ReviewInduction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27
Highlights
► IL-27 controls autoimmune responses by promoting Tr1 cells and inhibiting TH17 cells. ► IL-27 triggers Stat1 and Stat3 signaling. ► IL-27 induces Maf and AhR that control IL-10 secretion from Tr1 cells. ► Stat1 activation represses TH17 cells and induces Tr1 cells. ► IL-27 alleviates human autoimmune diseases.
Introduction
Since the original classification by Mosmann and Coffman of CD4+ helper T (TH) lymphocytes into TH1 and TH2 subsets [1], the repertoire of TH subsets has expanded to include additional effector and regulatory T cell subsets such as TH17 cells and regulatory T cells (Foxp3+Tregs and Tr1 cells). TH1 cells, which predominantly produce interferon (IFN)-γ and lymphotoxin, are essential for eliminating intracellular pathogens, but were also regarded as the major effector T cells in inducing tissue inflammation in organ-specific autoimmunity. However, mice lacking the component of TH1-IFN-γ pathway (Il12−/−, Ifng−/−, Ifngr1−/−, Il12rb2−/−) were not protected but overly susceptible to autoimmune diseases including Experimental Autoimmune Encephalomyelitis (EAE) [2], Experimental Autoimmune Uveitis (EAU) [3] and collagen-induced arthritis (CIA) [4]. Subsequent studies revealed that TH17 cells, instead of TH1 cells, induce tissue inflammation in autoimmune diseases. Although TH17 cells are essential for eliminating extracellular pathogens [5], [6], exaggerated TH17 response promotes autoimmunity. Elevated amounts of IL-17A and IL-17F are detected in several autoimmune diseases including multiple sclerosis (MS) [7], rheumatoid arthritis (RA) [8] and psoriasis [9]. The involvement of TH17 cells in tissue inflammation was confirmed in mouse models such as EAE where IL-17-neutralizing antibodies ameliorate clinical scores [10] or CIA where IL-17-deficient animals develop attenuated disease [11]. The differentiation factors for both mouse and human TH17 cells were found to be a combination of TGF-β1 and IL-6 or TGF-β1 and IL-21 [12]. The activation of signal transducer and activator of transcription (Stat)3 by IL-6 or IL-21 is critical for inducing the expression of the TH17 cell master transcription factors retinoid-related orphan receptor (ROR)γt, encoded by the gene Rorc, and RORα (Rora) [13], [14], [15]. Rorc−/− and Rora−/− mice show defective TH17 cell generation [15]. In addition, Chip-Sequencing analysis revealed Stat3 binding sites in the promoters regions of il17a and il17f genes [12]. Furthermore RORγt drives the expression of GM-CSF that is essential for inducing pathogenic TH17 cells, and mice deficient in making GM-CSF are resistant to develop EAE [16]. These observations indicate that RORγt is essential for the development of TH17 cells. Indeed TH17 cell generation can be inhibited by directly targeting RORγt using small chemical compounds such as digoxin and SR1001 [17]. While IL-23 is not required for the induction of TH17 cell differentiation, IL-23 has a prominent role in expansion and stabilization of pathogenic TH17 cells [18], [19], [20]. Both IL-12p19−/− and IL-23R−/− mice are resistant to EAE, and few TH17 cells are found in the central nervous system (CNS) of those mice [21], [22], [23]. The IL-23-TH17 pathway has been shown to be critical in many autoimmune diseases, which is consistent with the fact that IL-23R polymorphisms have been genetically associated with a number of human autoimmune diseases including psoriasis, inflammatory bowel diseases (IBD) and ankylosing spondylitis [24]. More recent studies suggested that TH17 cells could also be induced with the combination of IL-1β, IL-6 and IL-23 in the absence of TGF-β1, suggesting that TH17 cells might actually represent a heterogeneous population of proinflammatory cells that are highly pathogenic and can be induced by multiple different ways.
