Functions and regulation of T cell-derived interleukin-10

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Review

Functions and regulation of T cell-derived interleukin-10 Christian Neumanna, Alexander Scheffoldb,*, Sascha Rutzc a b c

Institute of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin, Berlin, Germany Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany Department of Cancer Immunology, Genentech, South San Francisco, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: IL-10 T cell Human GWAS Regulatory T cell Transcriptional regulation Intestinal homeostasis Inflammatory bowel disease Tumor Autoimmune disease Allergy c-Maf Blimp-1 Infection

Interleukin (IL)-10 is an essential anti-inflammatory cytokine and functions as a negative regulator of immune responses to microbial antigens. IL-10 is particularly important in maintaining the intestinal microbe-immune homeostasis. Loss of IL-10 promotes the development of inflammatory bowel disease (IBD) as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions more generally to prevent excessive inflammation during the course of infection. Although IL-10 can be produced by virtually all cells of the innate and adaptive immune system, T cells constitute a non-redundant source for IL-10 in many cases. The various roles of T cell-derived IL-10 will be discussed in this review. Given that IL-10 is at the center of maintaining the delicate balance between effective immunity and tissue protection, it is not surprising that IL-10 expression is highly dynamic and tightly regulated. We summarize the environmental signals and molecular pathways that regulate IL-10 expression. While numerous studies have provided us with a deep understanding of IL-10 biology, the majority of findings have been made in murine models, prompting us to highlight gaps in our knowledge about T cell-derived IL-10 in the human system.

1. Introduction Multicellular organisms have developed complex immune systems to detect and fight a plethora of pathogens very effectively. At the same time, the immune system needs to provide regulatory and anti-inflammatory mechanisms to allow for symbiotic relationships with microbes to occur and to limit collateral damage inflicted to host cells and tissues during an inflammatory response. The secretion of immunosuppressive cytokines, such as interleukin-10 (IL-10), is one such mechanism. IL-10 exerts its suppressive effects on both the innate and adaptive arms of the immune system, and functions primarily to limit inflammatory responses to maintain homeostasis to commensal microbes in the intestine and to aid the resolution phase during pathogenic infections [1–7]. Consequently, loss of IL-10 leads to inflammatory diseases, most notably the development of inflammatory bowel disease (IBD), and immunopathology during infections. Excessive IL-10 production, on the other hand, can contribute to chronic infection [3,5,8–10]. IL-10 is a homodimeric cytokine, with each monomer comprised of six α-helices (A–F) and connecting loops, with four helices compacted into the classic left-handed four-helix bundle [11,12]. IL-10 binds to a

⁎

heterodimeric receptor composed of an α-chain (IL-10R1) and a β-chain (IL-10R2) subunit [13–15]. Only IL-10R1 engages in high-affinity IL-10 binding [16,17]. IL-10 receptor engagement triggers signaling mainly through STAT3 (STAT1 and STAT5 to a lesser extent), mediated through Jak1 and Tyk2, which are associated with IL-10R1 and IL10R2, respectively [18–22]. The target cell specificity of IL-10 is largely driven by the restricted expression of the IL-10R1 receptor subunit on leukocytes. In contrast to IL-10 itself, several other IL-10 cytokine family members have tissue protective functions, and primarily act directly on tissue cells, where their respective receptor α-chains are expressed [5,23]. IL-10 has pleiotropic immunosuppressive functions. Initially described as a secreted cytokine synthesis inhibitory factor (CSIF) produced by T helper (Th)2 T cell clones, which inhibits the production of several cytokines from Th1 cells [24], IL-10 has since been recognized to mainly target antigen-presenting cells (APC), such as monocytes and macrophages. IL-10 inhibits the release of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, IL-8, G-CSF, and GM-CSF from these cells [24,25]. Additionally, IL-10 inhibits antigen presentation by reducing the expression of MHC II and co-stimulatory (e.g. CD86) and adhesion (e.g. CD54) molecules [26–28]. IL-10 also inhibits the production and/

Corresponding author. E-mail address: alexander.scheff[email protected] (A. Scheffold).

https://doi.org/10.1016/j.smim.2019.101344 Received 13 October 2019; Accepted 28 October 2019 1044-5323/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Christian Neumann, Alexander Scheffold and Sascha Rutz, Seminars in Immunology, https://doi.org/10.1016/j.smim.2019.101344

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or secretion of cytokines required for CD4+ T cell differentiation, such as IL-12 and IL-23 [29,30]. In addition to its effects on APC, IL-10 exerts direct inhibitory effects on T cells, including memory Th17 and Th2 cells [31–33]. Importantly, IL-10 also stimulates certain immune cells, including mast cells, B cells, regulatory T (Treg) cells and CD8+ T cells [3,4,34–37]. IL-10 can be produced by most cells of the innate and adaptive immune system, including monocytes, macrophages, dendritic cells (DCs), mast cells, eosinophils, neutrophils, natural killer (NK) cells, B cells and T cells [3,5]. However, cell type-specific knock-out models have revealed non-redundant functions for IL-10 derived from Th cells, the orchestrators of adaptive immune responses and immune pathologies. Although IL-10 can be produced by all Th cell subsets [38,39], its regulation in these various T cell populations is dependent on different regulatory circuits allowing for context-dependent expression. In this review, we focus on the non-redundant functions of IL-10 derived from various T cell populations in controlling immune homeostasis and immune responses during infections. We discuss how T cells integrate cues from the microenvironment and use molecular signaling pathways to regulate IL-10 expression. Since mechanistic studies have mainly been conducted in the murine models, we highlight known similarities and potential differences between mouse and human system, and call out significant gaps in our knowledge of IL-10 function and regulation in human T cells.

non-hematopoietic cells in the gut, such as intestinal epithelial cells. 2.2. Non-redundant functions of regulatory T cell-derived IL-10 in the gut The use of various conditional IL-10-deficient mouse strains has revealed significant differences in the contribution of certain cell types to the IL-10-mediated regulation of intestinal homeostasis. Indeed, unlike myeloid-, macrophage- or B cell-specific ablation [55–57], CD4+ T cell-specific deletion of IL-10 (Il10fl/flCd4Cre) results in the development of spontaneous colitis in naïve mice comparable to the phenotype of complete Il10−/− mice, demonstrating a non-redundant role of CD4+ T cell-derived IL-10 production in maintaining intestinal homeostasis [58]. Among CD4+ T cells, Foxp3+ Treg cells represent a major IL-10producing cell subset. Consequently, genetic deletion of IL-10 selectively in Foxp3+ Treg cells also leads to spontaneous intestinal inflammation albeit with less severity than deletion in all CD4+ T cells, implicating that both Foxp3+ and Foxp3− CD4+ T cells critically contribute to IL-10 production in the gut [59]. In steady state, IL-10producing Treg cells are enriched in the intestinal lamina propria and make up the vast majority (ca. 80%) of IL-10-producing CD4+ T cells in the intestine [60]. Transfer experiments demonstrate that antigen-experienced CD45RBlow CD4+ T cells, containing regulatory T cells, suppress T cell-induced colitis (transfer colitis) via an IL-10-dependent mechanism [61,62], providing further evidence that T cell-derived IL10 plays an essential role in preventing intestinal inflammation (Fig. 1).

