title: Activation of invariant NKT cells by alphaGalCer administration protects mice from MOG35-55-induced EAE: critical roles for administration route and IFN-gamma.
abstract: Invariant NKT (inv. NKT) cells co-express an invariant alpha beta T cell receptor and the NK receptor NK1.1 and, upon CD1d-restricted recognition of the glycosphingolipid antigen alpha-galactosyl ceramide (alphaGalCer), secrete large amounts of regulatory cytokines. We investigated whether alphaGalCer-dependent activation of inv. NKT cells protects from experimental autoimmune encephalomyelitis (EAE), an immune-mediated disease of the central nervous system mimicking multiple sclerosis, induced in C57BL/6 mice by the myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptide aa 35-55. alphaGalCer was administered at the time of immunization s.c., mixed with complete Freund's adjuvant and MOG35-55 peptide, or administered i.p., diluted in PBS. EAE onset was delayed and disease severity was decreased only when alphaGalCer was s.c. administered. The protective effect of s.c. administration of alphaGalCer was associated with a markedly enhanced IFN-gamma production by liver-confined inv. NKT cells which, in turn, suppressed Th1-cytokine production and fostered secretion of IL-10 from MOG35-55-specific T cells. In vivo neutralization of IFN-gamma, but notIL-4, reversed the protective effect induced by s.c. administration of alphaGalCer, further confirming the critical regulatory role exerted by IFN-gamma-producing inv. NKT cells. Our results indicate that alphaGalCer, properly administered, may elicit an inv. NKT-cell-mediated suppressive effect on the effector function of encephalitogenic T cells; this effect is able to ameliorate autoimmunedemyelination.
authors.affiliation: Neuroimmunology Unit-DIBIT, Department of Neurology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. furlan.roberto@hsr.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bergami
authors.forename: Daniela
authors.initials: D
authors.lastname: Cantarella
authors.forename: Elena
authors.initials: E
authors.lastname: Brambilla
authors.forename: Masaro
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Paolo
authors.initials: P
authors.lastname: Dellabona
authors.forename: Giulia
authors.initials: G
authors.lastname: Casorati
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D000519:alpha-Galactosidase / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D000519:alpha-Galactosidase