Seminars in Immunology 44 (2019) 101335

Contents lists available at ScienceDirect

Seminars in Immunology
journal homepage: www.elsevier.com/locate/ysmim

Review

IL-10-producing T cells and their dual functions T

a,1 b,1 a a,b,c, ,2 a, ,2
Tanja Bedke , Franziska Muscate , Shiwa Soukou , Nicola Gagliani * , Samuel Huber *
a
I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
b
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
c
Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, 17176 Stockholm, Sweden

ARTICLE INFO ABSTRACT

Keywords: Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, which significantly contributes to
Interleukin-10 the maintenance and reestablishment of immune homeostasis. However, this classical view fails to fully describe
T-cells the pleiotropic roles of IL-10. Indeed, IL-10 can also promote immune responses, e.g. by supporting B-cell and
Immune regulation CD8+ T-cell activation. The reasons for these seemingly opposing functions are unclear to a large extent. Recent
Inflammation
and previous studies suggest that the cellular source and the microenvironment impact the function of IL-10.
However, studies addressing the mechanisms which determine whether IL-10 promotes inflammation or controls
it have just begun. This review first summarizes the recent findings on the heterogeneity of IL-10 producing T
cells and their impact on the target cells. Finally, we will propose two possible explanations for the dual
functions of IL-10.

1. Introduction IL-10R subunits or IL-10 are associated with immune-mediated in-

flammatory diseases such as inflammatory bowel disease (IBD), sys-
IL-10, the eponym of the IL-10 cytokine family, is an anti-in- temic lupus erythematosus (SLE) or rheumatoid arthritis (RA) high-
flammatory cytokine, which plays a crucial role in maintaining immune lighting the important immune regulatory function of IL-10 [9–12].
homeostasis, preventing immune mediated inflammatory diseases and However, while IL-10 suppresses pro-inflammatory processes in CD4+
exuberant immune responses to pathogens [1,2]. In keeping with these T cells, it can also promote the killing capacity and memory formation
pleiotropic functions, a variety of different immune cell types from the in CD8+ T cells [13–15]. Similarly, B-cell survival, proliferation and the
innate, but also from the adaptive immune system are able to produce capacity to produce antibodies are promoted by IL-10 [16,17]. This can
and respond to IL-10. Immune regulation by IL-10 is a phylogenetic either benefit the humoral response to foreign antigens or drive pa-
ancient mechanism to induce tolerance and fine-tune the inflammatory thology in SLE, for example. Antigen-presenting cells such as dendritic
response; it can not only be observed in mammals, but also across all cells or macrophages down regulate pro-inflammatory mechanisms in
vertebrates including birds, amphibians and fish [3]. response to IL-10 signaling [18–22].
Despite its well-known anti-inflammatory role, IL-10 has dual This review will focus on the role of IL-10´s versatile function in
functions depending on the context. In T cells, IL-10 was initially de- immune regulation with regard to the heterogenous population of IL-10
scribed as a signature cytokine of TH2 cells [4,5]. However, IL-10 can producing CD4+ T cells and IL-10 sensing innate and adaptive cells.
also be expressed by other effector subsets, such as TH1 or TH17 cells Moreover, it will summarize the seemingly opposing therapeutic ben-
[1,2,6]. Additionally, IL-10 is a key cytokine produced by regulatory T- efits of IL-10 in autoimmune disease and cancer and will discuss the
cell subsets (Foxp3+ regulatory T cells (Treg) and T regulatory type 1 impact of the cellular source, responder cell, and the particular mi-
cells (TR1)) in which sensing of IL-10 is an important signal to maintain croenvironment on the dual function of IL-10.
their phenotype and function [7,8]. Accordingly, in humans the loss of
function mutations and single-nucleotide polymorphisms (SNPs) in the

Abbreviations: IL, Interleukin; TH, T helper; Treg, regulatory T cell; TR1, type1 regulatory T cell; IFN, interferon; TNF, tumor necrosis factor; APC, antigen
presenting cell; DC, dendritic cell; LAG-3, Lymphocyte-activation gene 3; CTLA-4, cytotoxic T lymphocyte associated protein 4, Programmed cell death protein 1;
TIM-3, T-cell immunoglobulin mucin 3
⁎
Corresponding author at: I. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
E-mail addresses: [email protected] (N. Gagliani), [email protected] (S. Huber).
1
Equally contributed.
2
These authors jointly supervised the work (alphabetical order).

https://doi.org/10.1016/j.smim.2019.101335
Received 12 August 2019; Accepted 21 October 2019
Available online 14 November 2019
1044-5323/ © 2019 Elsevier Ltd. All rights reserved.

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

2. IL-10 producing T cells and their target cells 2.2. IL-10 sensing by innate and adaptive immune cells

2.1. T cells as a source of IL-10 In this section, we will first summarize how IL-10 signals are
transduced via its receptor complex in IL-10 responder cells. Second, we
The role of IL-10 in regulating CD4+ T cell responses has been will discuss the contribution of IL-10 signaling in innate and adaptive
shown in several organs and mouse disease models [23]. For example, immune cells to the maintenance and reestablishment of immune
in the intestine, IL-10 is a key molecule displaying suppressive activity homeostasis.
against effector T cells and it is important in maintaining intestinal
homeostasis [24]. However, this is not the case in every tissue. In this 2.2.1. IL-10 receptor signaling
section we will highlight several IL-10 producing T helper cell subsets The IL-10 receptor is a heterodimer composed of two IL-10 receptor
[25,26]. α-subunits (IL-10Rα), that are specific for IL-10 binding, and two IL-10
Expression and sensing of IL-10 by TH2 cells has been shown to be receptor β-subunits (IL-10Rβ), that are commonly shared by all mem-
important in mice in vivo and in vitro [27,28]. In a mouse model for bers of the IL-10 cytokine family [55,56]. The initiation of IL-10 sig-
pulmonary inflammation IL-10 produced by TH2 cells was described to naling is a two-step process. First, IL-10 binds with a high affinity to the
suppress CD4+ T-cell proliferation and survival in an auto-regulatory IL-10Rα dimer inducing a conformational change. Second, the IL-10Rβ
feedback loop [27]. Consequently, deletion of the IL-10 receptor in TH2 dimer is recruited and forms a tetra-heterodimer that stabilizes the
cells exacerbated TH2-cell driven airway inflammation [27,28]. An- binding of IL-10 and enables intracellular signaling [56]. The Janus-
other source of IL-10 are T helper 1 (TH1) cells, that were originally tyrosine kinases Janus kinase 1 (JAK1) and the protein Tyrosine kinase
described as producing mainly the cytokines IFN-γ and IL-2 [4]. Indeed, 2 (TYK2), that are constitutively associated with IL-10Rα and IL-10Rβ,
CD4+ T cells co-producing IFN-γ and IL-10 were observed in various respectively, phosphorylate the IL-10Rα subunit [57,58]. This process
bacterial, parasitic and viral infection models (reviewed in [29,30]). allows binding of STAT1, STAT3, and STAT5 (Signal Transducer and
Additionally, IL-10 expression by TH1 cells promoted tissue regenera- Activator of Transcription 1, 3, and 5) to the IL-10Rα subunit and in
tion after spinal cord injury and reduced colitis development [31,32]. turn, induces their phosphorylation and therefore, activation [58,59].
Another pro-inflammatory T helper cell subset, the T helper 17 (TH17) Depending on additional intracellular molecules that can interact with
cells can express their major cytokine IL-17 and additionally, co-pro- the intracellular domain of the IL-10Rα subunit, different protein/
duce IL-10 [33–36]. Interestingly, some of these TH17 cells have even protein-interactions are able to regulate the function of IL-10 to pro-
been described as undergoing conversion in order to adapt to en- mote survival, proliferation, and block the production of pro-in-
vironmental changes [36]. For example, the cells showed regulatory flammatory cytokines, e.g. TNF-α production [60].
functions after a switch from IL-17 to IL-10 production. Thus, TH17
conversion into regulatory cells is a mechanism for TH17 cells to reg- 2.2.2. IL-10 target cells within the innate and adaptive immune system
ulate themselves and consequently, to support gut homeostasis [36]. Antigen-presenting cells (APCs) constitutively express high IL-10
In addition to effector T helper cells, Foxp3+ regulatory T cells receptor levels, that are further upregulated upon activation. Thus, the
(Treg) are an important source of IL-10 in multiple organs such as the general function of IL-10 signaling in APCs is to maintain immune
intestine, lung, skin, and CNS, that control immune homeostasis and homeostasis and to suppress pro-inflammatory immune responses. It is
inflammation via production of IL-10 [8,35,37–39]. It has been shown well-established that IL-10 controls the maturation and function of
mechanistically that IL-10 produced by Foxp3+ Treg promotes their macrophages and dendritic cells (DCs). In both myeloid cell subsets, IL-
own activity via a positive feedback loop and suppresses the pro-in- 10 acts via an autocrine feedback loop leading to the downregulation of
flammatory function of APCs and TH17 cells. In addition, Foxp3+ Treg MHC-II and costimulatory molecules such as CD80 and CD86, reduction
cells which co-produce IL-10 and IL-35 in a CD8+ T cell driven tumor of pro-inflammatory cytokine production and a decrease in their mo-
mouse model have been shown to promote the upregulation of co-in- bility in vitro and in vivo [61–63]. Accordingly, a mouse model of
hibitory receptors LAG-3, PD-1, and TIM-3 on intra-tumoral CD8+ T transfer colitis in which macrophages cannot sense IL-10 were found to
cells and therefore support exhaustion of these cells [23]. develop spontaneous colitis and to be insufficient to control TH17 cell
Besides Foxp3+ Treg, another subpopulation of CD4+ T cell, response [64]. Moreover, during the resolution of inflammation, IL-10
Foxp3− Type 1 regulatory T cells (TR1), produces IL-10. These cells are signaling in macrophages promotes the phagocytosis of apoptotic cells
characterized by combined expression of surface molecules such as in mouse models of peritonitis, LPS-induced lung inflammation, and
LAG-3, PD-1, CTLA-4, TIM-3, TIGIT, CCR5 and CD49b on Foxp3- CD4+ arteriosclerosis [37,65,66]. Similarly, deletion of IL-10 signaling in
T cells [40–44]. Of note, these markers are not exclusively expressed on DCs, results in exaggerated immune responses in murine models of
TR1 cells but are also enriched in others IL-10 producing cells, including bacterial and fungal infection or allergic contact hypersensitivity re-
B cells [45], CD8+ T cells [46] and Foxp3+ Treg cells [47,48]. Con- actions [67–70].
sequently, the use of these surface markers to isolate TR1 cells requires a In contrast to APCs, T cells upregulate the IL-10 receptor after ac-
combination of them [40,49] in addition to an acurate pre-gating on tivation, with the lowest expression on naïve T cells and highest levels
Foxp3- CD4+ T cells as originally mentioned [40,50]. on memory T cells. Consequently, IL-10 sensing impacts the function of
Beside the surface markers, the major characteristic of Tr1 cells is T cells during all phases of inflammation. The predominant T-cell
the capacity to suppress the proliferation of many effector T helper cells subset sensing IL-10 during homeostasis are Foxp3+ Treg. Different
like TH17 or TH1 cells via IL-10 in different models of inflammation mouse models of colitis in which Foxp3+ Treg cannot sense or produce
[35,49,51]. In addition, IL-10 produced by TR1 cells is also important to IL-10 have shown that a positive IL-10 feedback loop in these cells is
maintain the suppressive function and stability of TR1 cells via a posi- essential to control their stability and suppressive function during
tive feedback loop [7]. This process can be further supported by CD4+ homeostasis and intestinal inflammation [8,71,72]. In addition to its
T cell-derived IL-21. On the one hand, it promotes IL-10 production and effect on to the stability of Foxp3+ Treg, IL-10 also promotes stability
on the other hand, it suppresses the induction of T-bet expression and function of TR1 cells [7]. During inflammation IL-10 also directly
[52–54]. In conclusion, T cells are an important source and target cell controls the effector function of CD4+ T cells. In this process, particu-
for IL-10 to ensure an appropriate response to pathogens and to mediate larly IL-10 signaling in pro-inflammatory TH17 cells has been shown to
homeostasis. be important to restrict colitis development [35]. In keeping with stu-
dies using colitis models, IL-10 signaling in TH17 cells has also been
shown to be essential to restrict TH17 cell mediated nephritis and ar-
thritis [73,74].

