates and
functions. Although these master regulators cross-regulate each other, their expression can be
dynamic. Sometimes, they are even coexpressed, resulting in massive Th-cell heterogeneity
and plasticity. Similar regulation mediated by these master regulators is also found in innate
lymphoid cells (ILCs) that are innate counterparts of Th cells.
C ytokines are the central mediators of im-

mune responses, and CD4 T helper (Th)
cells are the professional cytokine-producing
et al. 2005; Acosta-Rodriguez et al. 2007;
Weaver et al. 2007; Korn et al. 2009). All of
the Th1, Th2, and Th17 cells are differentiated
cells. By producing effector cytokines, Th cells from naïve CD4 T cells when they are activated
play critical roles during adaptive immune re- through T-cell receptor (TCR)-mediated sig-
sponses to infections; distinct Th subsets are naling. Not only are the Th effector cells im-
involved in protective immunity to different portant for protective immunity, they can also
pathogens (Murphy and Reiner 2002; Zhu and induce inflammatory responses to self-antigens
Paul 2008; Zhu et al. 2010). There are different or to nonharmful allergens, resulting in auto-
types of Th cells based on their cytokine pro- immunity or allergic diseases, respectively
files. Initially, type 1 T helper (Th1) and type 2 (Paul and Zhu 2010; Zhu et al. 2010). Inter-
T helper (Th2) cell clones that preferentially estingly, naïve CD4 T cells can also develop
produce interferon γ (IFN-γ) and interleukin into regulatory T cells (Tregs), which are im-
(IL)-4, respectively, were reported (Mosmann portant for maintaining immune tolerance
et al. 1986; Mosmann and Coffman 1989; Paul and for regulating the magnitude of immune
and Seder 1994). A third major CD4 Th effec- responses (Shevach 2000; Chen et al. 2003;
tor cell population Th17 that produces IL-17 Sakaguchi 2004; Josefowicz et al. 2012; Abbas
was not discovered until decades later (Park et al. 2013).
Editors: Warren J. Leonard and Robert D. Schreiber