2. Maintenance of intestinal homeostasis by regulatory T cellderived IL-10

2.2.1. Role of regulatory T cell-derived IL-10 for the control of intestinal Th17 cells Th17 cells have emerged as important mediators of host defence against extracellular bacteria and fungi. During homeostasis, Th17 cells primarily accumulate at mucosal barriers, such as the intestinal lamina propria, where they secrete the cytokines IL-17 and IL-22 and thereby contribute to epithelial barrier function and tissue homeostasis [63,64]. Several mechanisms have been uncovered that control intestinal Th17 cells. These include the elimination of Th17 cells via the intestinal lumen, the direct inhibition of Th17 cell expansion by IL-10, and the acquisition of an immunosuppressive IL-10-producing phenotype by Th17 cells [32,65,66]. Th17 cells respond to IL-10 by virtue of their high-level expression of the IL-10 receptor. Both Foxp3+ Treg cells as well as Foxp3− Tr1 cells inhibit pathogenic Th17 cells in an IL-10 dependent manner in a transfer colitis model [32]. Importantly, IL-10 production by CD4+ T cells is itself dependent on IL-10 receptor signalling in these cells [36,67]. This autocrine regulatory loop amplifies IL-10-dependent regulatory functions, a mechanism which is crucial for the maintenance of intestinal homeostasis, as evidenced by the development of severe spontaneous colitis in mice with a Treg cell-specific IL-10 receptor deletion [36]. Accordingly, IL-10R-deficient Treg cells, as well as STAT3-deficient Treg cells, are selectively impaired in their ability to control inflammatory Th17 cell responses [36,68]. In addition to acting directly on T cells, CD4+ T cell-derived IL-10 also suppresses antigen-presenting cells and thereby controls Th17 cells. Specifically, IL-10 produced by Treg cells has been implicated in the silencing of gutresident CX3CR1+ macrophages, which have recently been identified as essential mediators of intestinal commensal-specific Th17 cell induction [57,69]. IL-10 receptor (but not IL-10) deficiency in CXC3R1+ macrophages results in spontaneous colitis, highlighting the pivotal role of these cells as an intermediary in controlling intestinal inflammation [57].

2.1. Control of intestinal homeostasis and inflammation by IL-10 The gastrointestinal tract constitutes the largest interface between the immune system and the environment. Daily exposure to a plethora of dietary antigens and microorganisms, termed the microbiota, requires specific and highly regulated immune responses to induce and maintain intestinal homeostasis, a dynamic state of equilibrium. The first evidence for a crucial role of IL-10 in maintaining intestinal homeostasis stems from studies in mice that genetically lack IL-10 (Il10−/−) or the IL-10 receptor chain (Il10rb−/−) [8,40]. In both cases, ablation of IL-10 signalling leads to the development of severe spontaneous intestinal inflammation, predominantly in the colon. In contrast, when kept in a germ-free environment, the mice do not develop enterocolitis [41]. Similarly, antibiotic treatment attenuates disease severity in Il10−/− mice [42], indicating that intestinal inflammation originates from uncontrolled immune responses to the gut microbiota. In humans, polymorphisms in IL-10 and IL-10 receptor are strongly associated with IBD, such as Crohn's disease (CD) and Ulcerative Colitis (UC) [43–46]. Rare loss-of-function mutations in IL-10 or IL-10 receptor were found to cause severe, very early-onset IBD (VEO-IBD) in infants and children [47–53] (reviewed in [1]). Interestingly, these patients do not suffer from other immune pathologies, such as allergies or autoimmune diseases, highlighting the selective importance of IL-10 for gut integrity and homeostasis. Since the initial studies in IL-10-deficient mice, much has been learned about the multiple mechanisms by which IL-10 contributes to the maintenance of intestinal homeostasis (Fig. 1). IL-10 prevents immune hypersensitivity to innocuous intestinal antigens, particularly components of the microbiota and thereby averts intestinal inflammation [54]. However, despite the deregulated intestinal immune homeostasis, IL-10/IL-10R-deficient patients do not show increased IgE levels against food antigens [1], suggesting that IL-10 is not required to prevent allergy against non-microbial antigens. Overall these data suggest that in humans IL-10 plays a selective role for the active regulation of anti-microbial immune responses during homeostasis and infections but may be dispensable for the prevention of inappropriate immune reactions against allergens or autoantigens. In addition, it has recently become clear that IL-10 is also involved in modulating the function of

2.2.2. Role of regulatory T cell-derived IL-10 for intestinal IgA production IgA is essential to intestinal homeostasis by both maintaining noninvasive commensal bacteria and by neutralizing invasive pathogens [70]. Treg cells have been shown to be critical to the diversification of gut microbiota [71]. The control of commensal bacteria by Treg cells involves regulatory functions both outside and inside germinal centers 2

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Fig. 1. Role of regulatory T cell-derived IL-10 in maintaining intestinal homeostasis. Gut-resident regulatory T cells (Foxp3+ Treg cells and Foxp3− Tr1 cells) are the major source of IL-10 in the intestinal lamina propria. Regulatory T cell-derived IL-10 restrains intestinal immune responses by silencing antigen-presenting cells (APC) and effector Th cells, such as microbiota-dependent Th17 cells, thereby establishing mucosal tolerance. Effector Th cells also possess the capacity to produce IL-10 themselves, a mechanism known as self-regulation. Regulatory T cell-derived IL10 also directly and indirectly controls intestinal epithelial cell (IEC) function. IL-10 from Foxp3+ Treg cells is critical for the renewal of the intestinal stem cell niche. In addition, Treg cell-derived IL-10 indirectly regulates IECs by controlling the abundance of IL22-producing cells (e.g. Th17 cells) in the gut, by that contributing to tissue homeostasis and integrity of the mucosal barrier. The role of regulatory T cell-derived IL-10 for intestinal IgA production is context-dependent, since IL10-producing T follicular regulatory (Tfr) cells have been associated with both promotion and inhibition of the germinal center response.

negatively regulating their fucosylation [78], a microbiota-induced process that has recently emerged as a key cross-communication tool and immunological factor in the control of luminal microbes (reviewed in [79]). IL-10 has been shown to protect IECs from endoplasmic reticulum (ER) stress [80,81] and from Fas-mediated apoptosis [82], although the cellular source of IL-10 was not elucidated in these studies. Both ISCs and subsets of IECs express the IL-10 receptor either constitutively or upon cytokine stimulation [83–86]. Consequently, epithelial-specific IL-10R knock-out mice display heightened epithelial permeability and develop exacerbated colitis upon DSS treatment [86]. In addition to direct effects on IECs, Treg cell-derived IL-10 indirectly regulates IEC function by controlling the abundance of IL-22-producing cells (e.g. Th17 cells) in the gut. IECs constitutively express the IL-22 receptor, and IL-22 signaling in IECs is critical for maintaining the integrity of the mucosal barrier [87]. In an extension of previous observations [57], a recent study demonstrated that lack of IL-10-mediated control of CX3CR1+ macrophages results in aberrant IL-22 production from intestinal Th17 cells, which induces epithelial chemokine expression and detrimental neutrophil recruitment [88]. Collectively, these findings provide novel perspectives on the regulatory role of IL-10 in the gut, showing that IL-10 not only regulates intestinal immune cells but also directly and indirectly controls IEC function.