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

Also CD8+ T cells respond to IL-10. However, the role of IL-10 in responses in different tumor types [92]. In addition, a recent preclinical
regulating CD8+ T cells is more heterogenous. Thus, expression of high study using an “armed” antibody has shown that IL-10 fused to anti-
IL-10 receptor levels on intra-tumoral CD8+ T cells induces IL-10- EGFR effectively induced CD8+ T cell-mediated tumor rejection [93].
mediated concomitant phosphorylation of STAT3 and STAT1 and in Besides treatment with IL-10 itself or as a modified protein, other
turn, enables them to release IFN-γ and Granzymes/Perforin [14,75]. In clinical trials aim to prevent immunopathology by transfer of sup-
accordance, IL-10 stimulates the cytotoxic function of CD8+ T cells pressive, IL-10 producing cells. Several clinical studies investigating the
facilitating the virus clearance in mouse models of lymphocytic chor- safety and effectiveness of TR1 therapy in Graft-versus-host disease,
iomeningitis virus infection (LCMV) (as reviewed in [29]). Of note, in kidney transplantation and Crohn’s disease are currently ongoing [50].
the same mouse model IL-10 produced by Foxp3+ Treg is essential to Mild yet promising improvements in disease progression due to the TR1
induce the development of a long-lived CD8+ T cell memory and to therapy show the potential for an IL-10 therapy by transferring not the
reduce the T cell receptor (TCR)-antigen-sensitivity of these cells during protein but rather the producing cell. However, further understanding
chronic infection [76–78]. of the biology of TR1 cells is key to develop an effective and safe ap-
Overall, these studies underline the anti- and pro-inflammatory proach.
properties of IL-10. Therefore, a tight control is necessary to maintain Overall, these new IL-10 targeting strategies are promising tools to
the delicate balance of IL-10´s versatile function. improve the therapeutic benefit of IL-10 in autoimmunity, cancer and
chronic infection. However, in order to achieve this goal, it will be
3. Therapeutic potential of IL-10 indispensable to better understand the versatile nature of IL-10. In the
following section we want to propose two concepts that could help to
Given its role as an important cytokine with anti- and pro-in- better understand the factors that affect the dual function of IL-10.
flammatory properties, IL-10 has been tested in several clinical trials for
the treatment of autoimmune diseases and cancer. For example, re- 4. Factors that shape the dual function of IL-10
combinant human (rhu) IL-10 has been tested for the treatment of in-
flammatory bowel disease (IBD) in several clinical studies. Not only do First, we will discuss the recently observed heterogeneity in IL-10
Il10−/− mice develop spontaneous colitis [79], but also in humans, producing CD4+ T cells for the dual function of IL-10 (summarized in
mutations and single nucleotide polymorphisms (SNPs) in IL10 and Fig. 1). Despite its source, additional factors may promote the IL-10´s
IL10RA/IL10RB genes are associated with the development of juvenile versatile nature, such as its target cells and the signal strength of IL-10.
and adult IBD [12,80–82]. Overall, these findings propose IL-10 as a Second, we will discuss the impact of these factors on the function of IL-
valuable target for the treatment of IBD. However, contrary to the ex- 10 (summarized in Graphical Table 1).
pectations, administration of rhuIL-10 did not result in a significant
clinical improvement, but its efficacy was rather heterogenous between
4.1. CD4+ T cell intrinsic factors shape the function of IL-10
patients. Although the patient-to-patient difference was high, it can be
summarized, that the beneficial effect of rhuIL-10 was higher in pa-
4.1.1. Heterogeneity of IL-10 producing CD4+ T cells
tients with high disease activity and low endogenous IL-10 serum levels
Originally, CD4+ T cell subsets have been classified according to the
compared to patients with low disease activity and high IL-10 levels. In
expression of signature cytokines: IFN-γ characterizes TH1 cells, while
addition, low to moderate doses of rhuIL-10 administration resulted in
a clinical improvement, whereas systemic administration of high rhIL-
10 doses was associated with increased serum levels of pro-in-
flammatory cytokines and promoted disease progression [83–85].
These studies suggest that the degree of inflammation and the IL-10
dosage are factors that determine the clinical benefit of rhuIL-10. Thus,
the lack of a broad efficacy may be due to insufficient suppression of
effector CD4+ T cells such as TH17 cells in patients with high disease
activity. Moreover, this lack of efficacy may be further promoted by IL-
10´s capacity to induce the systemic production of pro-inflammatory
cytokines such as IFN-γ or TNF-α and to activate CD8+ T cells at high
dosages.
Recombinant huIL-10 has also been suggested for the treatment of
other autoimmune diseases. However, in accordance with the IBD
clinical studies, a subcutaneous application of rhuIL-10 to psoriasis
patients only slightly improved skin inflammation [86,87]. Indeed,
increased IL-10 levels resulted in increased NK and B cell activation and
function. Likewise, the efficacy of rhuIL-10 treatment was also poor in
rheumatic arthritis (RA), Multiple Sclerosis (MS) and Type-1 diabetes
(T1D)(as reviewed in [88]). More recently, clinical studies are ongoing
to improve the beneficial effect of IL-10. For example, “armed” anti-
bodies have been developed, that allow specific binding and IL-10 de-
livery to the target-cell of interest. Ongoing clinical studies using De-
Fig. 1. CD4+ T cell intrinsic factors shape the function of IL-10.
kavil (IL-10 fused to anti-EDA (fibronectin) variable chain) for the IL-10+ CD4+ T cells can either promote inflammation or act suppressive.
treatment of RA and IBD are promising [89,90]. CD40L on IL-10 producing CD4+ T cells can support B cell help and thereby
In addition to its expected anti-inflammatory properties in auto- increase inflammation. In contrast, highly suppressive IL-10+ CD4+ T cells are
immune diseases, IL-10´s ability to promote pro-inflammatory CD8+ T characterized by the secretion of IFNγ, granzymes and perforins, the expression
cell activity has been tested in clinical trials for cancer treatment. In of a variety of co-inhibitory receptors (LAG-3,TIM-3, PD-1, CTLA-4, TIGIT),
preclinical murine cancer models administration of muPEG-IL-10 re- integrins (CD49b), and the chemokine receptor CCR5. Important transcriptional
sulted in tumor shrinkage and rejection [14,75,91]. Moreover, in initial regulators of these factors are Eomes, Egr2 and LXR. Which additional factors
dose-escalation studies, huPEG-IL-10 (pegilodecakin) alone or in com- may drive inflammation or contribute to the suppressive capacity and their
bination with chemotherapy or anti-PD-1 blockade induced anti-tumor transcriptional regulators still need further investigation.

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

Table 1 microenvironment or cellular origin plays in order to generate and

The interplay of several factors determines the function of IL-10. maintain either suppressive or effector function of IL-10+ CD4+ T cells.
It remains unclear whether the subsets within the IL-10+ population
are stable or able to differentiate into each other and which particular
molecular mechanism controls this.
Considering all of this, IL-10 expression is not sufficient to identify
TR1 cells, which are by definition suppressive cells. Additionally,
functional differences within the IL-10+ CD4+ T cell population
highlight the importance of other factors acting in conjunction with IL-
10. In the following sections we will discuss these other factors and
their underlying molecular mechanisms.