Additional Perspectives on Cytokines available at www.cshperspectives.org
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a030338
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J. Zhu
Th cells can produce the majority of the cells induce B-cell immunoglobulin (Ig) switch-
known cytokines. In addition to the signature ing to IgG1 and IgE (Kopf et al. 1993); by
effector cytokines, IFN-γ, IL-4, and IL-17A, Th producing IL-5, Th2 cells recruit eosinophils
cells may preferentially express many other (Coffman et al. 1989); and by producing IL-13,
important cytokines, such as lymphotoxin α Th2 cells can induce the movement of smooth
for Th1; IL-5, IL-9, IL-13, and IL-24 for Th2; muscle cells and mucus production by epithelial
and IL-17F and IL-22 for Th17 cells. In addition, cells (Urban et al. 1998; Kuperman et al. 2002;
all of the Th subsets are capable of producing Wynn 2003). IL-4 and IL-13 produced by Th2
IL-2, IL-6, IL-10, IL-21, tumor necrosis factor α cells can also induce alternatively activated mac-
(TNF-α), and granulocyte macrophage colony- rophages (Gordon 2003).
stimulating factor (GM-CSF). Furthermore, Th17 cells are essential for orchestrating im-
some regulatory functions of Tregs are mediated mune responses to extracellular bacteria and
through production of anti-inflammatory cyto- fungi. They are also responsible for different
kines such as transforming growth factor forms of autoimmunity, including psoriasis,
(TGF)-β, IL-10, and IL-35. Not only are Th cells multiple sclerosis, rheumatoid arthritis, and in-
professional cytokine producers, they can also flammatory bowel diseases (Ouyang et al. 2008;
respond to a variety of cytokines, including IL-1, Korn et al. 2009). Th17 cells are also involved in
IL-7, IL-12, IL-15, IL-18, IL-23, IL-27, IL-33, severe asthma (McKinley et al. 2008). Th17 cells
and type 1 IFNs, etc., that are produced by produce three major cytokines: IL-17A, IL-17F,
accessory cells. During differentiation, Th cells and IL-22. IL-17A and IL-17F have redundant
can also respond to their own cytokines, includ- functions in diseases, but they may also have
ing IFN-γ and IL-4, resulting in powerful posi- unique functions (Iwakura et al. 2011). The
tive feedback or cross-inhibitory effects. major function of IL-17A and IL-17F is to re-
In this review, I will mainly focus on effector cruit and activate neutrophils. They can also
Th-cell differentiation, heterogeneity, and plas- stimulate different cell types to produce inflam-
ticity regulated by cytokines and transcription matory cytokines, including IL-6. IL-22 is a crit-
factors. Because innate lymphoid cells ([ILCs], ical cytokine for stimulating cells at mucosal
an innate equivalent of Th cells) are also profes- barriers to produce antimicrobial peptides and
sional cytokine-producing cells (Artis and Spits proinflammatory cytokines and chemokines
2015), the relationships between conventional (Liang et al. 2006).
Th cells and ILCs will also be discussed. Treg cells include thymus-derived Treg
(tTreg) cells and peripherally derived Treg (pTreg)
cells (Shevach 2009; Sakaguchi et al. 2010; Josefo-
DISTINCT FUNCTIONS OF Th-CELL
wicz et al. 2012; Abbas et al. 2013). Together with
SUBSETS
the tTreg cells, pTreg cells play important roles
Different Th-cell subsets have distinct immune in maintaining immune tolerance and regulat-
functions in protective immunity. Th1 cells ing the magnitude of immune responses by con-
(Szabo et al. 2003) are mainly important for trolling the differentiation and functions of T
host defense against intracellular pathogens, in- effector cells (Korn et al. 2009; Zhu et al. 2010;
cluding viruses, protozoa, and bacteria; they are Crotty 2011; Bilate and Lafaille 2012).
also responsible for the development of certain
forms of organ-specific autoimmunity. One of
the major functions of Th1 cells is to activate CYTOKINE-MEDIATED SIGNAL
macrophages through IFN-γ production. TRANSDUCERS AND ACTIVATORS
OF TRANSCRIPTION (STATs) ACTIVATION
Th2 cells are critical for mediating immune
IS CRITICAL FOR Th-CELL-FATE
responses against extracellular parasites, includ-
DETERMINATION
ing helminthes. These cells are also responsible
for the pathogenesis of inflammatory asthmatic Th-cell differentiation involves T-cell activation.
and allergic diseases. By producing IL-4, Th2 Indeed, the strength of TCR signaling has a ma-
2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity
jor impact on Th-cell-fate determination (Tao Jankovic et al. 2000; Min et al. 2004; Voehringer
et al. 1997). Sometimes the TCR signaling et al. 2004; van Panhuys et al. 2008).
strength may even have a dominant effect over In addition to IL-4, IL-2 through activating
adjuvants that usually create the cytokine envi- STAT5 is critical for the differentiation of Th2
ronments that drive T-cell differentiation (Tubo cells in vitro (Zhu et al. 2003; Cote-Sierra et al.
et al. 2013; Nelson et al. 2014; van Panhuys et al. 2004). IL-2-mediated STAT5 activation is
2014). In particular, stimulation with low-dose detectable 24 h after T-cell activation with a
peptide favors Th2-cell differentiation (Yamane low dose of TCR stimulation, which induces
et al. 2005), consistent with the finding that Th2 differentiation (Yamane et al. 2005). CD4
resting dendritic cells (DCs) promote Th2-cell T-cell proliferation and survival only need low
differentiation (Stumbles et al. 1998; Everts et al. levels of STAT5 activation (Moriggl et al. 1999;
2009; Steinfelder et al. 2009). TCR costimulation Cote-Sierra et al. 2004); however, Th2-cell dif-
mediated by CD28, which is required for ferentiation requires high levels of STAT5 acti-
optimal T-cell activation, is also involved in vation (Kagami et al. 2000, 2001; Zhu et al. 2003;
Th-cell differentiation (Seder et al. 1994). In Cote-Sierra et al. 2004). Other cytokines such as
contrast, cytotoxic T-lymphocyte-associated IL-7 and thymic stromal lymphopoietin (TSLP)
protein 4 (CTLA-4) negatively regulates T-cell can also activate STAT5 in T cells. Indeed, TSLP
differentiation (Oosterwegel et al. 1999; Bour- expression may trigger the initiation of Th2-cell
Jordan et al. 2003). differentiation in vivo (Ito et al. 2005; Zhou et al.
It is well known that, besides TCR-mediated 2005; Liu 2006; Sokol et al. 2008). Although
signaling, cytokine-mediated signals are critical TSLP mainly acts on DCs (Ito et al. 2005; Liu
for the differentiation of Th cells. For example, et al. 2007), it may also directly stimulate naïve
IL-12, mainly produced by antigen-presenting CD4 T cells to become Th2 cells (Al-Shami et al.
cells, including macrophages and DCs, induces 2005; Omori and Ziegler 2007; Rochman et al.
Th1-cell differentiation (Hsieh et al. 1993). IL- 2007; He et al. 2008). IL-7 can promote Th2-cell
12 activates a transcription factor, STAT4, in differentiation in vitro; however, its physiologi-
differentiating CD4 T cells (Hsieh et al. 1993; cal function during Th2 differentiation in vivo is
Kaplan et al. 1996b; Thierfelder et al. 1996). still elusive. Activated STAT5 directly regulates
IFN-γ, which is produced by Th1 cells them- IL-4 production by binding to the Il4/Il13 locus
selves, also promotes Th1-cell differentiation at different regulatory regions (Zhu et al. 2003;
through activating STAT1 (Lighvani et al. Cote-Sierra et al. 2004; Liao et al. 2008). Further-
2001; Afkarian et al. 2002; Martin-Fontecha more, IL-2-mediated STAT5 activation induces
et al. 2004). Indeed, either IL-12 or IFN-γ is IL-4Rα expression at the early stage of Th2-cell
capable of inducing Th1-cell differentiation at differentiation (Liao et al. 2008).
least in vitro (Zhu et al. 2012). However, during For Th17 and pTreg differentiation, TGF-β
Toxoplasma gondii infection, which elicits a is involved (Chen et al. 2003; Korn et al. 2009).
robust Th1 response, IFN-γ signaling seems to Together with IL-2-mediated STAT5 activation,
be dispensable for generating IFN-γ-producing TGF-β induces Treg differentiation; on the oth-
T cells, whereas IL-12 is essential. er hand, together with IL-6-mediated STAT3
IL-4 induces Th2-cell differentiation by ac- activation, TGF-β induces Th17-cell differenti-
tivating STAT6 (Kaplan et al. 1996a; Shimoda ation (Bettelli et al. 2006; Veldhoen et al. 2006).
et al. 1996; Takeda et al. 1996). A constitutively IL-21 and IL-23 have a similar function as IL-6
active STAT6 mutant is sufficient to replace IL-4 in inducing STAT3 activation and, thus, Th17-
in inducing Th2-cell differentiation (Kurata cell differentiation. However, IL-6, IL-21, and
et al. 1999; Zhu et al. 2001). However, under IL-23 may be involved in the different stages of
certain circumstances, Th2-cell differentiation Th17-cell development and maintenance (Korn
in vivo particularly in response to parasite infec- et al. 2009). IL-2 signaling is important for Treg
tion may occur in an IL-4/IL-4Rα/STAT6- generation. In the absence of IL-2, IL-2Rα, or
independent manner (Finkelman et al. 2000; IL-2Rβ, Treg-cell numbers are reduced and mice
Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 3