(GCs), including suppression of inflammation and regulation of immunoglobulin A (IgA) selection in Peyer's patches [71]. While IL-10 is known to promote the proliferation of activated B cells and subsequent IgA production in vitro [35,72], the role of IL-10 for intestinal IgA production in vivo is less clear. By analysing IL-10-deficient mice, one study found that a unique microbe-dependent subset of IgA+ plasma cells required IL-10 for their development and/or maintenance [73] Importantly, the authors found no differences in the differentiation of IgA+ B cells in the Peyer’s Patches in the absence of IL-10, suggesting that IL-10 promotes the maintenance of IgA+ cells in the intestinal lamina propria, rather than their generation. We recently showed that intestinal Treg cells require the transcription factor c-Maf to produce IL-10 and to adopt a T follicular regulatory (Tfr) phenotype [60], a specialized subset of Foxp3+ Treg cells that suppresses B cell responses through modulation of follicular helper T (Tfh) cells in germinal centers (GC) [74,75]. Interestingly, Treg cell-specific deletion of c-Maf did not suppress gut IgA production, but instead we observed strongly elevated frequencies of lamina propria IgA+ plasma cells, whereas the differentiation of IgA+ B cells in Peyer's patches was normal [60]. While c-Maf clearly controls multiple Treg cell functions beyond their ability to produce IL-10, we also observed a slight increase in intestinal IgA levels in Treg cell-specific IL-10-deficient mice [60]. Collectively these findings suggest a highly contextdependent function of Treg cell-derived IL-10. Clearly, more work is needed to precisely define the role for IL-10 in regulating humoral immunity in the gut. In humans, IL-10 seems to be non-essential for IgA production, as patients with IL-10/IL-10R deficiency have normal or even increased levels of serum immunoglobulins including IgA [1].

3. Self-limitation of T effector cell responses during infection by IL-10 3.1. Limiting inflammation – between tissue damage and chronic infection During infection, IL-10 is produced to limit inflammation and collateral tissue damage [9,89]. Deficiencies in the IL-10 pathway are frequently associated with immune pathology and tissue destruction, even mortality. On the flipside, excessive IL-10 may prevent effective pathogen clearance in certain infections and thus lead to chronic disease [3,6,9,10]. The role for IL-10 in supporting chronic infection has been studied extensively in the LCMV clone 13 model in mice, where IL10 is critical to establish viral persistence and T cell exhaustion, both of which are prevented in IL-10-deficient mice or upon IL-10 receptor blockade [90–92]. Some pathogens, such as Epstein Barr Virus [93], employ mechanisms to elicit IL-10 production by the host as a means of evading the immune system. Similarly, the virulence of the M.

2.2.3. Role of regulatory T cell-derived IL-10 for maintaining intestinal barrier function Positioned as a physical barrier between the intestinal lumen and the immune cells in the lamina propria, intestinal epithelial cells (IEC) have the ability to sense and respond to immune as well as microbial stimuli, thereby mediating the crosstalk between host and microbiota [76]. IL-10 from Foxp3+ Treg cells is critical for the renewal of the intestinal stem cell niche by preventing the differentiation of intestinal stem cells (ISC), thereby contributing to epithelial tissue homeostasis [77]. CD4+ T cell-derived IL-10 also helps to maintain IEC function by 3

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Table 1 IL-10 targeting modalities that have been or are currently being evaluated in clinical trials for the treatment of RA, SLE and psoriasis. Indication

Treatment

Stage

Osteoarthritis, Knee Osteoarthritis, Knee Osteoarthritis, Knee Rheumatoid Arthritis Rheumatoid Arthritis Vasculitis|Wegener's Granulomatosis Moderately Active Ulcerative Colitis Systemic Lupus Erythematosus Cicatrix|Wound Healing Psoriasis Blood disorders Healthy Subjects Healthy Subjects Advanced Solid Tumors Non Small Cell Lung Cancer Non Small Cell Lung Cancer Pancreatic Cancer

XT-150 XT-150 XT-150 F8IL10|Methotrexate F8IL10|MTX IL-10 AG011 BT063 Prevascar IL-10 T-allo10 Pegilodecakin Pegilodecakin Pegilodecakin|Multiple Pegilodecakin|Nivolumab Pegilodecakin|Pembrolizumab Pegilodecakin|FOLFOX

Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase Phase

1 1 1 1 2 1 1|2 2 2 2 1 1 1 1 2 2 3

Status

Sponsor

NCT Number

Active By invitation Completed Completed Unknown Completed Completed Completed Completed Completed Recruiting Completed Completed Active Recruiting Recruiting Recruiting

Xalud Therapeutics Xalud Therapeutics Xalud Therapeutics Philogen S.p.A. Philogen S.p.A. National Institute of Allergy and Infectious Diseases ActoGeniX N.V. Biotest Renovo National Cancer Institute Stanford University Eli Lilly |ARMO BioSciences Eli Lilly |ARMO BioSciences Eli Lilly |ARMO BioSciences Eli Lilly |ARMO BioSciences Eli Lilly |ARMO BioSciences Eli Lilly |ARMO BioSciences

NCT03477487 NCT03769662 NCT03282149 NCT02076659 NCT02270632 NCT00001761 NCT00729872 NCT02554019 NCT00984646 NCT00001797 NCT03198234 NCT03267732 NCT03381547 NCT02009449 NCT03382912 NCT03382899 NCT02923921

essential for IL-10 production in Th2 cells [108–112]. Similarly, TGF-β and IL-6 drive the production of IL-10 as part of the Th17 cell differentiation program [113,114]. IL-27, a member of the IL-12 cytokine family, is produced mostly by innate immune cells during infections [115,116] and is critical for IL-10 production in vivo. For example, IL10+IFN-γ+ Th1 cells, which are critical to prevent immune pathology in mice infected with T. gondii, are absent in IL-27 receptor-deficient mice, and these mice develop lethal CD4+ T cell-mediated inflammation upon T. gondii infection [117,118]. The Notch pathway is a critical regulator of IL-10 production under pro-inflammatory conditions in Th1 cells. Notch, when triggered through ligands of the Delta-like family, Dll-4 in particular, synergizes with IL-12 or IL-27 to strongly enhance IL-10 production and anti-inflammatory capacity in IFN-γ-producing Th1 cells [119,120]. Recent findings suggest that type I IFNs can promote chronic bacterial and viral infections at least partially through the induction of IL10 [121,122]. Accordingly, blocking IFN-mediated signalling before or after establishment of persistent virus infection results in enhanced virus clearance in a CD4+ T cell–dependent manner [123,124]. Ifnar1–/ – mice are more resistant to L. monocytogenes infection, with a longer survival and lower spleen and liver bacterial loads after infection than wild-type mice [121].

tuberculosis CH strain is associated with its ability to elicit elevated IL10 expression and reduced IL-12p40 production [94]. 3.2. Self-limitation of T cell responses through IL-10 While dendritic cells are the dominant source of IL-10 during LCMV infection [95], in many infections that trigger an adaptive immune response it is IL-10 produced by effector T cells at the height of the response that is critical to limit inflammation [89,96–100]. Here, IL-10 functions as a self-limiting mechanism of effector T cells. During Toxoplasma gondii infection, for example, IL-10 produced by Th1 cells is essential to limit an otherwise excessive and detrimental Th1 cell response [99,101]. Mice with a T cell-specific deficiency in IL-10 succumb to severe immunopathology upon infection with T. gondii similar to mice with global IL-10 deficiency [58,99]. Infection with Plasmodium chabaudi is another example where deficiency in IL-10 production in T cells results in decreased survival, greater weight loss, and increased levels of effector cytokines, such as IFN-γ, and TNF-α [102]. Infection with the Leishmania major strain NIH/S, which induces non-healing lesions in infected wildtype mice, is an example of an infection where IL-10 production from effector T cells prevents effective pathogen clearance and establishes a chronic infection instead [9,96]. Similarly, IL-10 production by CD4+ T cells is essential in controlling the immune response to M. tuberculosis [100]. IL-10-deficient mice can control the mycobacterial load during M. tuberculosis infection [10,103], whereas increased IL-10 expression facilitates chronic mycobacterial infection [104,105]. Consistently, elevated IL-10 production is found in lungs and sera of patients with advanced tuberculosis [10]. However, despite large genome-wide association studies no genetic polymorphisms of IL-10/IL-10R have been described to be associated with increased susceptibility to M. tuberculosis infection [106,107].

