IL-23 drives a pathogenic T cell population that induces autoimmune inflammation

Interleukin (IL)-23 is a heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-12 is important for the development of T helper (Th)1 cells that are essential for host defense and tumor suppression. In contrast, IL-23 does not promote the development of interferon-γ–producing Th1 cells, but is one of the essential factors required for the expansion of a pathogenic CD4+ T cell population, which is characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor. Gene expression analysis of IL-23–driven autoreactive T cells identified a unique expression pattern of proinflammatory cytokines and other novel factors, distinguishing them from IL-12–driven T cells. Using passive transfer studies, we confirm that these IL-23–dependent CD4+ T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.

[1]  R. Kastelein,et al.  IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-121 , 2004, The Journal of Immunology.

[2]  A. Amadori,et al.  The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignancies , 2004 .

[3]  A. Gurney,et al.  Compromised Humoral and Delayed-Type Hypersensitivity Responses in IL-23-Deficient Mice1 , 2004, The Journal of Immunology.

[4]  L. Joosten,et al.  Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of collagen-induced arthritis reduces joint inflammation, cartilage destruction, and bone erosion. , 2004, Arthritis and rheumatism.

[5]  A. Amadori,et al.  The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies. , 2004, The Journal of clinical investigation.

[6]  T. Mcclanahan,et al.  Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation , 2003, The Journal of experimental medicine.

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

[8]  J. Shellito,et al.  Cutting Edge: Roles of Toll-Like Receptor 4 and IL-23 in IL-17 Expression in Response to Klebsiella pneumoniae Infection1 , 2003, The Journal of Immunology.

[9]  S. Nakae,et al.  IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  C. Dong Inducible costimulator is essential for collagen-induced arthritis. , 2003, The Journal of clinical investigation.

[11]  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.

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

[13]  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.

[14]  Ruslan Medzhitov,et al.  Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells , 2003, Science.

[15]  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.

[16]  Daniel C. Douek,et al.  Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo , 2002, Nature Immunology.

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

[18]  M. Feldmann,et al.  Development of anti-TNF therapy for rheumatoid arthritis , 2002, Nature Reviews Immunology.

[19]  A. Gurney,et al.  IL‐17: prototype member of an emerging cytokine family , 2002, Journal of leukocyte biology.

[20]  F. Brombacher,et al.  A Protective and Agonistic Function of IL-12p40 in Mycobacterial Infection1 , 2001, The Journal of Immunology.

[21]  C. Samuel,et al.  The role of gamma interferon in antimicrobial immunity. , 2001, Current opinion in microbiology.

[22]  A. O’Garra,et al.  The molecular basis of T helper 1 and T helper 2 cell differentiation. , 2000, Trends in cell biology.

[23]  M. Byrne,et al.  Microbial Lipopeptides Induce the Production of IL-17 in Th Cells1 , 2000, The Journal of Immunology.

[24]  J Wagner,et al.  Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. , 2000, Immunity.

[25]  W. Maśliński,et al.  High Levels of IL-17 in Rheumatoid Arthritis Patients: IL-15 Triggers In Vitro IL-17 Production Via Cyclosporin A-Sensitive Mechanism1 , 2000, The Journal of Immunology.

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

[27]  P. Miossec,et al.  IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. , 1999, Journal of immunology.

[28]  R. Simone,et al.  Interferon-γ in Progression to Chronic Demyelination and Neurological Deficit Following Acute EAE , 1998, Molecular and Cellular Neuroscience.

[29]  R. de Waal Malefyt,et al.  Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. , 1998, The Journal of investigative dermatology.

[30]  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.

[31]  E. Shevach,et al.  IL-12 unmasks latent autoimmune disease in resistant mice , 1996, The Journal of experimental medicine.

[32]  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.

[33]  Meijuan Zhao,et al.  Interferon-γ-Induced Oligodendrocyte Cell Death: Implications for the Pathogenesis of Multiple Sclerosis , 1995, Molecular medicine.

[34]  J. Leonard,et al.  Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12 , 1995, The Journal of experimental medicine.

[35]  W. Hickey Migration of Hematogenous Cells Through the Blood‐Brain Barrier and the Initiation of CNS Inflammation , 1991, Brain pathology.

[36]  W. Carter,et al.  Extracellular matrix receptors, ECMRII and ECMRI, for collagen and fibronectin correspond to VLA‐2 and VLA‐3 in the VLA family of heterodimers , 1988, Journal of cellular biochemistry.

[37]  R. Hirsch,et al.  EXACERBATIONS OF MULTIPLE SCLEROSIS IN PATIENTS TREATED WITH GAMMA INTERFERON , 1987, The Lancet.