J. Zhu
or humans bearing mutations in the genes production (Szabo et al. 2000, 2002). Because
encoding IL-2, IL-2Rα, or IL-2Rβ develop auto- IFN-γ also induces T-bet expression, this ex-
immune disease (Fontenot et al. 2005; Caudy plains the positive feedback for Th1-cell differ-
et al. 2007). In contrast, IL-2-mediated STAT5 entiation (Lighvani et al. 2001; Afkarian et al.
activation suppresses Th17-cell differentiation 2002). IL-12 can also induce T-bet independent
(Laurence et al. 2007; Liao et al. 2011; Yang of IFN-γ signaling (Yang et al. 2007; Zhu et al.
et al. 2011). 2012). Thus, IL-12 and IFN-γ redundantly in-
duce T-bet expression both in vitro and in vivo.
In addition to IL-12 and IFN-γ, other cytokines
CYTOKINE-MEDIATED POSITIVE FEEDBACK
such as IL-27 and type I IFNs are also capable of
DURING Th-CELL DIFFERENTIATION
inducing T-bet, although their actual functions
The cytokine-mediated positive feedback mech- during Th-cell differentiation in vivo are still
anism is one of the basic principles of Th-cell elusive (Zhu et al. 2012). T-bet is capable of
differentiation. During Th1-cell differentiation, inducing its own expression (Mullen et al.
IFN-γ produced by developing Th1 cells may 2001); however, such autoregulation may not
instruct IFN-γ nonproducers to produce IFN- be required when either IL-12 or IFN-γ is
γ. Similarly, IL-4 produced during Th2-cell present (Zhu et al. 2012). Nevertheless, T-bet
differentiation may induce IL-4 expression by collaborates with STAT4 to induce optimal
the previous IL-4 nonproducers. Furthermore, IFN-γ production, and one of the main func-
low amounts of IFN-γ or IL-4 derived from T tions of T-bet in Th1-cell differentiation is
cells may further induce these cells to produce to remodel the Ifng locus. Genome-wide study
high levels of IFN-γ or IL-4 in an autocrine has shown that T-bet directly regulates a large
manner. Therefore, Th1- and Th2-cell differen- number of Th1-specific genes (Zhu et al. 2012).
tiation is enforced by the positive feedback GATA3 is the master transcription factor
loops. TGF-β produced by Treg cells may for Th2-cell differentiation (Zhang et al. 1997;
be important for the generation of pTreg cells Zheng and Flavell 1997; Pai et al. 2004; Zhu et al.
(Andersson et al. 2008). Th17 cells are also ca- 2004). Retroviral expression of GATA3 is suffi-
pable of producing either TGF-β1 or TGF-β3, cient to induce endogenous GATA3 expression
both of which may serve as positive feed- (Ouyang et al. 1998, 2000); however, GATA3
back mechanisms for Th17-cell differentiation may not be required for its own expression
(Gutcher et al. 2011; Lee et al. 2012). Because when IL-4 is present (Wei et al. 2011). Unlike
TGF-β induces both Th17 and pTreg-cell T-bet, which is not expressed in naïve T cells,
differentiation and both cell types can produce GATA3 is expressed in naïve CD4+ T cells at low
TGF-β, how TGF-β exactly works in vivo may levels, possibly because of its critical role during
depend on other factors such as the presence of CD4 T-cell development in the thymus (Ho
inflammatory cytokines and the stage of Th-cell et al. 2009; Wei et al. 2011). STAT6 activation
differentiation. by IL-4 is one of the major inducers for GATA3
up-regulation. However, low-dose TCR stimu-
lation is sufficient to up-regulate GATA3 expres-
MASTER TRANSCRIPTION FACTORS
sion independent of IL-4/STAT6 signaling
DICTATE T-CELL DIFFERENTIATION
(Yamane et al. 2005); this may offer a mecha-
Although networks of transcription factors reg- nism through which IL-4-independent Th2
ulate Th-cell differentiation (Zhu and Paul differentiation may occur in vivo. Alternatively,
2010b; Ciofani et al. 2012; Hu et al. 2013; Yosef the initiation of Th2-cell differentiation in vivo
et al. 2013), lineage-specific master transcrip- may occur with low amounts of GATA3 expres-
tion factors play the most critical roles during sion when STAT5 is highly activated (Zhu et al.
the differentiation process (Fig.1). T-bet is 2003; Cote-Sierra et al. 2004; Rochman et al.
the master transcription factor for Th1-cell 2009). Nevertheless, both IL-4-dependent and
differentiation, and it directly regulates IFN-γ IL-4-independent Th2-cell differentiation re-