4. Non-redundant functions of IL-10 in human disease Roles for IL-10 in inflammatory bowel disease, autoimmune diseases, allergy and asthma, infections as well as in cancer have been described. However, most of these studies are based on data from either murine disease models involving the knock-out of IL-10 or IL-10 receptor components in various immune cell types or from extended in vitro analyses of human cells or tissues derived from patients [125]. Both types of analyses may not properly and fully reflect human IL-10 biology. Nonetheless, different IL-10 targeting modalities have been or are currently being evaluated in clinical trials for the treatment of RA, SLE and psoriasis (Table 1). These studies have not demonstrated a clear clinical benefit to date [7]. Perhaps somewhat surprisingly, PEGylated IL-10 has shown clinical activity in the treatment of cancer (reviewed in this issue). It was found to promote IFN-γ secretion and perforin and granzyme B production from CD8+ T cells [126,127], consistent with earlier studies in mice [128–130]. Interestingly, some partial clinical responses have been observed with PEGylated IL-10 as a monotherapy in 4 of 15 patients with intermediate to poor risk in renal cell cancer (RCC) without inducing autoimmune toxicities [126]. A phase III clinical trial investigating PEG-rhuIL-10 in combination with FOLFOX in metastatic pancreatic cancer patients is currently ongoing (Table 1).

3.3. Signals inducing IL-10 production in T cells upon microbial encounter and infection In myeloid cells, including macrophages and DCs, IL-10 production is largely driven by signals downstream of various pattern-recognition receptors (PRRs), including TLR ligands, co-stimulatory receptors and pro-inflammatory cytokines [2]. Effector T cells express IL-10 at the peak of the response, which is consistent with its role as a negative feedback mechanism [6,108]. The ability to express IL-10 appears to be an intricate part of the T cell activation and differentiation program triggered by the same stimuli. Accordingly, TCR stimulation together with the Th1-polarizing cytokine IL-12 promotes IL-10 expression in Th1 cells, whereas IL-4 is 4

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4.2. The difficulty of pinpointing IL-10 from antigen-specific T cells in human disease

4.1. Learnings from human genetics In stark contrast to experimental systems, data from genetic studies in different patient groups suggest a rather specific and non-redundant function of IL-10 in the regulation of intestinal inflammation [1]. Patients with monogenic defects in IL-10 or IL-10R display rather isolated inflammatory bowel disease syndromes very early in life. Importantly, neither elevated IgE levels nor allergies to food or airborne allergens were found [1]. These clinical data suggest that the control of intestinal responses mediated by IL-10 is largely limited to the restriction of proinflammatory Th1 and Th17 responses directed against microbes. In contrast, the maintenance of tolerance, e.g. via the prevention of immune responses against harmless, non-microbial mucosal antigens as well as the prevention and control of Th2 responses, seems to be less dependent on IL-10 [1,131]. In this regard, the phenotype of IL-10/IL10R-deficient patients is quite different from the broad autoimmune, allergic and auto-inflammatory phenotype seen in patients with a deficiency in Foxp3+ regulatory T cells [132,133]. This suggests that Treg cell-derived IL-10, which is often described as a central immunosuppressive mechanism, is not essential for the prevention of these immune pathologies. Conceivably, the small number of patients and the very early and life-threatening consequences of complete IL-10/ IL-10R deficiency requiring immediate therapeutic intervention, could mask more subtle effects on immune responses occurring later in life. In this regard, genome-wide genetic association studies in large patient cohorts provide valuable information for disease association of certain genetic polymorphisms modulating IL-10 regulation or signalling. Indeed, strong genetic associations with IBD have been identified for IL10 or IL-10 receptor variants [134] as well as for several other members of the IL-10 regulatory network, such as PRDM1, the gene coding for BLIMP-1, an essential transcription factor for IL-10 production by effector regulatory and certain Th effector cell subsets [135] (and Table 2). Interestingly, the effect of polymorphisms on IL10RA expression was most pronounced in Th and Treg cells but not in other immune cells ([136] and https://dice-database.org/genes/IL10RA), suggesting functional importance of an IL-10-mediated regulation of T cells. In contrast, IL-10 is not among the major poly- and monogenic traits associated with autoimmune diseases (AID) [137], and no associations have been described in classical T cell-mediated autoimmune diseases, such as multiple sclerosis [138,139] or rheumatoid arthritis (RA) [140], nor in allergic or asthmatic patients [141,142]. Only weak genetic associations were identified for other autoimmune diseases, including type 1 diabetes [143], ankylosing spondylitis [144] and systemic lupus erythematosus (SLE) [145,146]. The functional consequences of most identified polymorphisms remain poorly explored [147]. At first, the genes whose expression is altered by a specific polymorphism must be identified. A major difficulty arises from the fact that certain polymorphisms may impact on gene expression differentially in different cell types. A recent genomewide study analyzed the effects of SNPs known to alter target gene expression in 13 different immune cell types [136]. Surprisingly more than 40% of those SNPs modulated target gene expression only in one single cell type [136]. Thus, considering the diversity of T helper cell subsets, which contribute to IL-10 production in vivo, genetic variation most likely affects individual IL-10 producing T cell subsets differently. To be able to decipher the impact of genetic variation, it is inevitable to fully determine the IL-10 regulatory network in different T cell subsets. In addition, more work is needed to identify, which T cell subsets are critical for a particular type of immune reaction or disease (see also next paragraph). Thus, the combination of molecular understanding of the human (T) cell-type specific IL-10 regulatory network with results from genome-wide association studies will be instrumental to determine the functional relevance of T cell-derived IL-10 for diverse human diseases.

CD4+ T cells are the orchestrators of adaptive immune responses and thus play a central role in many immune-mediated diseases. T cell responses are highly antigen-specific and context-dependent. Therefore, T cell subset diversity and effector functions, such as IL-10 production, have to be resolved ultimately at the level of T cells with disease-relevant specificities [148]. Unfortunately, for most human immune pathologies, such as autoimmune diseases [149,150], chronic inflammatory diseases [151] and many allergies and asthma [131,152], disease-relevant antigen-specific T cells remain elusive. Indeed, the contribution of CD4+ T cells is implied largely based on indirect evidence, such as T cell-directed treatment strategies, MHC class II association and animal models. Undefined antigen targets in many immunemediated diseases and difficulties to identify rare T cell populations with defined specificities without major in vitro manipulation have prevented their detailed characterization (as discussed in [148]). For example, impaired IL-10 production by human T cell subsets from patients with allergies, inflammatory bowel disease, cancer as well as autoimmune diseases have been reported (reviewed in [125]). But still the disease-relevant antigens have not been defined for most of these disorders, preventing the assessment of antigen-specific IL-10 production. One exception are allergens derived from airborne particles, which are relatively well-defined, mainly due to their IgE-inducing potential [153]. However, the basis for tolerance towards allergens in healthy individuals and the mechanism underlying successful allergen-specific immune therapy are still largely unclear. An involvement of various types of allergen-specific regulatory T cells, including IL-10 producing T cells has been postulated [154,155] but these data appear confounded by the experimental strategy used to detect allergen-specific T cells [131,152]. Recent data relying on direct ex vivo identification of allergen-specific T cells did not demonstrate robust IL-10 production, neither in healthy donors nor following allergen-specific immune therapy, which rather induced the deletion of pathogenic Th2 cells [131,156]. Similarly, Foxp3+ regulatory T cells reactive to ubiquitous airborne pollen antigens do not produce IL-10 [157]. These data seem to corroborate the absence of a genetic association between IL-10/IL10R variants and allergic diseases. Taken together, strong evidence for a non-redundant role for human IL-10 only exists in the context of intestinal homeostasis and the control of anti-microbial Th1/Th17 responses. The contribution of IL-10 to other inflammatory human diseases, and the maintenance of tolerance against self and other non-microbial antigens in particular, requires further investigation. 5. Transcriptional regulation of IL-10 in T cells T cells, both conventional CD4+ T cells and Treg cells, need to undergo activation and differentiation into effector-(like) cells in order to express IL-10. Accordingly, they integrate signals through their TCR as well as co-stimulatory and cytokine receptors to regulate IL-10 expression. The complex circuitry regulating IL-10 expression has been studied most deeply in murine T cells (Fig. 2). Although several central mechanisms have been confirmed directly or via genetic association studies in humans, several unknowns remain. In Table 2 we summarize the various factors implicated in IL-10 regulation and indicate if data is available for the murine and/or human system. We also screened for available genetic evidence for the various factors to be associated with immune pathology. 5.1. Transcription factors mediating TCR signalling are required for IL-10 expression in T cells TCR signalling is a fundamental requirement for IL-10 transcription in T cells. TCR activation triggers several downstream signalling 5

