Analyzing the contributions of TCR affinity to the pathogenesis of experimental autoimmune encephalomyelitis (P4129)

Myelin oligodendrocyte glycoprotein (MOG) specific CD4+ T cell infiltrates from the central nervous system (CNS) have exhibited a range of affinities (low to high) for MOG peptide:MHC class II during peak EAE symptoms. Tetramer binding analyses and two-dimensional affinity assays have indicated that high affinity, MOG specific T cells comprise a rare yet significant population within the polyclonal repertoire; however, their functional contributions to the pathogenesis of chronic autoimmunity is not clear. Preliminary experiments suggested that a high precursor frequency (15 x 106) of polyclonal tetramer positive MOG specific T cells promotes early onset and greater disease severity when compared to tetramer negative T cells. Analysis of a high affinity MOG specific, CD4+ T cell (TCR Vα4β1) revealed a two dimensional affinity of 6.4x10-4 μm4 that was similar to the mean affinity (1.6x10-4 μm4) of pathogenic CD4+ T cells at peak LCMV Armstrong infection. Retrogenic models were used to assess the pathogenicity of TCR affinity in order to circumvent the limited number of endogenous high affinity T cells. The TCR Vα4β1 retrogenic mice developed spontaneous EAE even in the presence of FoxP3 positive (6%) T cells. T cells progressed though thymic selection without altering CD4 or TCR expression while maintaining their high two-dimensional affinity. Overall, MOG specific, high affinity CD4+ T cells are pathogenic and may predispose mice to a rapid progressive course of EAE.