4.1.2. Interplay of factors important for the anti-inflammatory function of

IL-10+ CD4+ T cells
The signature of highly suppressive IL-10+ CD4+ T cells includes
co-inhibitory receptors such as LAG-3, CTLA-4, PD-1 and TIM-3, the
cytokine IFN-γ and the cytotoxic molecule granzyme B [49]. Cytotoxic/
cytolytic molecules have been described in regulatory T cells and re-
IL-17A-F identifies TH17 cells [25]. This simplified view on CD4+ T present one mechanism of suppression [102–104]. However, the func-
helper subsets always ignores the known fact that signature -cytokines tion of IFN-γ expressed from regulatory cells is more unclear. In gen-
can be co-expressed [25]. This suggested a certain degree of hetero- eral, IFN-γ is reported to promote a pro-inflammatory response
geneity at the beginning of the study of the CD4+ T cell subsets. In the (reviewed in [1,29,105]). However, few reports describe a suppressive
last years, novel technologies such as single-cell-sequencing or CyTOF function of IFN-γ via restriction of intestinal epithelial cell proliferation
have highlighted again the heterogeneity of CD4+ T cell subsets, which [106] or induction of PD-L1 on neutrophils, which in turn, suppress T
is now clearly visualized by using techniques for dimensionality re- cells via the PD1-PDL1 axis [107]. Therefore, IFN-γ and IL-10 might
duction such as tSNE plots [94–96]. play a cooperative role in immunosuppression. However, whether IFN-γ
Foxp3+ Treg cells have been subdivided according to their ex- promotes or suppresses inflammation dependent on the context is not
pression of surface markers, but also cytokine production (reviewed in clear.
[97,98]). In human Foxp3+ Treg cells, CD45RA expression can be used Co-inhibitory receptors are mostly reported as markers of T cell
to distinguish functionally different subsets [99]. CD45RA is expressed exhaustion in the context of tumors or chronic viral infection
by naïve CD4+ T cells and characterizes a population of resting Treg [108–110]. However, also highly activated T effector cells undergoing
cells with only low expression of Foxp3. These resting T cells can, upon proliferation and secreting cytokines do express co-inhibitory receptors
activation, lose expression of CD45RA, while further increasing the [92,111–114]. It seems plausible that co-inhibitory receptors may
expression level of Foxp3 (CD45RA−Foxp3hi). Subsequently, they control T cell stability by restricting e.g. proliferation. Increased sta-
suppress effector T cell proliferation. In contrast, CD45RA−Foxp3lo bility of TR1 cells could in turn, promote immune suppression. Indeed,
CD4+ T cells are not able to suppress. Additionally, IL-10 and IL-35 the co-inhibitory receptor LAG-3 represses Foxp3+ CD4+ T cell pro-
producing murine Treg cells are reported to represent distinct subsets liferation, but it also represses their suppressive function [47]. In con-
exerting complementary functions [23,100]. Single- cell RNA sequen- trast, Foxp3+ CD4+ T cells lacking the co-inhibitory receptor CTLA-4
cing showed transcriptional changes in Treg cells during the transition are not able to dampen the immune response, because CTLA-4 re-
from lymphoid tissue Treg to non-lymphoid tissue Treg [101] and presents an essential mechanism of suppression [115]. Consequently,
further adaptation to the respective non-lymphoid tissues [95]. How- for TR1 cells, co-inhibitory receptors may (I) be a direct mechanism of
ever, functional diversity within the Foxp3+ IL-10+ Treg has not yet suppression like CTLA-4 in Treg cells or (II) stabilize and maintain their
been described. identity, thereby indirectly promoting immune suppression.
In contrast, functional differences of IL-10+ Foxp3− CD4+ T cells In addition, TR1 cells efficiently suppress B cell response in healthy
were observed across different tissues [49]. IL-10+ CD4+ T cells from humans although they express IL-10, which usually promotes B cell
the inflamed small intestine of mice treated with an αCD3 monoclonal survival, proliferation and antibody secretion, since they do not express
antibody consist predominantly of suppressive cells. However, IL-10+ CD40 L [41]. This suggests, that the capacity of IL-10+ CD4+ T cells to
CD4+ T cells from the same mouse but a different tissue, i.e. the spleen, suppress B cell response, or vice versa to provide B cell help is depen-
caused colitis upon transfer in lymphopenic hosts. Apart from these dent on the presence or absence of CD40/CD40 L interaction.
functional differences, the IL-10+ CD4+ T cell populations in small In short, what remains unclear is whether a specific factor or rather
intestine and spleen mainly differed in their heterogeneity. While IL- a combination of factors are required in conjunction with IL-10 in order
10+ CD4+ T cells in the small intestine expressed to a large extent co- to act suppressive. One hypothesis is that the suppression mechanisms
inhibitory receptors, splenic IL-10+ CD4+ T cells were more hetero- by TR1 cells are diverse and one can compensate for each other as al-
geneous and only a small fraction shared the signature of intestinal IL- ready observed in Foxp3+ CD4+ T cells [116–119]. Another aspect
10+ CD4+ T cells, i.e. expression of co-inhibitory receptors. Once en- might be the “concentration”/expression level of the respective factors
riched for the expression of co-inhibitory receptors, also IL-10+ CD4+ T (see section 4.2.2).
cells isolated from the spleen were able to suppress T effector cells [49].
Especially regarding the clinical application of TR1 cells it is im- 4.1.3. Molecular mechanisms controlling the suppressive function of TR1
portant to ensure a stable anti-inflammatory function. One solution is cells
the selection of IL-10+ CD4+ T cells expressing co-inhibitory receptors. A deeper understanding of the molecular mechanism controlling the
The co-expression of a variety of co-inhibitory receptors was shown to identity of TR1 cells is critical for future therapeutic approaches aiming
be a characteristic of mouse and human TR1 cells [40–44]. Still, the pro- to convert CD4+ T effector cells into suppressive cells. The regulation of
inflammatory acting IL-10+ CD4+ T cell population is not yet char- IL-10 expression has been and still is a topic of intense research. While
acterized. Further characterization of these cells might allow another Blimp1, c-Maf, Ahr, Nfil3 and EGR2 are known for many years to
therapeutic approach by either their depletion or even conversion into control IL-10 expression [52,53,120–122], recently IRF1, IRF4, BATF,
TR1 cells. Additionally, it remains unknown which role the tissue/ Eomes and Bhlhe40 have also been described to play an important

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

function in IL-10 regulation in T cells [123–129]. The role of Eomes is of effector CD4+ T cells that in turn, exacerbate CNS inflammation.
further outlined in this collection. Still a regulatory network of TR1 cells However, the cellular and molecular mechanisms fully explaining this
is not yet finally defined. As discussed above, the suppressive function interesting observation remain to be elusive.
of TR1 cells goes beyond IL-10. Therefore, transcriptional regulators for Overall, these studies show that two factors determining the func-
the additional factors (e.g. co-inhibitory receptors and granzymes) will tion of IL-10 are its target cell population and also the immune response
be important to fully understand the molecular mechanism by which phase. However, further investigations are required to understand
TR1 cells are controlled and stabilized. Highly suppressive IL-10-pro- under which circumstances IL-10 promotes pro-inflammatory or anti-
ducing CD4+ T cells are characterized by the co-expression of diverse inflammatory signals in the same target cells e.g. CD8+ T cells, TH1,
co-inhibitory receptors [40,49], which might contribute to immune and TH17 cells. Furthermore, it remains to be elusive whether the cel-
suppression and/or improve the stability of these cells. Analyzing lular source of IL-10 and the availability of co-factors such as other
tumor-infiltrating lymphocytes in mouse melanomas, Chihara et al. cytokines may affect the dual function of IL-10.
identified Blimp1 and c-Maf as transcriptional regulators of the ‘co-in-
hibitory module’ on CD4+ and CD8+ T cells [130]. Thus, c-Maf and 4.2.2. The versatility of IL-10 depends on the target cell population
Blimp-1 are obvious candidates controlling the identity of TR1 cells. Another factor that may determine whether IL-10 suppresses or
However, the expression of IL-10 was not analyzed in this study, so a rather promotes inflammation could be its local availability. Thus, in
final conclusion about the role of Blimp-1 and c-Maf in TR1 cells cannot vivo IL-10 tolerance tests in healthy volunteers revealed that adminis-
be drawn. tration of high, but not low doses of rhuIL-10 induced cytotoxic CD8+
Besides the expression of co-inhibitory receptors, also cytotoxic T-cell activation in addition to the suppression of APCs and CD4+ T cell
molecules (e.g. granzymes and perforins) and IFNγ expression char- activation under the condition of LPS-induced endotoxemia [136]. This
acterize suppressive IL-10+ CD4+ T cells. Recently, it was shown, that study suggests that the dual function of IL-10 is not solely dependent on
the transcription factor Eomes not only controls the expression of the target cells, but also the signal strength induced in these cells.
granzymes and IFNγ of NK and CD8+ T cells, but also of human IL-10+ Thereby, APCs and CD4+ T cells may be controlled in the presence of
CD4+ T cells [126,131], suggesting an important role of this tran- low and high IL-10 levels whereas CD8+ T cells need a strong IL-10
scription factor for TR1 cells. signal for their activation.
Another candidate is LXR (liver X factor), which connects the Preclinical murine cancer models are helpful to better understand
transcriptional network and cell metabolism. Adoptively transferred the possible mechanisms involved in this dose-dependent promotion of
Lxra−/− CD4+ T cells showed an increased capacity to express IL-10 CD8+ T cell-mediated transient inflammation. Administration of
upon activation via αCD3 monoclonal antibody while the frequency of muPEG-IL-10, IL-10-coupled “armed” antibodies which specifically
cells with the signature for TR1 cells, i.e. expression of co-inhibitory deliver IL-10 to target cells, and overexpression of IL-10 by tumor cells
receptors was reduced [49]. Thus, LXR might contribute in controlling have constantly shown protective anti-tumor effects [75,91,93,137]. In
the identity of TR1 cells beyond the expression of IL-10. these models, high doses of intra-tumoral IL-10 induced local activation
In conclusion, there are major challenges for the dissection of the of CD8+ T cells and simultaneously suppressed the activation of APCs.
transcriptional network controlling function and stability of TR1 cells. In contrast, a recent study of Sawant et al. revealed that endogenous IL-
These include the complexity of the IL-10 regulatory network and the 10 levels produced by tumor-infiltrating Foxp3+ Treg were not suffi-
fact that the important factors for the suppressive capacity and their cient to promote anti-tumoral CD8+ T cell cytotoxicity but rather drove
transcriptional regulators are not yet fully defined. the exhaustion of these cells [23]. Of note, endogenous IL-10 levels
were still sufficient to suppress APC and CD4+ T cell activation in this
4.2. Environmental factors shape the function of IL-10 model [138].
Taking these preclinical cancer models into account, it is tempting
4.2.1. The concentration of IL-10 shapes its function in T cells to speculate that the lack of efficacy of rhuIL-10 treatment of patients
The predominant role of IL-10 is to maintain immune homeostasis. with high disease activity in IBD and MS may be due to the potential of
The main drivers of these processes are APCs and Foxp3+ Treg, that IL-10 to promote CD8+ T cell activation and thereby counterbalance
control effector T-cell activation, at least in part, via an autocrine IL-10 the IL-10-mediated suppression of the pro-inflammatory function of
feedback-loop. For example, specific deletion of the IL-10Rα subunit in APC and CD4+ cells. This consideration is further indicated by the
CX3CR1+ macrophages and Foxp3+ Treg results in reduced IL-10 observation that auto-reactive CD8+ T cells were able to promote in-
production and the development of spontaneous colitis [8,37]. testinal and neuronal inflammation in preclinical mouse models
During inflammation the role of IL-10 signaling is more complex. [139–141].
First, it is well-established that IL-10 produced by Foxp3+ Treg and TR1 Overall, these studies suggest that one factor responsible for the
cells directly suppresses pro-inflammatory TH17 cell responses in au- versatile function of IL-10 is the strength of its signal. A strong IL-10
toimmunity [35,38,73,74,132,133]. Second, IL-10 can promote the signal seems to promote CD8+ T-cell cytotoxicity, whereas a lower
exacerbation of immune responses via the induction of B cell pro- strength rather drives the exhaustion and memory-development of
liferation, survival and antibody production during autoimmunity, e.g. CD8+ T cells during chronic viral inflammation or resolution, as de-
in systemic lupus erythematodes (SLE) and RA [63,134]. In line with scribed above. In contrast, low IL-10 signals in APCs and CD4+ T cells
this pro-inflammatory function, IL-10 also promotes the cytotoxic ac- seem to be sufficient to control these cells. However, further in-
tivity of CD8+ T cells and the establishment of a long-lived CD8+ T cell vestigations will be essential to test this hypothesis and to obtain a
memory during the resolution phase of LMCV infection [76]. Third, IL- deeper understanding of how the IL-10 signal strength differentially
10 has been shown to reduce the antigen-sensitivity of CD8+ T cells via regulated the activation of CD4+ and CD8+ T cells. Furthermore, it
induction of N-glycan branching on glycoproteins including the T cell remains to be elucidated whether co-factors such as other cytokines or
receptor (TCR) during chronic viral infection [78]. Thus, IL-10 may also co-stimulatory signals may be able to fine-tune the IL-10 signal strength
promote exhaustion of CD8+ T cells under less inflammatory condi- in a cell and context-dependent manner.
tions.
In addition to these versatile properties of IL-10 during inflamma- 5. Conclusions
tion, T-cell specific deletion of the IL-10 signaling has been shown to
decrease neuronal inflammation in EAE. This process was associated IL-10 is a pleiotropic cytokine with anti-inflammatory and pro-in-
with an overall reduction of accumulating Foxp3neg CD4+ T effector flammatory properties. These dual effects might be due to the IL-10
cells in the CNS [135], suggesting that IL-10 may promote the survival producer, the target cell, the available IL-10 levels, and the