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Table 2 The table summarizes the available literature describing a role for the various factors within the IL-10 regulatory network. Data obtained in the murine and human system are depicted separately. Furthermore we have listed known genetic associations of identified SNP with major immune mediated diseases (collected from https://www.opentargets.org/: autoimmunity (T1D, RA, SLE, MS), Morbus Crohn (MC), colitis ulcerosa (UC) and allergy & asthma. The functional consequences of the identified polymorphisms in general and specifically on IL-10 expression are not considered in this table. Factor

Mode of regulation

Mouse

Human

Polymorphisms Disease association

Cytokine/Cytokine signaling IFN-α (STAT1/3) Promotes IL-10 in Th subsets

[121,122]

[217,218,219,170]

IL-2 (STAT5)

Promotes IL-10 in Treg cells

[228,229]

IL-4 (STAT6)

Promotes IL-10 in Th2 cells

[112,173]

IL-6 (STAT3)

Promotes IL-10 in Th17 cells

[113,114]

IL-10 (STAT3)

Promotes IL-10 in Tr1 cells

[67,235]

[67,235]

IL-10 (STAT3) IL-12 (STAT4)

Promotes IL-10 in Treg cells Promotes IL-10 in Th1 cells

[36] [173,108,172,119]

[109,110]

IL-21 (STAT3)

Promotes IL-10 in Th1/Th17 cells

[178]

[179,180]

IL-27 (STAT1/3)

Promotes IL-10 in Tr1 cells

[113,175,177,174,176]

[179,248]

TGF-β (SMAD3/4)

Promotes IL-10 in Th1/Tr1/Th17 cells

[172,182,181,184,183]

[184]

INF-α/β/type I IFNR: None STAT1: Arthritis [220] STAT3: SLE [221] MS [222,223,224,138] Arthritis [144] Psoriasis [144] MC [225,226] UC [144] Allergy [227] IL-2/IL-2R: multiple associations with allergy/asthma, AID, IBD STAT5: Allergy [230] Asthma [231] IL-4/IL-4R/STAT6: Allergy [230,142,226] Asthma [142,232,231] MS [226] IL-6/IL-6R: Asthma [231] Arthritis [233,234] SLE [221] MC/UC [144] STAT3: see above IL-10/IL-10R: MC [144] UC [236,237,238] SLE [221,239,226,146] STAT3: see above see above IL-12/IL-12R: MC/UC [236,144,240,45,241] SLE [221,226,239] Diabetes [242] RA [243] MS [223,138,224,244] STAT4: MC/UC [236,226] MS [138] Arthritis [242,243] SLE [245,246,243,221,146] IL-21/IL-21R: MC/UC [242,144] SLE [242] T1D [242] Allergy [247] STAT3: see above IL-27/IL-27R: MC/UC [144,236,249] STAT1/3: see above TGF-β/ TGF-β1/2: None SMAD3: Allergy/Asthma [142,250,247,230,251,232] MC [240,144,221,45] Arthritis, SLE [242] SMAD4: Asthma [232] MC [45]

TNF-α

Blocks IL-10 in human Th cell subsets via repression of Aiolos TCR signaling/Co-stimulation

[187,188]

(continued on next page) 6

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Table 2 (continued) Factor

Mode of regulation

Mouse

BATF

Promotes IL-10 in various T cell subsets

[165]

CD46 c-Jun, JunB ERK NFAT

Promotes Promotes Promotes Promotes

[158,159] [108] [160,169]

Notch1&2

Promotes IL-10 in Th1 cells

IL-10 IL-10 IL-10 IL-10

in in in in

P38 Promotes IL-10 in Transcription factor (Activator) AhR Promotes IL-10 in Aiolos Promotes IL-10 in Blimp-1 Promotes IL-10 in

Tr1 cells various T cell subsets various T cell subsets various T cell subsets

Human

[253,254]

[119,120]

various T cell subsets

[161]

Tr1/Th17 cells Th17 cells various T cell subsets

[195]

[204] [187]

[172,212,213,210]

c-Maf Egr-2 Eomes

Promotes IL-10 in various T cell subsets Promotes IL-10 via promoting Blimp-1 Promotes Tr1 differentiation

[114,177,196,60,195] [257,211] [215]

Etv5 E4BP4 GATA3

Promotes IL-10 in Th2 cells Promotes IL-10 in various T cell subsets Remodels Il10 locus in Th2 cells

[261] [262] [112,111]

IRF4 Promotes IL-10 in various T cell subsets Transcription factor (Repressor) Bhlhe40 Represses IL-10 in Th1/Th17 cells Ets-1 Represses IL-10 in Th1 cells

[167,264] [205,104,206] [266,267]

GSK3 RORγt

[268] [162,193]

GSK3 inhib. epigenetically activates Il10 Represses IL-10 via repression of Blimp-1

[199,200] [216]

[204]

[268]

Polymorphisms Disease association UC [226] MS [224,138] RA [252] Allergy [226,230] None None None NFATC2: Allergy [251,230] Notch1&2: MC/UC [236] Notch 2: SLE [221] None MC/UC [255] MC/UC, MS [255] MC/UC [255,225,236,45,256,144,240] SLE [221] MC [255] None MC [258] MS [138,224] RA [259,260] SLE [226] None None RA, SLE, T1D [263] Allergy [230] Asthma [232] MC, MS, RA, SLE [265] None MC, UC, RA, SLE [144] Allergy [230] Asthma [232] None MC/UC [236,144] Allergy [230] Asthma [232]

Nuclear factor of activated T-cells (NFAT)-1 translocates from the cytoplasm into the nucleus upon TCR stimulation. It interacts with AP-1 and other transcriptional partners to promote cytokine gene transcription [168]. NFAT1 binding to the Il10 promoter has been demonstrated in Th2 and to intron 4 in Th1 cell lines [160]. NFAT1/IRF4 co-binding to CNS-9 synergistically enhances IL-10 expression in Th2 cells [169]. Collectively these findings demonstrate that IL-10 expression is tightly linked to the activation state of the T cell and occurs in concert with other activation and differentiation events.