Treg Tfh
compartment compartment
Foxp3 Bcl6
Th effector ILC
compartment compartment
Foxp3/Bcl6
GATA3 GATA3
T-bet Foxp3 Bcl6 T-bet

GATA3 GATA3 GATA3 GATA3
T-bet T-bet
T-bet Foxp3 Bcl6 T-bet

RORγt T-bet T-bet RORγt
RORγt RORγt
Foxp3 Bcl6
RORγt RORγt
Figure 1. Combinatorial expression of master transcription factors determines the heterogeneity and function-
ality of effector T helper (Th) cells, follicular Th (Tfh) cells, regulatory T (Treg) cells, and innate lymphoid cell
(ILC) subsets. T-bet, GATA3, and RORγt are the master transcription factors of distinct Th cell and ILC subsets.
Within the Th effector compartment, T-bet/RORγt coexpressing cells have been found under inflammation
conditions. These cells could be derived from either T-bet- or RORγt-single positive cells. During type 2 immune
responses, GATA3/T-bet coexpressing cells are also found. Similarly, in the ILC compartment, NKp46+ ILC3s
coexpress T-bet and RORγt. Bcl6 is the master regulator for Tfh cells. Subsets of Tfh cells may either express low
levels of effector master regulators, T-bet, GATA3, or RORγt, or have expressed one of these factors during their
development. Interestingly, all of these master regulators, T-bet, GATA3, RORγt, and Bcl6, can be expressed by
subsets of Foxp3-expressing Treg cells albeit at lower levels. Furthermore, although it is not indicated in the figure,
all of these lymphocytes can express GATA3 but at various levels.
quire GATA3 (Zhu et al. 2004). Interestingly, Therefore, while GATA3 is required for the
during Th1 and/or Th17 differentiation, GATA3 acquisition of IL-4-producing capacity by Th2
expression is down-regulated (Zheng and Flavell cells, in fully differentiated Th2 cells, GATA3 is
1997; Wei et al. 2011). no longer important for IL-4 production but
GATA3 may promote Th2-cell differentia- it remains essential for the transcription of the
tion via different mechanisms (Yagi et al. 2011). Il5 and Il13 (Zhu et al. 2004). In addition,
Genome-wide profiling of GATA3 binding GATA3 directly regulates many other Th2-
indicates that it directly binds to the Il4/Il13 specific genes including Il1rl1, which encodes
gene locus at various regions (Wei et al. 2011). T1/ST2, the IL-33 receptor (Wei et al. 2011).
Through its binding to the promoters of the Il5 RORγt is the master transcription factor for
and the Il13 genes, GATA3 induces Il5 and Il13 Th17-cell differentiation (Ivanov et al. 2006).
transcription (Yamashita et al. 2002; Tanaka RORγt loss-of-function mutations in human
et al. 2011). However, GATA3 mainly affects patients results in susceptibility to both Candida
Il4 expression through regulating epigenetic and Mycobacterium infections (Okada et al.
modifications at the Th2 cytokine gene locus. 2015). The induction of RORγt expression de-