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

microenvironmental co-factors, such as other cytokines. While IL-10 interleukin-10 promoter polymorphisms with systemic lupus erythematosus,
predominantly controls the activation and migration of APCs and Genes Immun. 5 (6) (2004) 484–492.
[10] M.M. Fathy, H.F. Elsaadany, Y.F. Ali, M.A. Farghaly, M.E. Hamed, H.E. Ibrahim,
Foxp3+ Treg during homeostasis, its function during inflammation is M.A. Noah, M.A. Allah, S.S. Elashkar, N.I. Abdelsalam, H.M. Abdelrahman,
much more versatile. On the one hand, IL-10 produced by Foxp3+ Treg A.R. Ahmed, H.G. Anany, S.M. Ismail, B.R. Ibrahim, N.M. Al Azizi, H.H. Gawish,
and TR1 cells has been demonstrated to suppress pro-inflammatory G.M. Al-Akad, R.M. Nabil, D.S. Fahmy, S.F. Alsayed, Association of IL-10 gene
polymorphisms and susceptibility to Juvenile Idiopathic Arthritis in Egyptian
CD4+ T cell responses in different disease models and organs. On the children and adolescents: a case-control study, Ital. J. Pediatr. 43 (1) (2017) 9.
other hand, IL-10 is also known to promote pro-inflammatory B cells [11] B. Ying, Y. Shi, X. Pan, X. Song, Z. Huang, Q. Niu, B. Cai, L. Wang, Association of
and of CD8+ T cell function in different autoimmunity, infection, and polymorphisms in the human IL-10 and IL-18 genes with rheumatoid arthritis,
Mol. Biol. Rep. 38 (1) (2011) 379–385.
cancer models. In addition, during the resolution phase of infection, IL- [12] K.R. Engelhardt, B. Grimbacher, IL-10 in humans: lessons from the gut, IL-10/IL-
10 produced by Foxp3+ Treg and APCs supports the memory formation 10 receptor deficiencies, and IL-10 polymorphisms, Curr. Top. Microbiol.
of CD8+ T cells and the elimination of apoptotic cells by macrophages. Immunol. 380 (2014) 1–18.
[13] K.E. Foulds, M.J. Rotte, R.A. Seder, IL-10 is required for optimal CD8 T cell
However, how these versatile functions of IL-10 are regulated re-
memory following Listeria monocytogenes infection, J. Immunol. 177 (4) (2006)
mains poorly understood. As discussed, a context-dependent combina- 2565–2574.
tion of several factors, such as the cellular source, the type of cells re- [14] J.B. Mumm, J. Emmerich, X. Zhang, I. Chan, L. Wu, S. Mauze, S. Blaisdell,
sponding to IL-10, and the tissue microenvironment are involved. Thus, B. Basham, J. Dai, J. Grein, C. Sheppard, K. Hong, C. Cutler, S. Turner, D. LaFace,
M. Kleinschek, M. Judo, G. Ayanoglu, J. Langowski, D. Gu, B. Paporello,
despite the well-established role of IL-10 produced by Foxp3+ Treg to E. Murphy, V. Sriram, S. Naravula, B. Desai, S. Medicherla, W. Seghezzi,
suppress CD4+ T cell activity, IL-10 production by Foxp3− CD4+ T T. McClanahan, S. Cannon-Carlson, A.M. Beebe, M. Oft, IL-10 elicits IFNgamma-
cells on its own is insufficient to fulfill an anti-inflammatory function. dependent tumor immune surveillance, Cancer Cell 20 (6) (2011) 781–796.
[15] S. Fujii, K. Shimizu, T. Shimizu, M.T. Lotze, Interleukin-10 promotes the main-
Further expression of co-inhibitory receptors such as LAG-3, CTLA-4, tenance of antitumor CD8(+) T-cell effector function in situ, Blood 98 (7) (2001)
PD-1 and TIM-3 is essential to gain the full suppressive function. 2143–2151.
However, under which conditions TR1 cells upregulate co-inhibitory [16] Y. Levy, J.C. Brouet, Interleukin-10 prevents spontaneous death of germinal center
B cells by induction of the bcl-2 protein, J. Clin. Invest. 93 (1) (1994) 424–428.
receptors and whether they contribute to the suppressive capacity or to [17] G. Xin, R. Zander, D.M. Schauder, Y. Chen, J.S. Weinstein, W.R. Drobyski,
the stability of these cells remains to be fully elucidated. Another reg- V. Tarakanova, J. Craft, W. Cui, Single-cell RNA sequencing unveils an IL-10-
ulator of the IL-10 function may be the IL-10 signal strength in the producing helper subset that sustains humoral immunity during persistent infec-
tion, Nat. Commun. 9 (1) (2018) 5037.
target cells: high intra-tumoral IL-10 levels promote the CD8+ T cell [18] M.A. Boks, J.R. Kager-Groenland, M.S. Haasjes, J.J. Zwaginga, S.M. van Ham, A.
cytotoxicity, whereas endogenous IL-10 levels induce exhaustion of Ten Brinke, IL-10-generated tolerogenic dendritic cells are optimal for functional
intra-tumoral CD8+ T cells. However, it remains unclear whether the regulatory T cell induction–a comparative study of human clinical-applicable DC,
Clin. Immunol. 142 (3) (2012) 332–342.
IL-10 signal strength promotes this dual effect on CD8+ T cells alone, or
[19] T. De Smedt, M. Van Mechelen, G. De Becker, J. Urbain, O. Leo, M. Moser, Effect of
whether it does so in combination with other environmental factors interleukin-10 on dendritic cell maturation and function, Eur. J. Immunol. 27 (5)
such as co-stimulatory molecules or cytokines. Clarifying these concepts (1997) 1229–1235.
warrants further attention. [20] S. Schulke, Induction of Interleukin-10 producing dendritic cells As a tool to
suppress allergen-specific t helper 2 responses, Front. Immunol. 9 (2018) 455.
[21] S. Avdic, B.P. McSharry, B. Slobedman, Modulation of dendritic cell functions by
6. Funding viral IL-10 encoded by human cytomegalovirus, Front. Microbiol. 5 (2014) 337.
[22] Y. Chuang, M.E. Hung, B.K. Cangelose, J.N. Leonard, Regulation of the IL-10-
driven macrophage phenotype under incoherent stimuli, Innate Immun. 22 (8)
This work was supported by the DFG (HU1714/7-1, HU1714/9-1, (2016) 647–657.
HU1714/10-1 to S.H.) (SFB 1328, SFB 841 to N.G.) and the European [23] D.V. Sawant, H. Yano, M. Chikina, Q. Zhang, M. Liao, C. Liu, D.J. Callahan, Z. Sun,
Research Council (ERC 715271 to N.G.). T. Sun, T. Tabib, A. Pennathur, D.B. Corry, J.D. Luketich, R. Lafyatis, W. Chen,
A.C. Poholek, T.C. Bruno, C.J. Workman, D.A.A. Vignali, Adaptive plasticity of IL-
10(+) and IL-35(+) Treg cells cooperatively promotes tumor T cell exhaustion,
Declaration of Competing Interest Nat. Immunol. 20 (6) (2019) 724–735.
[24] B. Begue, J. Verdier, F. Rieux-Laucat, O. Goulet, A. Morali, D. Canioni, J.P. Hugot,
C. Daussy, V. Verkarre, B. Pigneur, A. Fischer, C. Klein, N. Cerf-Bensussan,
None.
F.M. Ruemmele, Defective IL10 signaling defining a subgroup of patients with
inflammatory bowel disease, Am. J. Gastroenterol. 106 (8) (2011) 1544–1555.
Acknowledgements [25] T.R. Mosmann, H. Cherwinski, M.W. Bond, M.A. Giedlin, R.L. Coffman, Two types
of murine helper T cell clone. I. Definition according to profiles of lymphokine
activities and secreted proteins, J. Immunol. 136 (7) (1986) 2348–2357.
The authors would like to thank Elaine Hussey for proof reading the [26] L.E. Harrington, R.D. Hatton, P.R. Mangan, H. Turner, T.L. Murphy, K.M. Murphy,
manuscript. C.T. Weaver, Interleukin 17-producing CD4+ effector T cells develop via a lineage
distinct from the T helper type 1 and 2 lineages, Nat. Immunol. 6 (11) (2005)
1123–1132.
References [27] S.M. Coomes, Y. Kannan, V.S. Pelly, L.J. Entwistle, R. Guidi, J. Perez-Lloret,
N. Nikolov, W. Muller, M.S. Wilson, CD4(+) Th2 cells are directly regulated by IL-
[1] K.N. Couper, D.G. Blount, E.M. Riley, IL-10: the master regulator of immunity to 10 during allergic airway inflammation, Mucosal Immunol. 10 (1) (2017)
infection, J. Immunol. 180 (9) (2008) 5771–5777. 150–161.
[2] J.L. Mege, S. Meghari, A. Honstettre, C. Capo, D. Raoult, The two faces of inter- [28] A.C. Poholek, D. Jankovic, A.V. Villarino, F. Petermann, A. Hettinga, D.S. Shouval,
leukin 10 in human infectious diseases, Lancet Infect. Dis. 6 (9) (2006) 557–569. S.B. Snapper, S.M. Kaech, S.R. Brooks, G. Vahedi, A. Sher, Y. Kanno, J.J. O’Shea,
[3] M.C. Piazzon, G. Lutfalla, M. Forlenza, IL10, A Tale of an Evolutionarily Conserved IL-10 induces a STAT3-dependent autoregulatory loop in TH2 cells that promotes
Cytokine across Vertebrates, Crit. Rev. Immunol. 36 (2) (2016) 99–129. Blimp-1 restriction of cell expansion via antagonism of STAT5 target genes, Sci.
[4] T.R. Mosmann, K.W. Moore, The role of IL-10 in crossregulation of TH1 and TH2 Immunol. 1 (5) (2016).
responses, Immunol. Today 12 (3) (1991) A49–53. [29] J.M. Rojas, M. Avia, V. Martin, N. Sevilla, IL-10: A Multifunctional Cytokine in
[5] D.F. Fiorentino, M.W. Bond, T.R. Mosmann, Two types of mouse T helper cell. IV. Viral Infections, J. Immunol. Res. 2017 (2017) 6104054.
Th2 clones secrete a factor that inhibits cytokine production by Th1 clones, J. Exp. [30] H.F. Penaloza, B.M. Schultz, P.A. Nieto, G.A. Salazar, I. Suazo, P.A. Gonzalez,
Med. 170 (6) (1989) 2081–2095. C.A. Riedel, M.M. Alvarez-Lobos, A.M. Kalergis, S.M. Bueno, Opposing roles of IL-
[6] A. O’Garra, P. Vieira, T(H)1 cells control themselves by producing interleukin-10, 10 in acute bacterial infection, Cytokine Growth Factor Rev. 32 (2016) 17–30.
Nat. Rev. Immunol. 7 (6) (2007) 425–428. [31] H. Ishii, S. Tanabe, M. Ueno, T. Kubo, H. Kayama, S. Serada, M. Fujimoto,
[7] L. Brockmann, N. Gagliani, B. Steglich, A.D. Giannou, J. Kempski, P. Pelczar, K. Takeda, T. Naka, T. Yamashita, Ifn-gamma-dependent secretion of IL-10 from
M. Geffken, B. Mfarrej, F. Huber, J. Herkel, Y.Y. Wan, E. Esplugues, M. Battaglia, Th1 cells and microglia/macrophages contributes to functional recovery after
C.F. Krebs, R.A. Flavell, S. Huber, IL-10 receptor signaling is essential for TR1 cell spinal cord injury, Cell Death Dis. 4 (2013) e710.
function in vivo, J. Immunol. 198 (3) (2017) 1130–1141. [32] M. Sun, W. Wu, L. Chen, W. Yang, X. Huang, C. Ma, F. Chen, Y. Xiao, Y. Zhao,
[8] A. Chaudhry, R.M. Samstein, P. Treuting, Y. Liang, M.C. Pils, J.M. Heinrich, C. Ma, S. Yao, V.H. Carpio, S.M. Dann, Q. Zhao, Z. Liu, Y. Cong, Microbiota-de-
R.S. Jack, F.T. Wunderlich, J.C. Bruning, W. Muller, A.Y. Rudensky, Interleukin-10 rived short-chain fatty acids promote Th1 cell IL-10 production to maintain in-
signaling in regulatory T cells is required for suppression of Th17 cell-mediated testinal homeostasis, Nat. Commun. 9 (1) (2018) 3555.
inflammation, Immunity 34 (4) (2011) 566–578. [33] E. Esplugues, S. Huber, N. Gagliani, A.E. Hauser, T. Town, Y.Y. Wan, W. O’Connor
[9] W.P. Chong, W.K. Ip, W.H. Wong, C.S. Lau, T.M. Chan, Y.L. Lau, Association of Jr, A. Rongvaux, N. Van Rooijen, A.M. Haberman, Y. Iwakura, V.K. Kuchroo,