pathways that converge onto the activation of common transcription factors, including AP-1, NFAT and NF-κB, all of which are involved in IL-10 expression [2,5,6]. Although most of the studies cited here have been conducted primarily in mouse T cells, the transcription factor binding motifs are generally conserved within the human IL10 locus, strongly suggesting that these pathways are shared in the human system [158–160]. ERK is a common positive regulator of IL-10 expression in different T helper cell subsets [108], with the p38 MAP kinase signalling pathway also regulating IL-10 production in CD8+ T cells [161]. Activation of members of the AP-1 family of transcription factors downstream of ERK promotes IL-10 expression in various T cell subsets. Several AP-1 binding motifs have been functionally characterized within the Il10 locus. In Th2, but not in Th1 cells, the AP-1 factors JunB and to a lesser extent c-Jun bind at HSS + 6.45 kb to promote IL-10 expression [158,159]. Ectopic expression of c-Jun and JunB enhances IL-10 production in activated naïve T cells, whereas a dominant negative c-Jun reduces IL-10 production [159]. ATF-Like (BATF) is an AP-1 family member that together with JunB and IRF4 functions as a ‘pioneer factor’ early after T cell activation by binding to a large number of loci, including CNS-9 in the Il10 locus [162–165]. Mutating either the IRF or AP-1 motif within CNS-9 results in a diminished luciferase reporter activity consistent with functional cooperation between these factors in Il10 gene regulation [165]. Deficiencies in BATF or IRF4 significantly impair Th2 or Th17 differentiation and effector cytokine production demonstrating a broader function beyond IL-10 regulation, consistent with their designation as pioneer factors [162,166,167].

5.2. Cytokine signalling promotes IL-10 expression in various T cell subsets Cytokines are main drivers of T cell polarization and act together with TCR signalling to specify the T cell differentiation path. Consistent with its role as a negative feedback mechanism, IL-10 expression is induced as part of various T cell differentiation programs. Signal transducers and activators of transcription (STATs), are essential signalling mediators downstream of many cytokines, and a large body of evidence demonstrates the requirement of STAT signalling in promoting IL-10 expression in both the murine and human systems. Two STAT-binding sites have been identified in the murine and human IL-10 promoters [170,171]. Different STATs mediate distinct differentiation programs but commonly induce IL-10 expression. STAT4 downstream of IL-12 during Th1 differentiation, STAT6 downstream of IL-4 during Th2 polarization, and STAT3 activated by IL-6 during Th17 differentiation are all essential drivers of IL-10 expression in the respective T cell subsets [108,112,114,119]. Accordingly, STAT4 and STAT6 bind to 7

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Fig. 2. Molecular regulation of IL-10 expression in different Th cell subsets. Schematic representation of crucial transcriptional activators (black frame) and repressors (red frame) implicated in IL-10 regulation in various Th cell subsets and their binding within the Il10 locus. Conserved non-coding sequences (CNS) upstream or downstream of Il10 are depicted in red.

and Th17 paths and have been previously thought of as lineage master transcription factors. However, it is becoming increasingly clear that these transcription factors only regulate a relatively small number of target genes, including the signature cytokine genes [162,189]. Their contribution to the regulation of IL-10 expression is rather limited and indirect. This has been best studied for GATA3 in Th2 cells. GATA3 is recruited to two locations in the Il10 locus, but it does not trans-activate the Il10 promoter. Accordingly, GATA3 is not required for IL-10 production in differentiated Th2 cells [190]. Instead, GATA3 facilities chromatin remodelling and histone acetylation at the Il10 locus [111], leading to an epigenetic imprinting and stable memory for IL-10 expression in Th2 cells [111,112,191]. The role for T-bet in IL-10 expression in Th1 cells is less well understood. However, one of the main functions of T-bet during Th1 polarization is the induction of the IL12RβII chain to enable IL-12 signalling [192], which in turn promotes IL-10 expression. Otherwise T-bet is likely dispensable for IL-10 expression in Th1 cells, as we demonstrated at least in the case of Notchinduced IL-10 production under Th1–polarizing conditions. Interestingly, IL-10 expression in Th1 cells remains strictly dependent on STAT4 [119]. RORγt, while positively regulating the expression of the Th17 signature cytokine Il17a, acts as a repressor of Il10 expression by suppressing Blimp-1 expression [162,193]. These examples demonstrate that IL-10 expression co-occurs with lineage differentiation of Th cells and is triggered by the same stimuli, but it is de-coupled from the core differentiation program.

the Il10 promoter in Th1 and Th2 cells, respectively [172,173]. STAT4 binding has also been demonstrated in the CNS-9 and intron 4 regions in Th1 cells [172,173], whereas STAT3 binds to the same intron 4 region in Th17 cells [165]. STAT3 downstream of IL-21 and STAT1/ STAT3 downstream of IL-27 function more broadly to induce IL-10 in multiple T cell subsets, both in mouse and human [113,114,174–180]. TGF-β, itself a critical immunosuppressive cytokine, is also a potent inducer of IL-10 in Th1, Th2 and Th17 cells [172,181,182]. TGF-β signals through SMAD2, SMAD3 in complex with SMAD4. Accordingly, binding and transactivation of the Il10 promoter by the downstream SMAD4 has been demonstrated in Th1 cells [182,183]. Similarly, SMAD3 together with GATA3 positively regulate IL-10 production in response to TGF-β in Th2 cells [184]. Concomitantly with promoting IL10 expression, TGF-β alters the expression of effector cytokines in T cells. While inducing IL-17 expression in Th17 cells, TGF-β potently suppresses the production of IFN-γ in Th1 cells [172,182] and alters the Th2 to a Th9 phenotype [185,186]. The cytokine TNF-α modulates the differentiation state and IL-10 expression in human CD4 T cell subsets, including Th17 cells. Therapeutic antibodies blocking TNF-α enhance IL-10 production by all effector T cell subsets in vitro [187,188], TNF-α blockade releases the expression of Aiolos, an Ikaros family member. Aiolos expression promotes IL-10 expression in human Th17 cells by binding to conserved regions in the IL10 locus [187]. Taken together these findings show that IL-10 expression is induced concomitantly with several T cell differentiation programs, which speaks to the broad role of IL-10 as a negative feedback mechanism in T cells.

5.4. c-Maf broadly promotes IL-10 expression in both effector and regulatory T cell subsets 5.3. Lineage transcription factors have limited impact on IL-10 expression The transcription factor c-Maf is one of the central nodes in the regulation of IL-10 expression across all T cell subsets in mice. c-Maf expression is induced downstream of several important drivers of IL-10

T cell subset-specific transcription factors, such as T-bet, GATA3 and RORγt, are required for proper T cell differentiation along the Th1, Th2, 8

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and its binding partner, AhR nuclear translocator (ARNT), interact with IRF-4 to form a transcription factor complex that is critical in the differentiation of human IL-10 producing Tr1-like cells, downstream of the TGF-β superfamily member, Activin-A [204].

