Recognition of a high affinity MHC class I-restricted epitope of myelin oligodendrocyte glycoprotein by CD8(+) T cells derived from autoantigen-deficient mice

CD4(+) T cells have a well-defined pathogenic role in experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS), yet CD8(+) T cells are commonly found in MS lesions. To determine whether immunological tolerance might impact differently on CD4(+) versus CD8(+) T cells, we studied T cell responses in mice genetically deficient for the central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG) versus wild type (WT) C57BL/6 mice. We show that MOG(-/-) mice have enhanced sensitivity to immunization with the immunodominant peptide of MOG (35-55), as evidenced by increased expansion of both CD4(+) and CD8(+) T cell subsets. Most strikingly, CD8(+) T cells from MOG(-/-) mice responded to a novel T cell epitope which binds to MHC class I with high affinity. Despite this, MOG-responsive CD8(+) T cells sourced from either WT or MOG(-/-) mice failed to initiate CNS inflammation upon transfer to MOG-sufficient mice. In our hands, this capacity was only found in CD4(+) T cells. However, MOG(-/-) CD4(+) cells did not show greater pathogenic activity than their WT counterparts. Our data indicate that, in the presence of endogenous MOG, CD8(+) T cells capable of responding to a MHC class I-restricted epitope that can be stably expressed are subject to rigorous control through central and/or peripheral tolerance.