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

J.K. Kolls, J.A. Bluestone, K.C. Herold, R.A. Flavell, Control of TH17 cells occurs in regulatory T cells modulates parasite clearance and pathology during malaria
the small intestine, Nature 475 (7357) (2011) 514–518. infection, PLoS Pathog. 4 (2) (2008) e1000004.
[34] M.J. McGeachy, K.S. Bak-Jensen, Y. Chen, C.M. Tato, W. Blumenschein, [52] C. Pot, H. Jin, A. Awasthi, S.M. Liu, C.Y. Lai, R. Madan, A.H. Sharpe, C.L. Karp,
T. McClanahan, D.J. Cua, TGF-beta and IL-6 drive the production of IL-17 and IL- S.C. Miaw, I.C. Ho, V.K. Kuchroo, Cutting edge: IL-27 induces the transcription
10 by T cells and restrain T(H)-17 cell-mediated pathology, Nat. Immunol. 8 (12) factor c-Maf, cytokine IL-21, and the costimulatory receptor ICOS that co-
(2007) 1390–1397. ordinately act together to promote differentiation of IL-10-producing Tr1 cells, J.
[35] S. Huber, N. Gagliani, E. Esplugues, W. O’Connor Jr, F.J. Huber, A. Chaudhry, Immunol. 183 (2) (2009) 797–801.
M. Kamanaka, Y. Kobayashi, C.J. Booth, A.Y. Rudensky, M.G. Roncarolo, [53] L. Apetoh, F.J. Quintana, C. Pot, N. Joller, S. Xiao, D. Kumar, E.J. Burns,
M. Battaglia, R.A. Flavell, Th17 cells express interleukin-10 receptor and are D.H. Sherr, H.L. Weiner, V.K. Kuchroo, The aryl hydrocarbon receptor interacts
controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10- with c-Maf to promote the differentiation of type 1 regulatory T cells induced by
dependent manner, Immunity 34 (4) (2011) 554–565. IL-27, Nat. Immunol. 11 (9) (2010) 854–861.
[36] N. Gagliani, M.C. Amezcua Vesely, A. Iseppon, L. Brockmann, H. Xu, N.W. Palm, [54] I. Kastirr, S. Maglie, M. Paroni, J.S. Alfen, G. Nizzoli, E. Sugliano, M.C. Crosti,
M.R. de Zoete, P. Licona-Limon, R.S. Paiva, T. Ching, C. Weaver, X. Zi, X. Pan, M. Moro, B. Steckel, S. Steinfelder, K. Stolzel, C. Romagnani, F. Botti, F. Caprioli,
R. Fan, L.X. Garmire, M.J. Cotton, Y. Drier, B. Bernstein, J. Geginat, B. Stockinger, M. Pagani, S. Abrignani, J. Geginat, IL-21 is a central memory T cell-associated
E. Esplugues, S. Huber, R.A. Flavell, Th17 cells transdifferentiate into regulatory T cytokine that inhibits the generation of pathogenic Th1/17 effector cells, J.
cells during resolution of inflammation, Nature 523 (7559) (2015) 221–225. Immunol. 193 (7) (2014) 3322–3331.
[37] E. Zigmond, B. Bernshtein, G. Friedlander, C.R. Walker, S. Yona, K.W. Kim, [55] S.V. Kotenko, C.D. Krause, L.S. Izotova, B.P. Pollack, W. Wu, S. Pestka,
O. Brenner, R. Krauthgamer, C. Varol, W. Muller, S. Jung, Macrophage-restricted Identification and functional characterization of a second chain of the interleukin-
interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spon- 10 receptor complex, EMBO J. 16 (19) (1997) 5894–5903.
taneous colitis, Immunity 40 (5) (2014) 720–733. [56] R.P. Donnelly, F. Sheikh, S.V. Kotenko, H. Dickensheets, The expanded family of
[38] D.J. Mekala, R.S. Alli, T.L. Geiger, IL-10-dependent infectious tolerance after the class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain, J. Leukoc. Biol.
treatment of experimental allergic encephalomyelitis with redirected 76 (2) (2004) 314–321.
CD4+CD25+ T lymphocytes, Proc. Natl. Acad. Sci. U. S. A. 102 (33) (2005) [57] D.S. Finbloom, K.D. Winestock, IL-10 induces the tyrosine phosphorylation of tyk2
11817–11822. and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in
[39] P. Yu, R.K. Gregg, J.J. Bell, J.S. Ellis, R. Divekar, H.H. Lee, R. Jain, H. Waldner, human T cells and monocytes, J. Immunol. 155 (3) (1995) 1079–1090.
J.C. Hardaway, M. Collins, V.K. Kuchroo, H. Zaghouani, Specific T regulatory cells [58] A.S. Ho, S.H. Wei, A.L. Mui, A. Miyajima, K.W. Moore, Functional regions of the
display broad suppressive functions against experimental allergic en- mouse interleukin-10 receptor cytoplasmic domain, Mol. Cell. Biol. 15 (9) (1995)
cephalomyelitis upon activation with cognate antigen, J. Immunol. 174 (11) 5043–5053.
(2005) 6772–6780. [59] J. Wehinger, F. Gouilleux, B. Groner, J. Finke, R. Mertelsmann, R.M. Weber-Nordt,
[40] N. Gagliani, C.F. Magnani, S. Huber, M.E. Gianolini, M. Pala, P. Licona-Limon, IL-10 induces DNA binding activity of three STAT proteins (Stat1, Stat3, and Stat5)
B. Guo, D.R. Herbert, A. Bulfone, F. Trentini, C. Di Serio, R. Bacchetta, and their distinct combinatorial assembly in the promoters of selected genes, FEBS
M. Andreani, L. Brockmann, S. Gregori, R.A. Flavell, M.G. Roncarolo, Lett. 394 (3) (1996) 365–370.
Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type [60] M.R. Walter, The molecular basis of IL-10 function: from receptor structure to the
1 cells, Nat. Med. 19 (6) (2013) 739–746. onset of signaling, Curr. Top. Microbiol. Immunol. 380 (2014) 191–212.
[41] F. Facciotti, N. Gagliani, B. Haringer, J.S. Alfen, A. Penatti, S. Maglie, M. Paroni, [61] X. Xu, X. Liu, J. Long, Z. Hu, Q. Zheng, C. Zhang, L. Li, Y. Wang, Y. Jia, W. Qiu,
A. Iseppon, M. Moro, M.C. Crosti, K. Stolzel, C. Romagnani, G. Moroni, J. Zhou, W. Yao, Z. Zeng, Interleukin-10 reorganizes the cytoskeleton of mature
F. Ingegnoli, S. Torretta, L. Pignataro, A. Annoni, F. Russo, M. Pagani, dendritic cells leading to their impaired biophysical properties and motilities,
S. Abrignani, P. Meroni, R. Flavell, J. Geginat, IL-10-producing forkhead box PLoS One 12 (2) (2017) e0172523.
protein 3-negative regulatory T cells inhibit B-cell responses and are involved in [62] W.K.E. Ip, N. Hoshi, D.S. Shouval, S. Snapper, R. Medzhitov, Anti-inflammatory
systemic lupus erythematosus, J. Allergy Clin. Immunol. 137 (1) (2016) effect of IL-10 mediated by metabolic reprogramming of macrophages, Science
318–321 e5. 356 (6337) (2017) 513–519.
[42] S. Sumitomo, S. Nakachi, T. Okamura, Y. Tsuchida, R. Kato, H. Shoda, [63] K.W. Moore, R. de Waal Malefyt, R.L. Coffman, A. O’Garra, Interleukin-10 and the
A. Furukawa, N. Kitahara, K. Kondo, T. Yamasoba, K. Yamamoto, K. Fujio, interleukin-10 receptor, Annu. Rev. Immunol. 19 (2001) 683–765.
Identification of tonsillar CD4(+)CD25(-)LAG3(+) T cells as naturally occurring [64] B. Li, P. Gurung, R.K. Malireddi, P. Vogel, T.D. Kanneganti, T.L. Geiger, IL-10
IL-10-producing regulatory T cells in human lymphoid tissue, J. Autoimmun. 76 engages macrophages to shift Th17 cytokine dependency and pathogenicity during
(2017) 75–84. T-cell-mediated colitis, Nat. Commun. 6 (2015) 6131.
[43] Y. Yao, J. Vent-Schmidt, M.D. McGeough, M. Wong, H.M. Hoffman, T.S. Steiner, [65] J.D. Proto, A.C. Doran, G. Gusarova, A. Yurdagul Jr, E. Sozen, M. Subramanian,
M.K. Levings, Tr1 cells, but not Foxp3+ regulatory t cells, suppress NLRP3 in- M.N. Islam, C.C. Rymond, J. Du, J. Hook, G. Kuriakose, J. Bhattacharya, I. Tabas,
flammasome activation via an IL-10-Dependent mechanism, J. Immunol. 195 (2) Regulatory t cells promote macrophage efferocytosis during inflammation re-
(2015) 488–497. solution, Immunity 49 (4) (2018) 666–677 e6.
[44] X. Clemente-Casares, J. Blanco, P. Ambalavanan, J. Yamanouchi, S. Singha, [66] D.S. Shouval, A. Biswas, J.A. Goettel, K. McCann, E. Conaway, N.S. Redhu,
C. Fandos, S. Tsai, J. Wang, N. Garabatos, C. Izquierdo, S. Agrawal, M.B. Keough, I.D. Mascanfroni, Z. Al Adham, S. Lavoie, M. Ibourk, D.D. Nguyen, J.N. Samsom,
V.W. Yong, E. James, A. Moore, Y. Yang, T. Stratmann, P. Serra, P. Santamaria, J.C. Escher, R. Somech, B. Weiss, R. Beier, L.S. Conklin, C.L. Ebens, F.G. Santos,
Expanding antigen-specific regulatory networks to treat autoimmunity, Nature A.R. Ferreira, M. Sherlock, A.K. Bhan, W. Muller, J.R. Mora, F.J. Quintana,
530 (7591) (2016) 434–440. C. Klein, A.M. Muise, B.H. Horwitz, S.B. Snapper, Interleukin-10 receptor signaling
[45] A.C. Lino, V.D. Dang, V. Lampropoulou, A. Welle, J. Joedicke, J. Pohar, Q. Simon, in innate immune cells regulates mucosal immune tolerance and anti-in-
J. Thalmensi, A. Baures, V. Fluhler, I. Sakwa, U. Stervbo, S. Ries, L. Jouneau, flammatory macrophage function, Immunity 40 (5) (2014) 706–719.
P. Boudinot, T. Tsubata, T. Adachi, A. Hutloff, T. Dorner, U. Zimber-Strobl, A.F. de [67] C. Demangel, P. Bertolino, W.J. Britton, Autocrine IL-10 impairs dendritic cell
Vos, K. Dahlke, G. Loh, S. Korniotis, C. Goosmann, J.C. Weill, C.A. Reynaud, (DC)-derived immune responses to mycobacterial infection by suppressing DC
S.H.E. Kaufmann, J. Walter, S. Fillatreau, LAG-3 inhibitory receptor expression trafficking to draining lymph nodes and local IL-12 production, Eur. J. Immunol.
identifies immunosuppressive natural regulatory plasma cells, Immunity 49 (1) 32 (4) (2002) 994–1002.
(2018) 120–133 e9. [68] M.C. Pils, F. Pisano, N. Fasnacht, J.M. Heinrich, L. Groebe, A. Schippers, B. Rozell,
[46] D.M. Elizondo, T.E. Andargie, N.L. Haddock, R.L.L. da Silva, T.R. de Moura, R.S. Jack, W. Muller, Monocytes/macrophages and/or neutrophils are the target of
M.W. Lipscomb, IL-10 producing CD8(+) CD122(+) PD-1(+) regulatory T cells IL-10 in the LPS endotoxemia model, Eur. J. Immunol. 40 (2) (2010) 443–448.
are expanded by dendritic cells silenced for Allograft Inflammatory Factor-1, J. [69] S. Teitz-Tennenbaum, S.P. Viglianti, J.A. Roussey, S.M. Levitz, M.A. Olszewski,
Leukoc. Biol. 105 (1) (2019) 123–130. J.J. Osterholzer, Autocrine IL-10 signaling promotes dendritic cell Type-2 acti-
[47] Q. Zhang, M. Chikina, A.L. Szymczak-Workman, W. Horne, J.K. Kolls, vation and persistence of murine cryptococcal lung infection, J. Immunol. 201 (7)
K.M. Vignali, D. Normolle, M. Bettini, C.J. Workman, D.A.A. Vignali, LAG3 limits (2018) 2004–2015.
regulatory T cell proliferation and function in autoimmune diabetes, Sci. Immunol. [70] M.J. Girard-Madoux, J.M. Kel, B. Reizis, B.E. Clausen, IL-10 controls dendritic cell-
2 (9) (2017). induced T-cell reactivation in the skin to limit contact hypersensitivity, J. Allergy
[48] N. Joller, E. Lozano, P.R. Burkett, B. Patel, S. Xiao, C. Zhu, J. Xia, T.G. Tan, Clin. Immunol. 129 (1) (2012) 143–150 e1-10.
E. Sefik, V. Yajnik, A.H. Sharpe, F.J. Quintana, D. Mathis, C. Benoist, D.A. Hafler, [71] M. Murai, O. Turovskaya, G. Kim, R. Madan, C.L. Karp, H. Cheroutre,
V.K. Kuchroo, Treg cells expressing the coinhibitory molecule TIGIT selectively M. Kronenberg, Interleukin 10 acts on regulatory T cells to maintain expression of
inhibit proinflammatory Th1 and Th17 cell responses, Immunity 40 (4) (2014) the transcription factor Foxp3 and suppressive function in mice with colitis, Nat.
569–581. Immunol. 10 (11) (2009) 1178–1184.
[49] L. Brockmann, S. Soukou, B. Steglich, P. Czarnewski, L. Zhao, S. Wende, T. Bedke, [72] Y.P. Rubtsov, J.P. Rasmussen, E.Y. Chi, J. Fontenot, L. Castelli, X. Ye, P. Treuting,
C. Ergen, C. Manthey, T. Agalioti, M. Geffken, O. Seiz, S.M. Parigi, C. Sorini, L. Siewe, A. Roers, W.R. Henderson Jr, W. Muller, A.Y. Rudensky, Regulatory T
J. Geginat, K. Fujio, T. Jacobs, T. Roesch, J.R. Izbicki, A.W. Lohse, R.A. Flavell, cell-derived interleukin-10 limits inflammation at environmental interfaces,
C. Krebs, J.A. Gustafsson, P. Antonson, M.G. Roncarolo, E.J. Villablanca, Immunity 28 (4) (2008) 546–558.
N. Gagliani, S. Huber, Molecular and functional heterogeneity of IL-10-producing [73] P. Diefenhardt, A. Nosko, M.A. Kluger, J.V. Richter, C. Wegscheid, Y. Kobayashi,
CD4(+) T cells, Nat. Commun. 9 (1) (2018) 5457. G. Tiegs, S. Huber, R.A. Flavell, R.A.K. Stahl, O.M. Steinmetz, IL-10 receptor sig-
[50] M.G. Roncarolo, S. Gregori, R. Bacchetta, M. Battaglia, N. Gagliani, The biology of naling empowers regulatory t cells to control Th17 responses and protect from GN,
t regulatory type 1 cells and their therapeutic application in immune-mediated J. Am. Soc. Nephrol. 29 (7) (2018) 1825–1837.
diseases, Immunity 49 (6) (2018) 1004–1019. [74] J. Tao, M. Kamanaka, J. Hao, Z. Hao, X. Jiang, J.E. Craft, R.A. Flavell, Z. Wu,
[51] K.N. Couper, D.G. Blount, M.S. Wilson, J.C. Hafalla, Y. Belkaid, M. Kamanaka, Z. Hong, L. Zhao, Z. Yin, IL-10 signaling in CD4+ T cells is critical for the pa-
R.A. Flavell, J.B. de Souza, E.M. Riley, IL-10 from CD4CD25Foxp3CD127 adaptive thogenesis of collagen-induced arthritis, Arthritis Res. Ther. 13 (6) (2011) R212.

