Elsevier

Seminars in Immunology

Volume 23, Issue 6, December 2011, Pages 438-445
Seminars in Immunology

Review
Induction of regulatory Tr1 cells and inhibition of TH17 cells by IL-27

https://doi.org/10.1016/j.smim.2011.08.003Get rights and content

Abstract

Accumulating evidence indicates that IL-27, a member of the IL-12 family of cytokines, alleviates the severity of autoimmune diseases in both mice and men. The IL-27-induced activation of signal transducer and activator of transcription (Stat)1 and Stat3 promotes the generation of IL-10- producing type 1 regulatory T (Tr1) cells that inhibit effector T cells. In addition, IL-27 also suppresses the development of pathogenic IL-17-producing CD4+ T cells (TH17) cells suggesting that pharmacological manipulations of IL-27 signaling pathway could be exploited therapeutically in regulating tissue inflammation. Here, we review how IL-27 controls inflammation through the regulation of Tr1 and TH17 responses.

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.).

References (103)

  • Y.K. Lee et al.

    Late developmental plasticity in the T helper 17 lineage

    Immunity

    (2009)
  • S. Huber et al.

    Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner

    Immunity

    (2011)
  • H. Wang et al.

    IL-27 induces the differentiation of Tr1-like cells from human naive CD4+ T cells via the phosphorylation of STAT1 and STAT3

    Immunol Lett

    (2011)
  • L. Xu et al.

    Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I

    Immunity

    (2010)
  • J. Wang et al.

    Interleukin-27 suppresses experimental autoimmune encephalomyelitis during bone marrow stromal cell treatment

    J Autoimmun

    (2008)
  • C.M. Sweeney et al.

    IL-27 mediates the response to IFN-beta therapy in multiple sclerosis patients by inhibiting Th17 cells

    Brain Behav Immun

    (2011)
  • P.S. Sorensen et al.

    Clinical importance of neutralising antibodies against interferon beta in patients with relapsing–remitting multiple sclerosis

    Lancet

    (2003)
  • G. Oldenhove et al.

    Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection

    Immunity

    (2009)
  • T.R. Mosmann et al.

    Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins

    J Immunol

    (1986)
  • I.A. Ferber et al.

    Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE)

    J Immunol

    (1996)
  • L.S. Jones et al.

    IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of a deviant effector response

    J Immunol

    (1997)
  • P. Matthys et al.

    Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice

    Eur J Immunol

    (1998)
  • S.A. Khader et al.

    IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge

    Nat Immunol

    (2007)
  • H.R. Conti et al.

    Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

    J Exp Med

    (2009)
  • D. Matusevicius et al.

    Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis

    Mult Scler

    (1999)
  • T. Aarvak et al.

    IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells

    J Immunol

    (1999)
  • S. Nakae et al.

    Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice

    J Immunol

    (2003)
  • K. Ghoreschi et al.

    Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling

    Nature

    (2010)
  • L. Codarri et al.

    RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation

    Nat Immunol

    (2011)
  • J.R. Huh et al.

    Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity

    Nature

    (2011)
  • E. Bettelli et al.

    Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

    Nature

    (2006)
  • P.R. Mangan et al.

    Transforming growth factor-beta induces development of the T(H)17 lineage

    Nature

    (2006)
  • D.J. Cua et al.

    Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

    Nature

    (2003)
  • M.J. McGeachy et al.

    The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo

    Nat Immunol

    (2009)
  • A. Awasthi et al.

    Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells

    J Immunol

    (2009)
  • X.J. Zhang et al.

    Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21

    Nat Genet

    (2009)
  • M.G. Roncarolo et al.

    Interleukin-10-secreting type 1 regulatory T cells in rodents and humans

    Immunol Rev

    (2006)
  • M.E. Brunkow et al.

    Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse

    Nat Genet

    (2001)
  • R.S. Wildin et al.

    X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy

    Nat Genet

    (2001)
  • C. Pasare et al.

    Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells

    Science

    (2003)
  • R. Bacchetta et al.

    High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells

    J Exp Med

    (1994)
  • C.F. Magnani et al.

    Killing of myeloid APC via HLA Class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells

    Eur J Immunol

    (2011)
  • C. Pot et al.

    Type 1 regulatory T cells (Tr1) in autoimmunity

    Semin Immunol

    (2011)
  • A. Awasthi et al.

    A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells

    Nat Immunol

    (2007)
  • D.C. Fitzgerald et al.

    Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells

    Nat Immunol

    (2007)
  • J.S. Stumhofer et al.

    Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10

    Nat Immunol

    (2007)
  • S. Pflanz et al.

    WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27

    J Immunol

    (2004)
  • C. Pot et al.

    Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cells

    J Interferon Cytokine Res

    (2010)
  • T. Yoshimoto et al.

    IL-27 suppresses Th2 cell development and Th2 cytokines production from polarized Th2 cells: a novel therapeutic way for Th2-mediated allergic inflammation

    J Immunol

    (2007)
  • S.C. Chae et al.

    Identification of polymorphisms in human interleukin-27 and their association with asthma in a Korean population

    J Hum Genet

    (2007)
  • Cited by (137)

    • Autoimmune diseases

      2022, Clinical Immunology
    • Azithromycin modulates Teff/Treg balance in retinal inflammation via the mTOR signaling pathway

      2021, Biochemical Pharmacology
      Citation Excerpt :

      In the meantime, Tregs, which can regulate the balance of the immune system and inhibit immune response, are potentiated by Azithromycin in EAU mice. Tregs are a class of immunosuppressive cells that include Foxp3 Treg and IL-10-secreting type 1 regulatory T cells [5,34–36]. To the best of our knowledge, Treg depletion leads to an enhanced retinal inflammatory response, which indicates that Tregs play a protective role in the development of uveitis [4].

    • Insights in intestinal immune tolerance: The role of the cleavage form of gasdermin D

      2024, Allergy: European Journal of Allergy and Clinical Immunology
    View all citing articles on Scopus
    1

    Authors equally contributed to the work.

    View full text