J. Zhu
pends on STAT3 activation by IL-6, IL-21, and/ ation by repressing STAT4 expression (Usui
or IL-23 (Zhu and Paul 2008; Korn et al. 2009). et al. 2003), and suppressing Runx3-mediation
RORγt directly regulates IL-17A and IL-17F IFN-γ production (Yagi et al. 2010) as well as
expression. At the genome scale, RORγt binds silencing the Tbx21 locus (Wei et al. 2011).
to and regulates only a selected set of Th17- Cross-regulation has also been found between
specific genes after BATF/IRF4 and STAT3 T-bet and RORγt (Lazarevic et al. 2011) and
have initiated the Th17 differentiation program between Foxp3 and RORγt (Yang et al. 2008;
(Ciofani et al. 2012). Zhou et al. 2008). RORγt and Foxp3 may antag-
The master regulator for Treg generation onize each other through protein–protein inter-
and function is Foxp3 (Fontenot et al. 2003; action (Yang et al. 2008; Zhang et al. 2008; Zhou
Hori et al. 2003). Mutations in the human et al. 2008).
FOXP3 gene are responsible for the immuno-
dysregulation polyendocrinopathy enteropathy
NONCANONICAL Th SUBSETS THAT
X-linked (IPEX) syndrome, and mutations in
COEXPRESS MULTIPLE MASTER
the Foxp3 gene in mice, such as Scurfy mice,
REGULATORS
result in fatal autoimmune diseases. Genome-
wide analysis indicates that Foxp3 directly binds Master regulators are usually expressed in a cell-
to hundreds of genes, many of which are either type-specific manner (i.e., T-bet for Th1,
positively or negatively regulated by Foxp3, GATA3 for Th2, RORγt for Th17, and Foxp3
especially in the thymus (Zheng et al. 2007). for Treg cells) (Fig. 1). However, because
Some of Foxp3-regulated genes encode mole- both Th17- and Treg-cell differentiation require
cules that regulate gene expression and/or are TGF-β, RORγt and Foxp3 are often coexpressed,
involved in epigenetic modifications. presumably at early stages of Th17/Treg-cell
differentiation. These cells may represent an in-
termediate stage before they eventually commit
CROSS-REGULATION OF Th-CELL
to either Th17 or Treg cells (Yang et al. 2008;
DIFFERENTIATION
Zhou et al. 2008; Komatsu et al. 2014). Interest-
During Th-cell differentiation toward a specific ingly, RORγt/Foxp3-coexpressing Treg cells,
type, signals/pathways that induce such differ- possibly representing a specialized Treg subset,
entiation also repress the alternative lineage are abundant in the large intestine (Ohnmacht
fates. At the transcriptional level, the transcrip- et al. 2015; Sefik et al. 2015). Indeed, Treg-
tion factors that are either activated or induced specific deletion of RORγt results in gut inflam-
in one lineage often cross-regulate the expres- mation with an uncontrolled Th2 response
sion and/or functions of the transcription fac- (Ohnmacht et al. 2015).
tors that are involved in making other lineage In addition to RORγt, T-bet and GATA3 can
decisions. For example, overexpression of T-bet be expressed by Treg subsets as well. Therefore,
suppresses Gata3 transcription (Usui et al. it has been suggested that Treg cells may hijack
2006) and inhibits GATA3 function through di- the master regulators of distinct T effector cells
rect protein–protein interaction (Hwang et al. to specifically control a given type of immune
2005). Interestingly, T-bet and GATA3 binding response. According to this model, T-bet ex-
sites colocalize at several critical Th1- or Th2- pression by Treg cells is critical for inhibiting
specific genes (Jenner et al. 2009; Kanhere et al. Th1 responses (Koch et al. 2009). However,
2012; Zhu et al. 2012). It has also been shown Treg-specific deletion of T-bet does not result
that endogenous T-bet inhibits GATA3 func- in the development of Th1-related autoimmune
tion during Th1-cell differentiation, thus pre- diseases, indicating that T-bet is not required
venting the activation of a “default” program for Treg cells to control autoreactive Th1 cells
for Th2-cell differentiation (Zhu et al. 2012). at steady state (Yu et al. 2015). Because the func-
On the other hand, during Th2-cell differentia- tions of Treg cells during inflammation and/or
tion, GATA3 may suppress Th1-cell differenti- immune responses may be different from their

functions at steady state, it remains to be deter- cans antigens, are also found in human patients
mined whether T-bet expression in Treg cells is (Zielinski et al. 2012). Interestingly, these cells
important for their ability to limit Th1-related may represent an important population that is
immune responses (Oldenhove et al. 2009; Ya- involved in immune responses to Mycobacteri-
maguchi et al. 2011). um tuberculosis (Mtb) infection in humans.
GATA3 is expressed in all T cells, albeit at RORγt-deficient patients fail to control Mtb in-
different levels. Interestingly, some Treg cells fections (Okada et al. 2015). Besides T-bet/RORγt
can express high levels of GATA3 (Wang et al. coexpressing cells, GATA3/T-bet coexpressing
2011; Wohlfert et al. 2011; Rudra et al. 2012; Yu cells have been detected in helminth-infected an-
et al. 2015), potentially explaining why a slight imals (Peine et al. 2013) and GATA3/RORγt co-
reduction in Foxp3 expression results in a Th2 expressing cells are found in asthmatic mice and
phenotype in these “Treg cells” (Wan and Flavell patients (Cosmi et al. 2010; Wang et al. 2010).
2007). In fact, even with normal levels of Foxp3
expression, GATA3 may induce the expression
EPIGENETIC MODIFICATIONS AND CELL
of many “Th2-specific” genes such as Il1rl1 and
PLASTICITY
Ccr8 in Treg cells (Wei et al. 2011). One study
has shown that GATA3 deletion in Treg cells Different modifications at the histones binding
results in spontaneous Th2-like autoimmunity to the genomic regions correlate with gene acti-
(Wang et al. 2011), but other studies show that vation or silencing (Barski et al. 2007). Trimeth-
the mice with GATA3 deletion specifically in ylation at the lysine position 4 of histone 3
Treg cells do not develop Th2-specific systemic (H3K4me3), particularly in gene-promoter re-
diseases (Wohlfert et al. 2011; Rudra et al. 2012; gions, is usually associated with active gene loci.
Yu et al. 2015). On the other hand, H3K27me3 is generally a
Interestingly, T-bet- and GATA3-expressing marker of repressed genes. Epigenetic status at
Treg cells do not represent stable Treg subsets. the effector cytokine loci is usually reflected by
The expression T-bet and GATA3 in Treg cells H3K4me3 in cells that express such cytokines,
is dynamic (Yu et al. 2015). Although deletion or by H3K27me3 in cells where these cytokine
of either T-bet or GATA3 in Treg cells does genes are silenced (Wei et al. 2009). However,
not affect the overall function of these cells, bivalent modifications with both H3K4me3 and
Treg cells lacking expression of both T-bet and H3K27me3, which are indicative for the genes
GATA3 up-regulate RORγt expression and poised for expression, are found in the promot-
acquire IL-17-producing capacity. These Treg ers of the master regulator genes, such as Tbx21,
cells are unstable and many lose Foxp3 expres- Gata3, and Rorc, etc., even in the cells that do not
sion over time. Thus, dynamic expression of express such transcription factors (Wei et al.
T-bet and GATA3 together with cross-regula- 2009). Such bivalent modifications may allow
tion among T-bet, GATA3, RORγt, and Foxp3 the induction of a master regulator expression
are important for maintaining Treg functions in cells of alternative lineage fate, resulting in
(Yu et al. 2015). the generation of master regulator coexpressing
In addition to the heterogeneity of Tregs, cells and cell plasticity. Therefore, a transient
within T effector populations, multiple master signal that alters the balance of key master
regulators may also be expressed in the same regulators, which will cross-regulate each other
cell. For example, T-bet/RORγt coexpressing when coexpressed, may ultimately result in a
cells are found in the gut and inflamed brain lineage switch.
(Ivanov et al. 2006; Hirota et al. 2011). Many Although there are some reports showing
of these cells are capable of expressing both that Th1 and Th2 cells may alter their lineage
IFN-γ and IL-17 (Lee et al. 2009; Ghoreschi fates (Hegazy et al. 2010), these cells are relative-
et al. 2010; Lexberg et al. 2010; Hirota et al. ly stable (Zhu and Paul 2010a). Cell plasticity is
2011). T-bet/RORγt (IFN-γ/IL-17) coexpress- more common for Th17 and Treg cells (Zhou
ing T cells, which are specific for Candida albi- et al. 2009a). Th17 cells may acquire IFN-γ-