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

[75] J. Emmerich, J.B. Mumm, I.H. Chan, D. LaFace, H. Truong, T. McClanahan, gene expression reveals a landscape of regulatory T cell phenotypes shaped by the
D.M. Gorman, M. Oft, IL-10 directly activates and expands tumor-resident CD8(+) TCR, Nat. Immunol. 19 (3) (2018) 291–301.
T cells without de novo infiltration from secondary lymphoid organs, Cancer Res. [97] A. Mohr, R. Malhotra, G. Mayer, G. Gorochov, M. Miyara, Human FOXP3(+) t
72 (14) (2012) 3570–3581. regulatory cell heterogeneity, Clin. Transl. Immunology 7 (1) (2018) e1005.
[76] B.J. Laidlaw, W. Cui, R.A. Amezquita, S.M. Gray, T. Guan, Y. Lu, Y. Kobayashi, [98] A. Sharma, D. Rudra, Emerging functions of regulatory t cells in tissue home-
R.A. Flavell, S.H. Kleinstein, J. Craft, S.M. Kaech, Production of IL-10 by CD4(+) ostasis, Front. Immunol. 9 (2018) 883.
regulatory T cells during the resolution of infection promotes the maturation of [99] M. Miyara, Y. Yoshioka, A. Kitoh, T. Shima, K. Wing, A. Niwa, C. Parizot, C. Taflin,
memory CD8(+) T cells, Nat. Immunol. 16 (8) (2015) 871–879. T. Heike, D. Valeyre, A. Mathian, T. Nakahata, T. Yamaguchi, T. Nomura, M. Ono,
[77] I.A. Parish, H.D. Marshall, M.M. Staron, P.A. Lang, A. Brustle, J.H. Chen, W. Cui, Z. Amoura, G. Gorochov, S. Sakaguchi, Functional delineation and differentiation
Y.C. Tsui, C. Perry, B.J. Laidlaw, P.S. Ohashi, C.T. Weaver, S.M. Kaech, Chronic dynamics of human CD4+ T cells expressing the FoxP3 transcription factor,
viral infection promotes sustained Th1-derived immunoregulatory IL-10 via Immunity 30 (6) (2009) 899–911.
BLIMP-1, J. Clin. Invest. 124 (8) (2014) 3455–3468. [100] X. Wei, J. Zhang, Q. Gu, M. Huang, W. Zhang, J. Guo, X. Zhou, Reciprocal ex-
[78] L.K. Smith, G.M. Boukhaled, S.A. Condotta, S. Mazouz, J.J. Guthmiller, R. Vijay, pression of IL-35 and IL-10 defines two distinct effector treg subsets that are re-
N.S. Butler, J. Bruneau, N.H. Shoukry, C.M. Krawczyk, M.J. Richer, Interleukin-10 quired for maintenance of immune tolerance, Cell Rep. 21 (7) (2017) 1853–1869.
directly inhibits CD8(+) t cell function by enhancing N-Glycan branching to de- [101] R.J. Miragaia, T. Gomes, A. Chomka, L. Jardine, A. Riedel, A.N. Hegazy,
crease antigen sensitivity, Immunity 48 (2) (2018) 299–312 e5. N. Whibley, A. Tucci, X. Chen, I. Lindeman, G. Emerton, T. Krausgruber, J. Shields,
[79] R. Kuhn, J. Lohler, D. Rennick, K. Rajewsky, W. Muller, Interleukin-10-deficient M. Haniffa, F. Powrie, S.A. Teichmann, Single-cell transcriptomics of regulatory t
mice develop chronic enterocolitis, Cell 75 (2) (1993) 263–274. cells reveals trajectories of tissue adaptation, Immunity 50 (2) (2019) 493–504 e7.
[80] E.O. Glocker, D. Kotlarz, C. Klein, N. Shah, B. Grimbacher, IL-10 and IL-10 re- [102] X. Cao, S.F. Cai, T.A. Fehniger, J. Song, L.I. Collins, D.R. Piwnica-Worms, T.J. Ley,
ceptor defects in humans, Ann. N. Y. Acad. Sci. 1246 (2011) 102–107. Granzyme B and perforin are important for regulatory T cell-mediated suppression
[81] E.O. Glocker, D. Kotlarz, K. Boztug, E.M. Gertz, A.A. Schaffer, F. Noyan, M. Perro, of tumor clearance, Immunity 27 (4) (2007) 635–646.
J. Diestelhorst, A. Allroth, D. Murugan, N. Hatscher, D. Pfeifer, K.W. Sykora, [103] J. Loebbermann, H. Thornton, L. Durant, T. Sparwasser, K.E. Webster, J. Sprent,
M. Sauer, H. Kreipe, M. Lacher, R. Nustede, C. Woellner, U. Baumann, U. Salzer, F.J. Culley, C. Johansson, P.J. Openshaw, Regulatory T cells expressing granzyme
S. Koletzko, N. Shah, A.W. Segal, A. Sauerbrey, S. Buderus, S.B. Snapper, B play a critical role in controlling lung inflammation during acute viral infection,
B. Grimbacher, C. Klein, Inflammatory bowel disease and mutations affecting the Mucosal Immunol. 5 (2) (2012) 161–172.
interleukin-10 receptor, N. Engl. J. Med. 361 (21) (2009) 2033–2045. [104] D.C. Gondek, L.F. Lu, S.A. Quezada, S. Sakaguchi, R.J. Noelle, Cutting edge:
[82] D. Ellinghaus, L. Jostins, S.L. Spain, A. Cortes, J. Bethune, B. Han, et al., Analysis contact-mediated suppression by CD4+CD25+ regulatory cells involves a gran-
of five chronic inflammatory diseases identifies 27 new associations and highlights zyme B-dependent, perforin-independent mechanism, J. Immunol. 174 (4) (2005)
disease-specific patterns at shared loci, Nat. Genet. 48 (5) (2016) 510–518. 1783–1786.
[83] R.N. Fedorak, A. Gangl, C.O. Elson, P. Rutgeerts, S. Schreiber, G. Wild, [105] A. Cope, G. Le Friec, J. Cardone, C. Kemper, The Th1 life cycle: molecular control
S.B. Hanauer, A. Kilian, M. Cohard, A. LeBeaut, B. Feagan, Recombinant human of IFN-gamma to IL-10 switching, Trends Immunol. 32 (6) (2011) 278–286.
interleukin 10 in the treatment of patients with mild to moderately active Crohn’s [106] C.T. Capaldo, N. Beeman, R.S. Hilgarth, P. Nava, N.A. Louis, E. Naschberger,
disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group, M. Sturzl, C.A. Parkos, A. Nusrat, IFN-gamma and TNF-alpha-induced GBP-1 in-
Gastroenterology 119 (6) (2000) 1473–1482. hibits epithelial cell proliferation through suppression of beta-catenin/TCF sig-
[84] S. Schreiber, R.N. Fedorak, O.H. Nielsen, G. Wild, C.N. Williams, S. Nikolaus, naling, Mucosal Immunol. 5 (6) (2012) 681–690.
M. Jacyna, B.A. Lashner, A. Gangl, P. Rutgeerts, K. Isaacs, S.J. van Deventer, [107] S. de Kleijn, J.D. Langereis, J. Leentjens, M. Kox, M.G. Netea, L. Koenderman,
J.C. Koningsberger, M. Cohard, A. LeBeaut, S.B. Hanauer, Safety and efficacy of G. Ferwerda, P. Pickkers, P.W. Hermans, IFN-gamma-stimulated neutrophils
recombinant human interleukin 10 in chronic active Crohn’s disease. Crohn’s suppress lymphocyte proliferation through expression of PD-L1, PLoS One 8 (8)
Disease IL-10 Cooperative Study Group, Gastroenterology 119 (6) (2000) (2013) e72249.
1461–1472. [108] E.J. Wherry, T cell exhaustion, Nat. Immunol. 12 (6) (2011) 492–499.
[85] H. Tilg, C. van Montfrans, A. van den Ende, A. Kaser, S.J. van Deventer, [109] J.S. Yi, M.A. Cox, A.J. Zajac, T-cell exhaustion: characteristics, causes and con-
S. Schreiber, M. Gregor, O. Ludwiczek, P. Rutgeerts, C. Gasche, version, Immunology 129 (4) (2010) 474–481.
