MHC class II-regulated central nervous system autoaggression and T cell responses in peripheral lymphoid tissues are dissociated in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis

immune encephalomyelitis in MHC (RT1 in rat) congenic rats with overlapping MOG peptides. Immunodominance with regard to peptide-specific T cell respo nses was purely MHC class II dependent, varied between different MHC haplot ypes, and was linked to encephalitogenicity only in RT1.B-n/D-n rats. Pepti des derived from the MOG sequence 91-114 were able to induce overt clinical signs of disease accompanied by demyelinated CNS lesions in the RTI1.B-n/D -n and RT1(n) haplotypes. Notably, there was no detectable T cell response against this encephalitogenic MOG sequence in the RT1(n) haplotype in perip heral lymphoid tissue. However, CNS-infiltrating lymphoid cells displayed h igh IFN-gamma, TNF-alpha, and IL-4 mRNA expression suggesting a localizatio n of peptide-specific reactivated T cells in this compartment. Despite the presence of MOG-specific T and B cell responses, no disease could be induce d in resistant RTIl and RT1(u) haplotypes. Comparison of the number of diff erent MOG peptides binding to MHC class II molecules from the different RT1 haplotypes suggested that susceptibility to MOG-experimental autoimmune en cephalomyelitis correlated with promiscuous peptide binding to RT1.B and RT 1.D molecules. This may suggest possibilities for a broader repertoire of p eptide-specific T cells to participate in disease induction. We demonstrate a powerful MHC class II regulation of autoaggression in which MHC class II peptide binding and peripheral T cell immunodominance fail to predict auto antigenic peptides relevant for an autoaggressive response. Instead, target organ responses may be decisive and should be further explored.