J. Zhu
producing capacity in a T-bet-dependent man- Johnston et al. 2012). The master transcription
ner (Mathur et al. 2006; Bending et al. 2009; Lee factor for Tfh cells is Bcl6 (Johnston et al. 2009;
et al. 2009). Through a fate-mapping study, Nurieva et al. 2009). Interestingly, some Treg
it has been shown that IFN-γ-producing cells cells are also found in the B-cell follicle and these
found in the brain of autoimmune mice are cells coexpress Foxp3 and Bcl6. These cells are
largely derived from the cells that express IL- named follicular regulatory T (Tfr) cells (Chung
17 (Hirota et al. 2011). Th17 cells may also et al. 2011; Linterman et al. 2011). Tfr cells may
trans-differentiate into Treg cells when inflam- play an important role in limiting the functions
mation is resolved (Gagliani et al. 2015). of Tfh cells in activating B cells.
Although several studies have shown that Treg Tfh cells do not express or express very low
cells are stable even under inflamed conditions levels of T-bet and GATA3. However, IgE
(Rubtsov et al. 2010; Sakaguchi et al. 2013), class switching completely depends on GATA3
other studies have shown the possible switch expression, indicating that GATA3 is required
from Treg cells to Th1, Th2, or Th17 cells (Xu for the development of IL-4-producing Tfh cells
et al. 2007; Komatsu et al. 2009, 2014; Olden- (Zhu et al. 2004). It is possible that low levels of
hove et al. 2009; Zhou et al. 2009b; Noval Rivas GATA3 expression in Tfh cells are sufficient for
et al. 2015). these cells to produce IL-4 production (Yusuf
et al. 2010; Liang et al. 2012). Alternatively,
just like the dynamic expression of GATA3
RELATIONSHIP BETWEEN T EFFECTOR
found in Treg cells, as mentioned earlier (Yu
CELLS AND CYTOKINE-PRODUCING Tfh
et al. 2015), GATA3 may have been expressed
CELLS
at high levels at early stage of IL-4-producing
A critical function of CD4 T cells during im- Tfh-cell differentiation. Once the Il4 locus is
mune responses is to help B cells produce anti- remodeled by GATA3, Tfh cells no longer re-
bodies and Ig class switching (Fig. 1). It has been quire GATA3 for IL-4 production and thus do
shown that CD4 Th cells that are found in the not need to express GATA3. This is consistent
B-cell follicle, termed as Tfh cells, are critical for with the observation that in fully differentiated
exerting such functions (Crotty 2011). Th-cell Th2 cells, Gata3 deletion does not abolish IL-4
effects on B cells rely on cytokine production; production (Zhu et al. 2004). Similarly, transient
although IL-4 is important for the Ig class expression of T-bet during the early stage of
switching to IgE and IgG1 (Kopf et al. 1993; Tfh-cell differentiation may allow these cells to
King and Mohrs 2009; Reinhardt et al. 2009; acquire IFN-γ-producing capacity.
Zaretsky et al. 2009), IFN-γ induces Ig switching The developmental relationship between
to IgG2a/IgG2c. Even though IL-21 produced IFN-γ- or IL-4-producing Tfh cells and conven-
by Tfh cells is important for helping B cells, tional Th1 or Th2 cells is still elusive. In vitro
there are at least two different types of Tfh cells, experiments suggest that conventional Th1 or
with one type producing IFN-γ and the other Th2 cells can become IFN-γ- or IL-4-producing
IL-4. In fact, most of the IL-4-producing Th cells Tfh cells or differentiated Tfh cells can acquire
in vivo have a Tfh phenotype (King and Mohrs IFN-γ- or IL-4-producing capacity (Lu et al.
2009). Different from conventional Th2 cells, 2011). In vivo, activated IL-4-producing T cells
however, IL-4-producing Tfh cells do not ex- may subsequently acquire a Tfh-cell phenotype
press IL-13 (Liang et al. 2012). through their interaction with B cells (Zaretsky
Tfh cells are considered as a fifth major Th- et al. 2009). It is also possible that activated T
cell population that is different from conven- cells may acquire IFN-γ- or IL-4-producing ca-
tional Th1, Th2, Th17, and Treg cells (Nurieva pacity and a Tfh phenotype simultaneously, and
et al. 2008). Tfh-cell differentiation requires thus their fate to become either conventional
STAT3 activation, presumably by IL-21, but Th1/Th2 effector cells or specific cytokine-
IL-2-mediated STAT5 activation suppresses producing Tfh cells may have been determined
Tfh-cell generation (Nurieva et al. 2008, 2012; at very early stages of T-cell differentiation (Na-