J.C. Koningsberger, L. Abreu, I. Kuhn, M. Cohard, A. LeBeaut, P. Grint, G. Weiss, [110] M. Hashimoto, A.O. Kamphorst, S.J. Im, H.T. Kissick, R.N. Pillai, S.S. Ramalingam,
Treatment of Crohn’s disease with recombinant human interleukin 10 induces the K. Araki, R. Ahmed, CD8 t cell exhaustion in chronic infection and Cancer: op-
proinflammatory cytokine interferon gamma, Gut 50 (2) (2002) 191–195. portunities for interventions, Annu. Rev. Med. 69 (2018) 301–318.
[86] K. Asadullah, W. Sterry, K. Stephanek, D. Jasulaitis, M. Leupold, H. Audring, [111] D.T. Utzschneider, A. Legat, S.A. Fuertes Marraco, L. Carrie, I. Luescher,
H.D. Volk, W.D. Docke, IL-10 is a key cytokine in psoriasis. Proof of principle by D.E. Speiser, D. Zehn, T cells maintain an exhausted phenotype after antigen
IL-10 therapy: a new therapeutic approach, J. Clin. Invest. 101 (4) (1998) withdrawal and population reexpansion, Nat. Immunol. 14 (6) (2013) 603–610.
783–794. [112] F. Muscate, N. Stetter, C. Schramm, J. Schulze Zur Wiesch, L. Bosurgi, T. Jacobs,
[87] M. Friedrich, W.D. Docke, A. Klein, S. Philipp, H.D. Volk, W. Sterry, K. Asadullah, HVEM and CD160: regulators of immunopathology during malaria blood-stage,
Immunomodulation by interleukin-10 therapy decreases the incidence of relapse Front. Immunol. 9 (2018) 2611.
and prolongs the relapse-free interval in Psoriasis, J. Invest. Dermatol. 118 (4) [113] M.S. Mackroth, A. Abel, C. Steeg, J. Schulze Zur Wiesch, T. Jacobs, Acute malaria
(2002) 672–677. induces PD1+CTLA4+ effector t cells with cell-extrinsic suppressor function,
[88] A. Saxena, S. Khosraviani, S. Noel, D. Mohan, T. Donner, A.R. Hamad, Interleukin- PLoS Pathog. 12 (11) (2016) e1005909.
10 paradox: a potent immunoregulatory cytokine that has been difficult to harness [114] A. Petrelli, G. Mijnheer, D.P. Hoytema van Konijnenburg, M.M. van der Wal,
for immunotherapy, Cytokine 74 (1) (2015) 27–34. B. Giovannone, E. Mocholi, N. Vazirpanah, J.C. Broen, D. Hijnen, B. Oldenburg,
[89] K. Schwager, M. Kaspar, F. Bootz, R. Marcolongo, E. Paresce, D. Neri, E. Trachsel, P.J. Coffer, S.J. Vastert, B.J. Prakken, E. Spierings, A. Pandit, M. Mokry, F. van
Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage im- Wijk, PD-1+CD8+ T cells are clonally expanding effectors in human chronic
munocytokine which inhibits the progression of collagen-induced arthritis, inflammation, J. Clin. Invest. 128 (10) (2018) 4669–4681.
Arthritis Res. Ther. 11 (5) (2009) R142. [115] K. Wing, Y. Onishi, P. Prieto-Martin, T. Yamaguchi, M. Miyara, Z. Fehervari,
[90] M. Galeazzi, L. Bazzichi, G.D. Sebastiani, D. Neri, E. Garcia, N. Ravenni, T. Nomura, S. Sakaguchi, CTLA-4 control over Foxp3+ regulatory T cell function,
L. Giovannoni, J. Wilton, M. Bardelli, C. Baldi, E. Selvi, A. Iuliano, G. Minisola, Science 322 (5899) (2008) 271–275.
R. Caporali, E. Prisco, S. Bombardieri, A phase IB clinical trial with Dekavil (F8- [116] D.A. Vignali, L.W. Collison, C.J. Workman, How regulatory T cells work, Nat. Rev.
IL10), an immunoregulatory’ armed antibody’ for the treatment of rheumatoid Immunol. 8 (7) (2008) 523–532.
arthritis, used in combination wiIh methotrexate, Isr. Med. Assoc. J. 16 (10) [117] S.Z. Josefowicz, L.F. Lu, A.Y. Rudensky, Regulatory T cells: mechanisms of dif-
(2014) 666. ferentiation and function, Annu. Rev. Immunol. 30 (2012) 531–564.
[91] J.B. Mumm, M. Oft, Pegylated IL-10 induces cancer immunity: the surprising role [118] L. Lu, J. Barbi, F. Pan, The regulation of immune tolerance by FOXP3, Nat. Rev.
of IL-10 as a potent inducer of IFN-gamma-mediated CD8(+) T cell cytotoxicity, Immunol. 17 (11) (2017) 703–717.
Bioessays 35 (7) (2013) 623–631. [119] L.M.S. Pereira, S.T.M. Gomes, R. Ishak, A.C.R. Vallinoto, Regulatory t cell and
[92] A. Naing, J.R. Infante, K.P. Papadopoulos, I.H. Chan, C. Shen, N.P. Ratti, B. Rojo, forkhead Box protein 3 as modulators of immune homeostasis, Front. Immunol. 8
K.A. Autio, D.J. Wong, M.R. Patel, P.A. Ott, G.S. Falchook, S. Pant, A. Hung, (2017) 605.
K.L. Pekarek, V. Wu, M. Adamow, S. McCauley, J.B. Mumm, P. Wong, P. Van [120] Y. Iwasaki, K. Fujio, T. Okamura, A. Yanai, S. Sumitomo, H. Shoda, T. Tamura,
Vlasselaer, J. Leveque, N.M. Tannir, M. Oft, PEGylated IL-10 (Pegilodecakin) H. Yoshida, P. Charnay, K. Yamamoto, Egr-2 transcription factor is required for
Induces Systemic Immune Activation, CD8(+) T Cell Invigoration and Polyclonal Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells, Eur. J.
T Cell Expansion in Cancer Patients, Cancer Cell 34 (5) (2018) 775–791 e3. Immunol. 43 (4) (2013) 1063–1073.
[93] J. Qiao, Z. Liu, C. Dong, Y. Luan, A. Zhang, C. Moore, K. Fu, J. Peng, Y. Wang, [121] T. Okamura, K. Fujio, M. Shibuya, S. Sumitomo, H. Shoda, S. Sakaguchi,
Z. Ren, C. Han, T. Xu, Y.X. Fu, Targeting tumors with IL-10 prevents dendritic cell- K. Yamamoto, CD4+CD25-LAG3+ regulatory T cells controlled by the tran-
mediated CD8(+) t cell apoptosis, Cancer Cell 35 (6) (2019) 901–915 e4. scription factor Egr-2, Proc. Natl. Acad. Sci. U. S. A. 106 (33) (2009)
[94] S. Dong, S. Maiella, A. Xhaard, Y. Pang, L. Wenandy, J. Larghero, C. Becavin, 13974–13979.
A. Benecke, E. Bianchi, G. Socie, L. Rogge, Multiparameter single-cell profiling of [122] C. Zhu, K. Sakuishi, S. Xiao, Z. Sun, S. Zaghouani, G. Gu, C. Wang, D.J. Tan, C. Wu,
human CD4+FOXP3+ regulatory T-cell populations in homeostatic conditions M. Rangachari, T. Pertel, H.T. Jin, R. Ahmed, A.C. Anderson, V.K. Kuchroo, An IL-
and during graft-versus-host disease, Blood 122 (10) (2013) 1802–1812. 27/NFIL3 signalling axis drives Tim-3 and IL-10 expression and T-cell dysfunction,
[95] J.R. DiSpirito, D. Zemmour, D. Ramanan, J. Cho, R. Zilionis, A.M. Klein, Nat. Commun. 6 (2015) 6072.
C. Benoist, D. Mathis, Molecular diversification of regulatory T cells in non- [123] K. Karwacz, E.R. Miraldi, M. Pokrovskii, A. Madi, N. Yosef, I. Wortman, X. Chen,
lymphoid tissues, Sci. Immunol. 3 (27) (2018). A. Watters, N. Carriero, A. Awasthi, A. Regev, R. Bonneau, D. Littman,
[96] D. Zemmour, R. Zilionis, E. Kiner, A.M. Klein, D. Mathis, C. Benoist, Single-cell V.K. Kuchroo, Critical role of IRF1 and BATF in forming chromatin landscape

