Dendritic cells and anergic type I NKT cells play a crucial role in sulfatide-mediated immune regulation in experimental autoimmune encephalomyelitis

• Published in: The Journal of immunology (1950) Vol. 193; no. 3; pp. 1035 - 1046
• Main Authors: Maricic, Igor, Halder, Ramesh, Bischof, Felix, Kumar, Vipin
• Format: Journal Article
• Language: English
• Published: United States 01.08.2014
• Subjects: Adoptive Transfer - methods; Animals; Cattle; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; Clonal Anergy - drug effects; Clonal Anergy - immunology; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - pathology; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Humans; Inflammation - drug therapy; Inflammation - immunology; Inflammation - pathology; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - immunology; Multiple Sclerosis, Relapsing-Remitting - pathology; Myelin Proteolipid Protein - administration & dosage; Myelin Proteolipid Protein - therapeutic use; Natural Killer T-Cells - drug effects; Natural Killer T-Cells - immunology; Natural Killer T-Cells - pathology; Sulfoglycosphingolipids - administration & dosage
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302898

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.