IL‐21 and IL‐21R are not required for development of Th17 cells and autoimmunity in vivo

Th17 cells have been recognized as the central effectors in organ‐related autoimmune diseases. IL‐6 is a key factor that reciprocally regulates Th17 and Foxp3+ Treg differentiation by inhibition of TGF‐β induced Foxp3 and induction of RORγt, a Th17 lineage‐specific transcription factor. Recently IL‐21 has been suggested to induce RORγt and Th17 development in the absence of IL‐6. However, the relevance of IL‐21 for Th17‐dependent inflammatory responses in vivo remains unclear. In this study, we demonstrate that differentiation of IL‐17‐producing CD4 T cells, their recruitment to inflamed organs, and the development of autoimmune disease was not affected in il21R–/– and il21–/– mice in models of myelin oligodendrocyte glycoprotein‐induced autoimmune encephalitis and autoimmune myocarditis. IL‐6 induced Th17 differentiation independent of and much more potently than IL‐21 in vitro. These data suggest that IL‐6 is sufficient to drive Th17 development and associated autoimmunity in vivo in the absence of IL‐21 or IL‐21R.

[1]  M. Smyth,et al.  Cutting Edge: IL-21 Is Not Essential for Th17 Differentiation or Experimental Autoimmune Encephalomyelitis1 , 2008, The Journal of Immunology.

[2]  D. Levy,et al.  IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways , 2007, Nature Immunology.

[3]  A. D. Panopoulos,et al.  Essential autocrine regulation by IL-21 in the generation of inflammatory T cells , 2007, Nature.

[4]  Terry B. Strom,et al.  IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells , 2007, Nature.

[5]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[6]  L. Hennighausen,et al.  Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. , 2007, Immunity.

[7]  M. Kurrer,et al.  IL-21 receptor signaling is integral to the development of Th2 effector responses in vivo. , 2007, Blood.

[8]  M. Kurrer,et al.  Neutralization of IL‐17 by active vaccination inhibits IL‐23‐dependent autoimmune myocarditis , 2006, European journal of immunology.

[9]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[10]  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.

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

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

[13]  T. Mcclanahan,et al.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. , 2006, The Journal of clinical investigation.

[14]  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.

[15]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[16]  W. Leonard,et al.  Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation , 2005, Nature Reviews Immunology.

[17]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[18]  S. Nakae,et al.  Suppression of Immune Induction of Collagen-Induced Arthritis in IL-17-Deficient Mice 1 , 2003, The Journal of Immunology.

[19]  M. Kamoun,et al.  Induction of Experimental Autoimmune Encephalomyelitis in IL-12 Receptor-β2-Deficient Mice: IL-12 Responsiveness Is Not Required in the Pathogenesis of Inflammatory Demyelination in the Central Nervous System1 , 2003, The Journal of Immunology.

[20]  R. Kastelein,et al.  Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain , 2003, Nature.

[21]  A. Gurney,et al.  Interleukin-23 Promotes a Distinct CD4 T Cell Activation State Characterized by the Production of Interleukin-17* , 2003, The Journal of Biological Chemistry.

[22]  M. Kamoun,et al.  IL-12p35-Deficient Mice Are Susceptible to Experimental Autoimmune Encephalomyelitis: Evidence for Redundancy in the IL-12 System in the Induction of Central Nervous System Autoimmune Demyelination1 , 2002, The Journal of Immunology.

[23]  A. Satoskar,et al.  Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells , 2002, The Journal of experimental medicine.

[24]  B. Becher,et al.  Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. , 2002, The Journal of clinical investigation.

[25]  M. Kurrer,et al.  Dual Role of the IL-12/IFN-γ Axis in the Development of Autoimmune Myocarditis: Induction by IL-12 and Protection by IFN-γ1 , 2001, The Journal of Immunology.

[26]  W. Cowden,et al.  IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. , 1996, Journal of immunology.

[27]  L. Steinman,et al.  Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). , 1996, Journal of immunology.

[28]  D. Littman,et al.  The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. , 2006, Cell.

[29]  M. Kurrer,et al.  Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: induction by IL-12 and protection by IFN-gamma. , 2001, Journal of immunology.