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
T. Bedke, et al. Seminars in Immunology 44 (2019) 101335

during type 1 regulatory cell differentiation, Nat. Immunol. 18 (4) (2017) T. Lindsten, J. Rossant, C.A. Hunter, S.L. Reiner, Control of effector CD8+ T cell
412–421. function by the transcription factor Eomesodermin, Science 302 (5647) (2003)
[124] W. Huang, S. Solouki, N. Koylass, S.G. Zheng, A. August, ITK signalling via the 1041–1043.
Ras/IRF4 pathway regulates the development and function of Tr1 cells, Nat. [132] A.P. Kohm, P.A. Carpentier, S.D. Miller, Regulation of experimental autoimmune
Commun. 8 (2017) 15871. encephalomyelitis (EAE) by CD4+CD25+ regulatory T cells, Novartis Found.
[125] S. Tousa, M. Semitekolou, I. Morianos, A. Banos, A.I. Trochoutsou, T.M. Brodie, Symp. 252 (2003) 45–52 discussion 52-4, 106-14.
N. Poulos, K. Samitas, M. Kapasa, D. Konstantopoulos, G. Paraskevopoulos, [133] E. Montero, G. Nussbaum, J.F. Kaye, R. Perez, A. Lage, A. Ben-Nun, I.R. Cohen,
M. Gaga, C.M. Hawrylowicz, F. Sallusto, G. Xanthou, Activin-A co-opts IRF4 and Regulation of experimental autoimmune encephalomyelitis by CD4+, CD25+
AhR signaling to induce human regulatory T cells that restrain asthmatic re- and CD8+ T cells: analysis using depleting antibodies, J. Autoimmun. 23 (1)
sponses, Proc. Natl. Acad. Sci. U. S. A. 114 (14) (2017) E2891–E2900. (2004) 1–7.
[126] P. Gruarin, S. Maglie, M. De Simone, B. Haringer, C. Vasco, V. Ranzani, R. Bosotti, [134] L. Llorente, W. Zou, Y. Levy, Y. Richaud-Patin, J. Wijdenes, J. Alcocer-Varela,
J.S. Noddings, P. Larghi, F. Facciotti, M.L. Sarnicola, M. Martinovic, M. Crosti, B. Morel-Fourrier, J.C. Brouet, D. Alarcon-Segovia, P. Galanaud, D. Emilie, Role of
M. Moro, R.L. Rossi, M.E. Bernardo, F. Caprioli, F. Locatelli, G. Rossetti, interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of
S. Abrignani, M. Pagani, J. Geginat, Eomesodermin controls a unique differ- human systemic lupus erythematosus, J. Exp. Med. 181 (3) (1995) 839–844.
entiation program in human IL-10 and IFN-gamma coproducing regulatory T cells, [135] X. Liu, R. Alli, M. Steeves, P. Nguyen, P. Vogel, T.L. Geiger, The T cell response to
Eur. J. Immunol. 49 (1) (2019) 96–111. IL-10 alters cellular dynamics and paradoxically promotes central nervous system
[127] F. Yu, S. Sharma, D. Jankovic, R.K. Gurram, P. Su, G. Hu, R. Li, S. Rieder, K. Zhao, autoimmunity, J. Immunol. 189 (2) (2012) 669–678.
B. Sun, J. Zhu, The transcription factor Bhlhe40 is a switch of inflammatory versus [136] F.N. Lauw, D. Pajkrt, C.E. Hack, M. Kurimoto, S.J. van Deventer, T. van der Poll,
antiinflammatory Th1 cell fate determination, J. Exp. Med. 215 (7) (2018) Proinflammatory effects of IL-10 during human endotoxemia, J. Immunol. 165 (5)
1813–1821. (2000) 2783–2789.
[128] J.P. Huynh, C.C. Lin, J.M. Kimmey, N.N. Jarjour, E.A. Schwarzkopf, [137] S. Mocellin, M.C. Panelli, E. Wang, D. Nagorsen, F.M. Marincola, The dual role of
T.R. Bradstreet, I. Shchukina, O. Shpynov, C.T. Weaver, R. Taneja, M.N. Artyomov, IL-10, Trends Immunol. 24 (1) (2003) 36–43.
B.T. Edelson, C.L. Stallings, Bhlhe40 is an essential repressor of IL-10 during [138] C.A. Stewart, H. Metheny, N. Iida, L. Smith, M. Hanson, F. Steinhagen,
Mycobacterium tuberculosis infection, J. Exp. Med. 215 (7) (2018) 1823–1838. R.M. Leighty, A. Roers, C.L. Karp, W. Muller, G. Trinchieri, Interferon-dependent
[129] P. Zhang, J.S. Lee, K.H. Gartlan, I.S. Schuster, I. Comerford, A. Varelias, IL-10 production by Tregs limits tumor Th17 inflammation, J. Clin. Invest. 123
M.A. Ullah, S. Vuckovic, M. Koyama, R.D. Kuns, K.R. Locke, K.J. Beckett, (11) (2013) 4859–4874.
S.D. Olver, L.D. Samson, M. Montes de Oca, F. de Labastida Rivera, A.D. Clouston, [139] A.M. Westendorf, D. Fleissner, S. Deppenmeier, A.D. Gruber, D. Bruder,
G.T. Belz, B.R. Blazar, K.P. MacDonald, S.R. McColl, R. Thomas, C.R. Engwerda, W. Hansen, R. Liblau, J. Buer, Autoimmune-mediated intestinal inflammation-
M.A. Degli-Esposti, A. Kallies, S.K. Tey, G.R. Hill, Eomesodermin promotes the impact and regulation of antigen-specific CD8+ T cells, Gastroenterology 131 (2)
development of type 1 regulatory T (TR1) cells, Sci. Immunol. 2 (10) (2017). (2006) 510–524.
[130] N. Chihara, A. Madi, T. Kondo, H. Zhang, N. Acharya, M. Singer, J. Nyman, [140] S. Nancey, S. Holvoet, I. Graber, G. Joubert, D. Philippe, S. Martin, J.F. Nicolas,
N.D. Marjanovic, M.S. Kowalczyk, C. Wang, S. Kurtulus, T. Law, Y. Etminan, P. Desreumaux, B. Flourie, D. Kaiserlian, CD8+ cytotoxic T cells induce relapsing
J. Nevin, C.D. Buckley, P.R. Burkett, J.D. Buenrostro, O. Rozenblatt-Rosen, colitis in normal mice, Gastroenterology 131 (2) (2006) 485–496.
A.C. Anderson, A. Regev, V.K. Kuchroo, Induction and transcriptional regulation [141] E.S. Huseby, D. Liggitt, T. Brabb, B. Schnabel, C. Ohlen, J. Goverman, A patho-
of the co-inhibitory gene module in T cells, Nature 558 (7710) (2018) 454–459. genic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis, J.
[131] E.L. Pearce, A.C. Mullen, G.A. Martins, C.M. Krawczyk, A.S. Hutchins, V.P. Zediak, Exp. Med. 194 (5) (2001) 669–676.
M. Banica, C.B. DiCioccio, D.A. Gross, C.A. Mao, H. Shen, N. Cereb, S.Y. Yang,

Downloaded for Anonymous User (n/a) at Autonomous University of Guadalajara from ClinicalKey.com by Elsevier on
September 12, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.