title: Neuroantigen-specific autoregulatory CD8+ T cells inhibit autoimmune demyelination through modulation of dendritic cell function.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a well-established murine model of multiple sclerosis, an immune-mediated demyelinating disorder of the central nervous system (CNS). We have previously shown that CNS-specific CD8+ T cells (CNS-CD8+) ameliorate EAE, at least in part through modulation of CNS-specific CD4+ T cell responses. In this study, we show that CNS-CD8+ also modulate the function of CD11c+ dendritic cells (DC), but not other APCs such as CD11b+ monocytes or B220+ B cells. DC from mice receiving either myelin oligodendrocyte glycoprotein-specific CD8+ (MOG-CD8+) or proteolipid protein-specific CD8+ (PLP-CD8+) T cells were rendered inefficient in priming T cell responses from naïve CD4+ T cells (OT-II) or supporting recall responses from CNS-specific CD4+ T cells. CNS-CD8+ did not alter DC subset distribution or MHC class II and CD86 expression, suggesting that DC maturation was not affected. However, the cytokine profile of DC from CNS-CD8+ recipients showed lower IL-12 and higher IL-10 production. These functions were not modulated in the absence of immunization with CD8-cognate antigen, suggesting an antigen-specific mechanism likely requiring CNS-CD8-DC interaction. Interestingly, blockade of IL-10 in vitro rescued CD4+ proliferation and in vivo expression of IL-10 was necessary for the suppression of EAE by MOG-CD8+. These studies demonstrate a complex interplay between CNS-specific CD8+ T cells, DC and pathogenic CD4+ T cells, with important implications for therapeutic interventions in this disease.
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Venkatesh P
authors.initials: VP
authors.lastname: Kashi
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Sterling B
authors.initials: SB
authors.lastname: Ortega
authors.affiliation: Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D051940:B7-2 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology*
chemical_list: D001324:Autoantigens; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; C556062:IL10 protein, mouse; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D016753:Interleukin-10; D018664:Interleukin-12