expression, including IL-27, IL-4, TGF-β, ICOS and Notch [114,172,177,194,195] and is readily detectable in T cell subsets differentiated in vitro. Although c-Maf expression is low in Th1 cells compared to other T cell populations, it is driven by IL-12 and can be potently upregulated by activation of the Notch pathway in order to promote IL-10 expression [172]. A large body of literature documents that c-Maf is critically required for IL-10 production in Th1, Th2, Th17, Tr1 cells and FoxP3+ Treg cells in vitro [2,60,108,114,162,172,177,195,196]. Furthermore, IL-10 production in various disease models is dependent on c-Maf, e.g. c-Maf deficiency in CD4+ T cells results in increased pathology in a Th1-dependent malaria model as well as in a Th2-dependent house dust mite allergy model, in both cases resembling an IL-10 deficient situation [196]. In the Th17-mediated model of experimental autoimmune encephalitis (EAE), c-Maf deficiency in CD4 T cells not only reduces IL-10 expression, but also leads to a decrease in IL-17 production and RORγt expression, as well as an increase in Foxp3+ Treg cells [196]. The authors observed enhanced NFAT activity and IL-2 production in the absence of c-Maf, which likely accounted for both the decreased IL-17 production and increased Foxp3+ Treg cells [196]. c-Maf deficiency in the Treg cell compartment impairs their differentiation and function, including the production of IL-10 by bacteria-specific iTreg cells [197]. We recently reported that c-Maf is not only required for IL-10 production from Treg cells in the intestine, but is also critical for their ability to control intestinal Th17 cells and immunoglobulin A (IgA) responses to maintain host-microbiota homeostasis [60]. c-Maf deficiency in Treg cells leads to a profound microbial dysbiosis [60]. However, the role for c-Maf in Th17 cells and Treg cells is clearly more complex than simply promoting IL-10 expression [60,196]. In Th17 cells, for instance, c-Maf acts mainly as a suppressor of pro-inflammatory gene expression most likely by antagonizing BATF [162,198]. In fact, IL-10 is among the few genes induced by c-Maf in Th17 cells [114,162]. In contrast to its well-established role as a critical regulator of IL-10 production in various murine T cell subsets, the function of c-Maf as a driver of IL-10 expression in human T cells remains underexplored. One report finds expression of c-Maf to be selectively up-regulated in IL-10 producing Th17 cells, where it is bound to a large set of enhancer-like regions and modulates an immunoregulatory and tissue-residency program, including IL10 expression [199]. Depletion of c-Maf via short hairpin RNA results in a significant reduction in the expression of IL10 mRNA and protein [199]. Another recent study reports a significant association between IL-10 and the expression of genes involved in cholesterol metabolism in cultured human Th1 cells. Inhibition of the cholesterol biosynthesis pathway reduces c-Maf expression and decreases IL-10 expression [200]. Together these findings are a first indication that the role for c-Maf in regulating IL-10 expression is conserved between mouse and human T cells. However, surprisingly little is known about IL-10 production by human Foxp3+ Treg cells, and our own data indicate that c-Maf alone is not sufficient to induce IL-10 by human Treg cells (A. Scheffold unpublished observation).

5.6. Bhlhe40 counteracts c-Maf and represses IL-10 expression Two recent reports describe the transcription factor basic helixloop-helix family member e40 (Bhlhe40) as a critical negative regulator of IL-10 expression during bacterial infections in mice [104,205]. Loss of Bhlhe40 results in higher IL-10 expression, higher bacterial burden, and early susceptibility during M. tuberculosis infection. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to M. tuberculosis [104]. Similarly, Bhlhe40-deficient CD4+ Th1 cells produce less IFN-γ but substantially more IL-10 than wildtype Th1 cells both in vitro and during T. gondii infection in vivo [205]. Mice harbouring a conditional deletion of Bhlhe40 in T cells succumb to T. gondii infection [205]. In both models, blockade of IL-10 signalling reversed the phonotype [104,205]. Bhlhe40 deficiency also confers resistance to EAE through increased IL-10 production from both Th1 and Th17 cells [206]. Bhlhe40 likely represses IL-10 expression through its binding to a cis-acting regulatory region +6 kb downstream of the Il10 transcriptional start site [104], a region previously identified as an enhancer element in Th2 cells and binding site for AP-1 and IRF4 [158,167]. Recently, this site was also found to bind c-Maf and Blimp-1 [196]. The identity of the IL-10 inducing factor antagonized by Bhlhe40 is currently unknown. Interestingly, however, accompanying the increase in IL-10 production in the absence of Bhlhe40 is an increase in c-Maf expression [205]. Conversely, Bhlhe40 is up-regulated and has increased activity in the absence of c-Maf in T cells [196]. This apparent reciprocal regulation between Bhlhe40 and c-Maf further suggests that Bhlhe40 might exert at least some of its repressive effects on IL-10 expression by repressing c-Maf [207]. These recent findings extend our view of c-Maf as a master regulator of IL-10 expression in T cells and suggest that the c-Maf/Bhlhe40 transcriptional module functions to fine-tune the balance between protective immunity to infection and immune-pathology [207]. It is currently not known if this pathway is active in human T cells. 5.7. Blimp-1 broadly promotes IL-10 expression across T cell subsets Mice with hematopoietic or T cell-specific deficiency in Blimp-1 develop spontaneous colitis [208,209]. Moreover, T cell–specific Blimp1 deficiency results in enhanced inflammation and immunopathology during T. gondii infection [172]. A large number of studies show that Blimp-1 promotes IL-10 production in both CD4+ T cells (effector and regulatory T cells) and in CD8+ T cells [172,209–213]. In CD8+ T cells, Blimp-1 expression requires CD4+ T cell help [208–210]. Blimp-1 expression in T cells is limited to the effector stage of T cell differentiation [209,214]. This is also true for Treg cells, where Blimp-1 is expressed in an effector-like Treg cell population that is found at the site of inflammation [212]. Blimp-1 deficiency does not prevent Treg cell development but strongly impairs the production of IL-10 by these cells in response to TCR stimulation [212]. IL-27–induced IL-10 production in CD4+ T cells is completely dependent on Blimp-1 [172], further suggesting a broad role in IL-10 regulation across T cell populations. Given its expression pattern, Blimp-1 is perfectly suited to restrict IL-10 production to an effector phase at the peak of an acute inflammatory response. However, Blimp-1 is not universally required for IL-10 expression in T cells, as differentiation of Blimp-1-deficient CD4+ T cells into Th2 cells results in normal IL-10 expression [208]. Blimp-1 is critical for IL-10 production in Th1 cells, where it binds mainly to CNS-9 [172] within the Il10 locus. Blimp-1 expression in Th1 cells in vitro is dependent on STAT4, which explains its late induction during Th1 polarization. The early phase of Th1 differentiation is IL-12

5.5. The aryl hydrocarbon receptor interacts with c-Maf to promote IL-10 expression Although c-Maf can transactivate Il10 by itself to some extent [114,195], robust IL-10 expression requires its interaction with additional transcriptional regulators. The aryl hydrocarbon receptor (AhR) cooperates with c-Maf to regulate IL-10 expression in mouse and human Tr1 cells [177,195,201]. AhR is a cytosolic sensor for a number of xenobiotic chemicals as well as endogenous indole derivatives, and modulates the development of several Th cell lineages, including Foxp3+ Treg cells, Tr1 and Th17 cells [195,201,202]. AhR binds to cMaf and acts synergistically in trans-activating the Il10 promoter in these cells. In Th17 cells, for instance, AhR expression is induced by TGF-β [198,203]. Furthermore, a recent study demonstrated that AhR 9

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phenotype.

independent and instead relies on IFN-γ–mediated induction of T-bet [192]. Consistent with the transient nature of IL-10 expression in Th1 cells, Blimp-1 activity is restricted to an effector state and is likely to coincide with high availability of pro-inflammatory cytokines such as IL-12. Although IL-12 and IL-27 seem to use different pathways to induce Blimp-1, IL-12 by signalling through STAT4 and IL-27 by signalling through STAT1/3, their co-expression in many Th1-driven immune responses makes it likely that both cytokines synergize in promoting Blimp-1–dependent IL-10 expression in Th1 cells in vivo. Blimp-1–deficient Th1 cells lack IL-10 production in vitro and in vivo [172]. In IL27-induced Tr1 cells, the transcription factor Egr-2 is upstream of Blimp-1 [211]. Accordingly, Egr-2-deficient Tr1 cells have reduced IL10 production but enhanced secretion of IL-17 or IFN-γ [211]. It was recently reported that Blimp-1 cooperates with Eomesodermin (Eomes) to transcriptionally activate IL-10 expression in murine Tr1 cells and prevent them from differentiating into other Th cell lineages [215]. Eomes is expressed downstream of T-bet and IL-27 in Tr1 cells [215]. Importantly, Eomes is also involved in controlling human IL-10-producing Tr1 cells [216]. Despite the granular data supporting an essential role for Blimp-1 in regulating IL-10 expression in murine T cells, direct evidence in the human system is still lacking. However, strong genetic associations have been identified for PRDM1 with IBD [135], suggesting that similar mechanisms are at play in regulating IL-10 production from human T cells.

