title: Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis.
abstract: CD1d-restricted NKT cells can be divided into two groups: type I NKT cells use a semi-invariant TCR, whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the CNS tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. In this article, we have addressed the mechanism of regulation, as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of myelin proteolipid proteins 139-151/I-A(s)-tetramer(+) cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells (DCs) in the periphery, as well as CNS-resident microglia, are inactivated after sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover, tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not α-galactosylceramide, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune-regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Because CD1 molecules are nonpolymorphic, the sulfatide-mediated immune-regulatory pathway can be targeted for development of non-HLA-dependent therapeutic approaches to T cell-mediated autoimmune diseases.
authors: Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and.
authors: Igor
authors: I
authors: Maricic
authors: Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and.
authors: Ramesh
authors: R
authors: Halder
authors: Department of Neurology, University of Tubingen, Tubingen D-72076, Germany.
authors: Felix
authors: F
authors: Bischof
authors: Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121; and vkumar@tpims.org.
authors: Vipin
authors: V
authors: Kumar
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002417:Cattle; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000627:therapeutic use; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D013433:Sulfoglycosphingolipids / Q000008:administration & dosage*
chemical_list: D018991:Myelin Proteolipid Protein; D013433:Sulfoglycosphingolipids