T-bet Regulates the Fate of Th1 and Th17 Lymphocytes in Autoimmunity1

IL-17-producing T cells (Th17) have recently been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. However, little is known about the transcription factors that regulate these cells. Although it is clear that the transcription factor T-bet plays an essential role in the differentiation of IFN-γ-producing CD4+ Th1 lymphocytes, the potential role of T-bet in the differentiation of Th17 cells is not completely understood. In this study, therapeutic administration of a small interfering RNA specific for T-bet significantly improved the clinical course of established EAE. The improved clinical course was associated with suppression of newly differentiated T cells that express IL-17 in the CNS as well as suppression of myelin basic protein-specific Th1 autoreactive T cells. Moreover, T-bet was found to directly regulate transcription of the IL-23R, and, in doing so, influenced the fate of Th17 cells, which depend on optimal IL-23 production for survival. We now show for the first time that suppression of T-bet ameliorates EAE by limiting the differentiation of autoreactive Th1 cells, as well as inhibiting pathogenic Th17 cells via regulation of IL-23R.

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

[2]  M. Kurrer,et al.  T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17 , 2006, The Journal of experimental medicine.

[3]  M. Racke,et al.  Peroxisome proliferator-activated receptor-α and retinoid X receptor agonists inhibit inflammatory responses of astrocytes , 2006, Journal of Neuroimmunology.

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

[5]  L. Presta,et al.  Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. , 2006, The Journal of clinical investigation.

[6]  R. D. Hatton,et al.  Transforming growth factor-β induces development of the TH17 lineage , 2006, Nature.

[7]  T. Huang,et al.  T-bet Binding to Newly Identified Target Gene Promoters Is Cell Type-independent but Results in Variable Context-dependent Functional Effects*♦ , 2006, Journal of Biological Chemistry.

[8]  B. Birnir,et al.  Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE , 2006, Nature Medicine.

[9]  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.

[10]  L. Glimcher,et al.  Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. , 2006, The Journal of clinical investigation.

[11]  R. Grencis.  Faculty Opinions recommendation of Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. , 2005 .

[12]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

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

[14]  L. Glimcher,et al.  T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Goldman,et al.  IL‐23 up‐regulates IL‐10 and induces IL‐17 synthesis by polyclonally activated naive T cells in human , 2005, European journal of immunology.

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

[17]  V. Kuchroo,et al.  IL-12– and IL-23–induced T helper cell subsets , 2005, The Journal of experimental medicine.

[18]  A. Lovett-racke,et al.  Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. , 2004, Immunity.

[19]  Toshifumi Hibi,et al.  T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease , 2004, Gut.

[20]  S. Szabo,et al.  Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis , 2004, The Journal of experimental medicine.

[21]  A. Lovett-racke,et al.  Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease1 , 2004, The Journal of Immunology.

[22]  L. Glimcher,et al.  T-bet Controls Autoaggressive CD8 Lymphocyte Responses in Type 1 Diabetes , 2004, The Journal of experimental medicine.

[23]  M. Kamoun,et al.  Differential expression and regulation of IL-23 and IL-12 subunits and receptors in adult mouse microglia , 2003, Journal of the Neurological Sciences.

[24]  B. Becher,et al.  IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. , 2003, The Journal of clinical investigation.

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

[26]  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.

[27]  Jorge R. Oksenberg,et al.  Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis , 2002, Nature Medicine.

[28]  S. Szabo,et al.  Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet , 2002, Science.

[29]  S. Szabo,et al.  Distinct Effects of T-bet in TH1 Lineage Commitment and IFN-γ Production in CD4 and CD8 T Cells , 2002, Science.

[30]  M. Neurath,et al.  Treatment of Allergic Airway Inflammation and Hyperresponsiveness by Antisense-Induced Local Blockade of Gata-3 Expression , 2001, The Journal of experimental medicine.

[31]  Xiao-Jun Ma,et al.  Tbt-1, a new T-box transcription factor induced in activated Th1 and CD8+ T cells , 2000, Immunogenetics.

[32]  Laurie H Glimcher,et al.  A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment , 2000, Cell.

[33]  P. Kivisäkk,et al.  Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis , 1999, Multiple sclerosis.

[34]  E. Shevach,et al.  Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. , 1994 .

[35]  W. Paul,et al.  Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease , 1994, Journal of Neuroimmunology.

[36]  L. Hood,et al.  Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity , 1993, Cell.

[37]  A. Lovett-racke,et al.  Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease. , 2004, Journal of immunology.

[38]  Jianfei Yang,et al.  T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells , 2002, Nature Immunology.