Declaration of Competing Interest Sascha Rutz is a full time employee of Genentech and shareholder of Roche. A.S. and C.N. have nothing to declare. Acknowledgements This work was supported by grants from The Deutsche Forschungsgemeinschaft (DFG) SCHEFF 670/2-1, CRC 877 project B15 and CRC/TR 241 project B07 to A.S. References [1] K.R. Engelhardt, B. Grimbacher, IL-10 in humans: lessons from the gut, IL-10/IL10 receptor deficiencies, and IL-10 polymorphisms, Curr. Top. Microbiol. Immunol. 380 (2014) 1–18. [2] L. Gabrysova, et al., The regulation of IL-10 expression, Curr. Top. Microbiol. Immunol. 380 (2014) 157–190. [3] K.W. Moore, et al., Interleukin-10 and the interleukin-10 receptor, Annu. Rev. Immunol. 19 (2001) 683–765. [4] A. O’Garra, et al., Strategies for use of IL-10 or its antagonists in human disease, Immunol. Rev. 223 (2008) 114–131. [5] W. Ouyang, et al., Regulation and functions of the IL-10 family of cytokines in inflammation and disease, Annu. Rev. Immunol. 29 (2011) 71–109. [6] M. Saraiva, A. O’Garra, The regulation of IL-10 production by immune cells, Nat. Rev. Immunol. 10 (3) (2010) 170–181. [7] X. Wang, et al., Targeting IL-10 family cytokines for the treatment of human diseases, Cold Spring Harb. Perspect. Biol. 11 (2) (2019). [8] R. Kuhn, et al., Interleukin-10-deficient mice develop chronic enterocolitis, Cell 75 (2) (1993) 263–274. [9] K.N. Couper, D.G. Blount, E.M. Riley, IL-10: the master regulator of immunity to infection, J. Immunol. 180 (9) (2008) 5771–5777. [10] P.S. Redford, P.J. Murray, A. O’Garra, The role of IL-10 in immune regulation during M. tuberculosis infection, Mucosal Immunol. 4 (3) (2011) 261–270. [11] K. Josephson, N.J. Logsdon, M.R. Walter, Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site, Immunity 15 (1) (2001) 35–46. [12] A. Zdanov, Structural analysis of cytokines comprising the IL-10 family, Cytokine Growth Factor Rev. 21 (5) (2010) 325–330. [13] A.S. Ho, et al., A receptor for interleukin 10 is related to interferon receptors, Proc. Natl. Acad. Sci. U. S. A. 90 (23) (1993) 11267–11271. [14] S.V. Kotenko, et al., Identification and functional characterization of a second chain of the interleukin-10 receptor complex, EMBO J. 16 (19) (1997) 5894–5903. [15] J.C. Tan, et al., Characterization of interleukin-10 receptors on human and mouse cells, J. Biol. Chem. 268 (28) (1993) 21053–21059. [16] S.I. Yoon, et al., Conformational changes mediate interleukin-10 receptor 2 (IL10R2) binding to IL-10 and assembly of the signaling complex, J. Biol. Chem. 281 (46) (2006) 35088–35096. [17] S.I. Yoon, et al., Structure and mechanism of receptor sharing by the IL-10R2 common chain, Structure 18 (5) (2010) 638–648. [18] A.S. Ho, et al., Functional regions of the mouse interleukin-10 receptor cytoplasmic domain, Mol. Cell. Biol. 15 (9) (1995) 5043–5053. [19] D.S. Finbloom, K.D. Winestock, IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes, J. Immunol. 155 (3) (1995) 1079–1090. [20] M.A. Meraz, et al., Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway, Cell 84 (3) (1996) 431–442. [21] K. Takeda, et al., Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils, Immunity 10 (1) (1999) 39–49. [22] M.H. Shaw, et al., Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation, J. Immunol. 176 (12) (2006) 7263–7271. [23] S. Rutz, X. Wang, W. Ouyang, The IL-20 subfamily of cytokines–from host defence to tissue homeostasis, Nat. Rev. Immunol. 14 (12) (2014) 783–795. [24] D.F. Fiorentino, M.W. Bond, T.R. Mosmann, Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones, J. Exp. Med. 170 (6) (1989) 2081–2095. [25] R. de Waal Malefyt, et al., Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes, J. Exp. Med. 174 (5) (1991) 1209–1220. [26] W.D. Creery, et al., Differential modulation of B7-1 and B7-2 isoform expression on human monocytes by cytokines which influence the development of T helper cell phenotype, Eur. J. Immunol. 26 (6) (1996) 1273–1277. [27] R. de Waal Malefyt, et al., Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression, J. Exp. Med. 174 (4) (1991) 915–924. [28] F. Willems, et al., Interleukin-10 inhibits B7 and intercellular adhesion molecule-1

6. Conclusion The role of IL-10 as a central regulator of intestinal homeostasis, maintaining a balanced immune response against microbiota and pathogens is firmly established in mice and man. Despite its important function there is currently no IL-10 targeted therapy. Several clinical trials are exploring the therapeutic potential of IL-10 in autoimmunity and chronic inflammatory diseases, including ulcerative colitis. PEGylated IL-10 has yielded promising results in early clinical trials as a cancer immunotherapy exploiting its capacity to activate cytotoxic T cells. However, to fully realize the therapeutic potential of IL-10 it will be critical to define and learn how to manipulate the molecular pathways contributing to IL-10 regulation specifically within disease-relevant human T cell populations. To date several open questions remain: 1 What are the physiologically relevant cellular sources of IL-10 in different immune response types and the cell type-specific regulatory networks. In particular, the question whether stable IL-10 producing subsets, such Tr1 or Treg cells play a dominant role or whether IL-10 is mainly produced “on demand” by all Th cell subsets. Especially, the role of IL-10 production by human Foxp3+ Treg cells is currently unknown. 2 Which pathways are essential for IL-10 regulation in human T cells? Despite significant progress towards understanding the molecular network governing IL-10 expression there are major gaps in our understanding of the human system. 3 Does dysregulated IL-10 production by T cells contribute to human diseases except for IBD? Human IL-10 deficiency results mainly in IBD but more subtle alterations of IL-10 production in relevant T cell subsets may contribute to other immune pathologies. This will require the identification of disease-relevant cell populations and elucidation of regulatory network controlling IL-10 production in those cells, and an integration of genetic polymorphisms and analysis of their effects on cell type-specific IL-10 expression. Finding answers to these questions will help to define strategies for the selective manipulation of IL-10 production by relevant T cell subsets, antigen-specific IL-10 induction or the in vitro generation of antigen-specific T cells with a predominant and stable IL-10 producing 10

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