kayamada et al. 2011; Johnston et al. 2012; whereas NK cells do not (Yagi et al. 2014); this
Oestreich et al. 2012). It is interesting to point mirrors the critical function of GATA3 in
out that Tfh cells may be an important source specifying CD4 but not CD8 lineage fate during
for generating memory Th cells, which could T-cell development (Ho et al. 2009). In addition,
subsequently give rise to conventional Th effec- GATA3 regulates IL-7Rα expression in both
tor cells on reactivation (Luthje et al. 2012). In T cells and ILCs (Wang et al. 2013; Zhong
the future, genome-wide assessment of the tran- et al. 2016).
scriptomes and epigenomes of conventional Because of similarities between ILC and Th
Th cells, cytokine-producing Tfh-cell subsets subsets (Yagi et al. 2014; Koues et al. 2016; Shih
and Th memory cells is necessary to further et al. 2016), a specific type of ILCs may partic-
understand the relationship between these ipate in the same class of immune responses in a
closely related cell types. similar manner to corresponding distinct Th
subsets. Therefore, ILC2s are important players
during type 2 immune responses, including im-
RELATIONSHIP BETWEEN Th CELLS AND
munity against helminth infections (Fallon et al.
INNATE LYMPHOID CELLS
2006; Moro et al. 2010; Neill et al. 2010; Price
During the past few years, ILCs have drawn et al. 2010) and during allergic lung and skin
much attention in the immunology field (Artis inflammation (Chang et al. 2011; Monticelli
and Spits 2015). ILCs do not express antigen et al. 2011; Halim et al. 2012; Roediger et al.
receptors, but they can respond to many inflam- 2013; Kim et al. 2014). Similarly, ILC1s may
matory cytokines, such as IL-1, IL-12, IL-18, participate in type 1 immune responses and
IL-23, IL-25, and IL-33, to produce their own ILC3s are important for controlling extracellu-
cytokines, including IFN-γ, IL-5/13, and IL-17/ lar bacteria, which induce Th17 responses (Qiu
22. ILCs express IL-7Rα and at least partially et al. 2013; Klose et al. 2014; Sano et al. 2015).
depend on IL-7 and/or TSLP for their develop- As mentioned above, ILCs mainly respond
ment. Because of their distinct cytokine-produc- to cytokine stimulation. Interestingly, in fully
ing capacity, ILCs are classified into group 1 differentiated Th cells, IL-1 family receptors
ILCs (ILC1s) that produce IFN-γ, group 2 IL-18R, IL-33R, and IL-1R, which are preferen-
ILCs (ILC2s) that produce IL-5 and IL-13, and tially expressed by ILC1s, ILC2s, and ILC3s,
group 3 ILCs (ILC3s) that produce IL-17 and IL- respectively, are also selectively expressed by
22. Not only do ILC subsets produce similar Th1, Th2, and Th17 cells, respectively (Guo
cytokines to those produced by Th-cell subsets, et al. 2009, 2012). As a result, just like ILCs, Th
but ILCs also use the same set of master regula- cells can also respond to cytokine stimulation,
tors, namely, T-bet, GATA3, and RORγt for which is independent of TCR stimulation, to pro-
their development and function. For example, duce effector cytokines in vivo (Guo et al. 2015).
the Th2 master regulator, GATA3, is also critical One major difference between ILCs and
for ILC2 development and the functional Th cells is antigen specificity. Because ILCs do
maintenance of these cells (Hoyler et al. 2012; not recognize specific antigen and they are
Mjosberg et al. 2012; Furusawa et al. 2013; Klein already developed even before possible microbi-
Wolterink et al. 2013; Yang et al. 2013; Yagi et al. al threats, these cells provide the first line of host
2014). Although some researchers have classi- defense to infections. Their unique position in
fied natural killer (NK) cells into ILC1s based on tissue sites fits quite well with their functionality.
their cytokine production, NK cells are in fact Interestingly, the same type of ILCs and Th cells
the innate counterparts of CD8 T cells in the may cross talk to each other. For example, IL-13
adaptive system (Cortez and Colonna 2016; produced by ILC2s on activation can induce the
Spits et al. 2016). Both NK and CD8 T cells migration of DCs to the draining lymph nodes,
express transcription factor Eomes. Develop- and these migratory DCs preferentially induce
mentally, all non-NK ILCs (or Th-like ILCs, or Th2-cell differentiation (Halim et al. 2014).
IL-7Rα-expressing ILCs) depend on GATA3, In addition, some ILC2s, by expressing major

