Abstract
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.
Highlights
Given their importance in orchestrating immune responses, both quantitatively and qualitatively, it is not surprising that much work has focused on the actions of CD4+ T helper cell responses to myelin autoantigens
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
Our own previous studies using immunization with the recombinant extracellular domain of mouse MOG had not identified additional naturally processed epitopes, out with the 35–55 region, that were recognized by T cells from WT C57BL/6 mice (Sweenie et al, 2007)
Summary
Given their importance in orchestrating immune responses, both quantitatively and qualitatively, it is not surprising that much work has focused on the actions of CD4+ T helper cell responses to myelin autoantigens. The clear importance of HLA class II alleles in genetic susceptibility to multiple sclerosis (MS) supports this (Holmes et al, 2005) as do studies in experimental autoimmune encephalomyelitis (EAE) which have overwhelmingly described this disease being absolutely dependent on the CD4+ T cell compartment (Zamvil et al, 1985; Flugel et al, 1999). A series of elegant studies have identified means by which immunological tolerance to MHC class II-restricted T cell epitopes of myelin can fail, providing for the immunodominance of certain encephalitogenic peptide antigens (reviewed in Goverman, 1999; Anderton and Wraith, 2002).
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