Exaggerated inflammatory responses are prevented by regulatory T cell subsets that suppress activation of effector T cells. CD4+ regulatory T cells comprise Foxp3+ regulatory T-cells (Tregs) and IL-10-producing regulatory type I (Tr1) cells [25]. Foxp3+Tregs are important to maintain self-tolerance as illustrated by the severe autoimmune inflammation observed in mice deficient in Foxp3 [26] or in patients with dysfunctional FOXP3 protein [27]. Although Foxp3+Tregs inhibit effector T cell responses, they lose their suppressive functions in inflammatory conditions [28]. Therefore, IL-10-producing Tr1 cells might be crucial in controlling tissue inflammation. In humans, Tr1 cells were first described in severe combined immunodeficient (SCID) patients who had developed long-term tolerance to stem cell allografts, supporting the existence of these cells in humans and suggesting that they may play a role in mediating T cell tolerance [29]. Tr1 cells mediate immune suppression by secreting the suppressive cytokine IL-10 and by killing effector cells via Granzyme-B and Perforin [30], [31]. While IL-10 was initially described to be the differentiation factor for Tr1 cells, these T cells could not expand in the presence of IL-10. Therefore there was an emphasis on identifying growth/differentiation factors for Tr1 cells. Recent identification of IL-27 as a differentiation/growth factor for Tr1 cells has revived the interest in examining their role in tissue inflammation [32], [33], [34].
Section snippets
IL-27 dampens autoimmune inflammation
IL-27, an heterodimeric cytokine composed by the subunit p28 (IL-27p28) and the Epstein–Barr virus-induced gene 3 (EBI3), is mainly produced by activated antigen-presenting cells APCs [35]. IL-27 signals through a receptor complex consisting of the common IL-6 receptor chain, gp130, and the unique IL-27 receptor alpha chain (IL-27Ra or WSX-1) that is homologous to IL-12Rβ2 of IL-12 receptor [35], [36]. Based on the structural homology between IL-12 and IL-27 and their receptors, IL-27 was
Regulation of TH1 and TH2 differentiation
While IL-27 induces T-bet and expression of IL-12Rβ2 in naïve CD4+ T cells, IL-27 signaling is not mandatory for TH1 differentiation as illustrated by mice lacking the IL-27R subunit (Il27ra−/−) that can mount adequate TH1 responses to eliminate intracellular pathogens [38], [39], [40]. Moreover, Il27ra−/− mice die due to uncontrolled immunopathology and severe tissue inflammation associated with exaggerated T cell responses and enhanced production of IFN-γ and TNF-α [38], [39], [40]. IL-27 was
Molecular pathways involved in IL-27 biology
Similar to other type 1 cytokine receptors, IL-27 also induces the activation of Janus kinase/Stat pathway. IL-27 predominantly induces the phosphorylation of Stat1 and Stat3. Here we will discuss the IL-27-induced signaling events following the activation of the Stats and analyze their roles in inhibiting TH17 cell and in inducing Tr1 cell differentiation.
IL-27 confers protection against multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system resulting in inflammation, demyelization and axonal loss. It is a common neurological disorder, which attacks young adults. TH17 cells were shown to contribute to MS development [75]. By contrast, IL-27 protects against autoimmune inflammation in the mouse model EAE as exemplified by Il27ra−/− mice which develop an accelerated EAE disease course compared to WT controls and show increased levels of TH
Open questions and concluding remarks
While IL-27 promotes Tr1 cells, it inhibits CD4+Foxp3+Tregs induced by TGF-β. These observations are reminiscent of the action of AhR ligands such as FICZ that promotes Tr1 cells but inhibits Foxp3+Tregs. This paradoxical effect on regulatory T cells might stem from different and/or complementary roles of regulatory T cells. Tr1 cells but not Foxp3+Tregs may develop in situ in the inflamed tissue as IL-27 can be secreted by resident cells in the target organ, such as in the brain during EAE and
Acknowledgements
The authors are supported by grants from Swiss National Science Foundation (SFGBM) and the Novartis Foundation (C.P.) and the Agence Nationale de la Recherche [ANR-10-PDOC-014-01] (L.A.). AA is supported by research grant from Crohn's and Colitis Foundation of America, New York. Studies in our laboratory were funded by the National Institutes of Health [NS030843, AI039671, and AI056299] (V.K.K.).
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Authors equally contributed to the work.