J. Zhu
histocompatibility complex (MHC) class II, can lators may determine the plasticity of Th cells.
activate T cells, and IL-2 produced by T cells Some master regulator coexpressers are relative-
may then act back onto ILC2s to influence their ly stable, that is, T-bet/RORγt coexpressers.
activation and cytokine production (Mirchan- Importantly, these cells are found abundant in
dani et al. 2014; Oliphant et al. 2014). Cross several inflammatory settings; they are consid-
talk between ILC3s and Th17 cells has also ered as the most potent cells in inducing auto-
been reported (Sano et al. 2015). Nevertheless, immunity and they may be an important cell
the functions of ILCs and Th cells may be sub- population to fight against Mtb infection in
stantially redundant. Optimal activation of ILCs humans. How T-bet and RORγt, two mutually
is sufficient to control infections in the absence inhibitory transcription factors, may stably co-
of Th cells, as shown in several mouse models. exist in the same cell and what unique programs
Interestingly, however, humans without ILCs, have been activated in these cells remain impor-
which can result because of the failure of ILC tant questions. Investigation of Th- and ILC-cell
reconstitution after bone marrow transplanta- heterogeneity and plasticity holds promise for
tion, are capable of controlling infections (Vely finding specific treatments for a variety of
et al. 2016). However, the collaboration as well human immunological diseases in the future.
as labor division between ILCs and Th cells High-dimensional single-cell analyses, includ-
may allow the host to survive severe infections. ing single-cell RNAseq and CyTOF mass cy-
Because of the activation of either ILCs or Th tometry, may allow us to gain deeper insights
cells alone is sufficient to induce many inflam- into the immune responses mediated by Th
matory diseases, investigating the development cell and ILC subsets in autoimmunity, allergy,
and functions of both ILCs and Th subsets is and infectious diseases.
clinically relevant.
ACKNOWLEDGMENTS
CONCLUDING REMARKS
J.Z. is supported by the Division of Intramural
CD4 Th cells are professional cytokine-produc-
Research (DIR), the National Institute of Aller-
ing cells. To acquire a unique cytokine-produc-
gy and Infectious Diseases (NIAID), and the
ing profile, naïve CD4 T cells need to go through
National Institutes of Health (NIH).
a differentiation process. During Th-cell differ-
entiation, TCR and cytokine-mediated signaling
pathways induce activation of STAT proteins
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T Helper Cell Differentiation, Heterogeneity, and Plasticity

Jinfang Zhu
Cold Spring Harb Perspect Biol 2018; doi: 10.1101/cshperspect.a030338 originally published online
August 28, 2017
Subject Collection Cytokines
Interleukin (IL)-33 and the IL-1 Family of Cytokines Interferon γ and Its Important Roles in Promoting
−−Regulators of Inflammation and Tissue and Inhibiting Spontaneous and Therapeutic
Homeostasis Cancer Immunity
Ajithkumar Vasanthakumar and Axel Kallies Elise Alspach, Danielle M. Lussier and Robert D.
Schreiber
Targeting IL-10 Family Cytokines for the Inflammasome-Dependent Cytokines at the
Treatment of Human Diseases Crossroads of Health and Autoinflammatory
Xiaoting Wang, Kit Wong, Wenjun Ouyang, et al. Disease
Hanne Van Gorp, Nina Van Opdenbosch and
Mohamed Lamkanfi
Cytokine-Mediated Regulation of CD8 T-Cell Innate Lymphoid Cells (ILCs): Cytokine Hubs
Responses During Acute and Chronic Viral Regulating Immunity and Tissue Homeostasis
Infection Maho Nagasawa, Hergen Spits and Xavier Romero
Masao Hashimoto, Se Jin Im, Koichi Araki, et al. Ros
Cytokines in Cancer Immunotherapy T Helper Cell Differentiation, Heterogeneity, and
Thomas A. Waldmann Plasticity
Jinfang Zhu
The Tumor Necrosis Factor Family: Family Development, Diversity, and Function of Dendritic
Conventions and Private Idiosyncrasies Cells in Mouse and Human
David Wallach David A. Anderson III, Kenneth M. Murphy and
Carlos G. Briseño
The Interferon (IFN) Class of Cytokines and the Cytokines and Long Noncoding RNAs
IFN Regulatory Factor (IRF) Transcription Factor Susan Carpenter and Katherine A. Fitzgerald
Family
Hideo Negishi, Tadatsugu Taniguchi and Hideyuki
Yanai
For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved
Role of the β Common (βc) Family of Cytokines in Negative Regulation of Cytokine Signaling in
Health and Disease Immunity
Timothy R. Hercus, Winnie L. T. Kan, Sophie E. Akihiko Yoshimura, Minako Ito, Shunsuke Chikuma,
Broughton, et al. et al.
Interleukin (IL)-12 and IL-23 and Their Conflicting Cancer Inflammation and Cytokines
Roles in Cancer Maria Rosaria Galdiero, Gianni Marone and Alberto
Juming Yan, Mark J. Smyth and Michele W.L. Teng Mantovani
For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/
Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved

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T Helper Cell Differentiation, Heterogeneity,

C ytokines are the central mediators of im-

Editors: Warren J. Leonard and Robert D. Schreiber

2 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 3

4 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

T-bet Foxp3 Bcl6 T-bet

T-bet Foxp3 Bcl6 T-bet

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 5

6 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

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8 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 9

10 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 11

12 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 13

14 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 15

16 Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338

Th-Cell Differentiation and Plasticity

Cite this article as Cold Spring Harb Perspect Biol 2018;10:a030338 17

T Helper Cell Differentiation, Heterogeneity, and Plasticity

Subject Collection Cytokines

For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

For additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/

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