IL‐27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1

IL‐27 is an IL‐12‐related cytokine frequently present at sites of inflammation that can promote both anti‐ and pro‐inflammatory immune responses. Here, we have analyzed the mechanisms how IL‐27 may drive such divergent immune responses. While IL‐27 suppressed the development of proinflammatory Th17 cells, a novel role for this cytokine in inhibiting the development of anti‐inflammatory, inducible regulatory T cells (iTreg) was identified. In fact, IL‐27 suppressed the development of adaptive, TGF‐β‐induced Forkhead box transcription factor p3‐positive (Foxp3+) Treg. Whereas the blockade of Th17 development was dependent on the transcription factor STAT1, the suppression of iTreg development was STAT1 independent, suggesting that IL‐27 utilizes different signaling pathways to shape T cell‐driven immune responses. Our data thus demonstrate that IL‐27 controls the development of Th17 and iTreg cells via differential effects on STAT1.

[1]  Chen Dong,et al.  STAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells* , 2007, Journal of Biological Chemistry.

[2]  S. Zheng,et al.  IL-2 Is Essential for TGF-β to Convert Naive CD4+CD25− Cells to CD25+Foxp3+ Regulatory T Cells and for Expansion of These Cells1 , 2007, The Journal of Immunology.

[3]  L. Hennighausen,et al.  Interleukin 27 negatively regulates the development of interleukin 17–producing T helper cells during chronic inflammation of the central nervous system , 2006, Nature Immunology.

[4]  D. Danilenko,et al.  Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells , 2006, Nature Immunology.

[5]  H. Schild,et al.  Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27 , 2006, The Journal of experimental medicine.

[6]  J. Lohr,et al.  Regulatory T cells in the periphery , 2006, Immunological reviews.

[7]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[8]  R. D. Hatton,et al.  Transforming growth factor-beta induces development of the T(H)17 lineage. , 2006, Nature.

[9]  K. Takeda,et al.  IL-27 Suppresses CD28-Medicated IL-2 Production through Suppressor of Cytokine Signaling 31 , 2006, The Journal of Immunology.

[10]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[11]  R. Kastelein,et al.  IL-27 Limits IL-2 Production during Th1 Differentiation1 , 2006, The Journal of Immunology.

[12]  M. Nussenzweig,et al.  Inducing and expanding regulatory T cell populations by foreign antigen , 2005, Nature Immunology.

[13]  L. Klein,et al.  Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling , 2005, Nature Immunology.

[14]  A. Rudensky,et al.  A function for interleukin 2 in Foxp3-expressing regulatory T cells , 2005, Nature Immunology.

[15]  M. Neurath,et al.  Transforming growth factor β induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis , 2005, Gut.

[16]  T. Macdonald,et al.  Immunity, Inflammation, and Allergy in the Gut , 2005, Science.

[17]  T. Mak,et al.  The IL-27 Receptor Chain WSX-1 Differentially Regulates Antibacterial Immunity and Survival during Experimental Tuberculosis 1 , 2005, The Journal of Immunology.

[18]  H. Schild,et al.  EBV-Induced Gene 3 Transcription Is Induced by TLR Signaling in Primary Dendritic Cells via NF-κB Activation , 2005, The Journal of Immunology.

[19]  Y. Zohar,et al.  Suppression of Ongoing Experimental Autoimmune Encephalomyelitis by Neutralizing the Function of the p28 Subunit of IL-271 , 2004, The Journal of Immunology.

[20]  C. Hunter,et al.  Understanding the Pro- and Anti-Inflammatory Properties of IL-271 , 2004, The Journal of Immunology.

[21]  Peter R. Galle,et al.  Cutting Edge: TGF-β Induces a Regulatory Phenotype in CD4+CD25− T Cells through Foxp3 Induction and Down-Regulation of Smad7 , 2004, The Journal of Immunology.

[22]  J. Buer,et al.  Developmental Stage, Phenotype, and Migration Distinguish Naive- and Effector/Memory-like CD4+ Regulatory T Cells , 2004, The Journal of experimental medicine.

[23]  H. Nawata,et al.  TGF-β1 Plays an Important Role in the Mechanism of CD4+CD25+ Regulatory T Cell Activity in Both Humans and Mice , 2004, The Journal of Immunology.

[24]  M. David,et al.  Impaired Development of CD4+ CD25+ Regulatory T Cells in the Absence of STAT1 , 2004, The Journal of experimental medicine.

[25]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[26]  F. D. de Sauvage,et al.  IL-27 regulates IL-12 responsiveness of naïve CD4+ T cells through Stat1-dependent and -independent mechanisms , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Neurath,et al.  Disruption of T helper 2-immune responses in Epstein–Barr virus-induced gene 3-deficient mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. Mcclanahan,et al.  IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. , 2002, Immunity.

[29]  F.J. Sauvage,et al.  Development of Th1-type immune responses requires the type I cytokine receptor TCCR , 2000, Nature.

[30]  S. Akira,et al.  Stat3 activation is responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. , 1998, Journal of immunology.

[31]  A. Rolink,et al.  Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor , 1994, The Journal of experimental medicine.

[32]  K. Takeda,et al.  IL-27 suppresses CD28-mediated [correction of medicated] IL-2 production through suppressor of cytokine signaling 3. , 2006, Journal of Immunology.

[33]  M. C. Fantini,et al.  Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. , 2006, Gut.

[34]  武田 篤信.  Cutting edge : Role of IL-27/WSX-1 signaling for induction of T-bet through activation of STAT1 during initial Th1 commitment , 2003 .