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Whereas increased affinity enhances T cell competitiveness after immunization, the role of affinity in modulating the pathogenicity of self-reactive T cells is less established. To assess this, we generated two myelin-specific, class II MHC-restricted TCR that differ only in a buried hydroxymethyl that forms a common TCR β-chain V region variant. The variation, predicted to increase TCR stability, resulted in a ~3log(10) difference in TCR sensitivity with preserved fine specificity. The high-affinity TCR markedly diminished T cell pathogenicity. T cells were not deleted, did not upregulate Foxp3, and barring disease induction were predominantly naive. However, high-affinity CD4(+) T cells showed an altered cytokine profile characterized by the production of protective cytokines prior to experimental allergic encephalomyelitis induction and decreased effector cytokines after. Further, the high-affinity TCR promoted the development of CD4(-)CD8(-) and CD8(+) T cells that possessed low intrinsic pathogenicity, were protective even in small numbers when transferred into wild-type mice and in mixed chimeras, and outcompete CD4(+) T cells during disease development. Therefore, TCR affinities exceeding an upper affinity threshold may impede the development of autoimmunity through altered development and functional maturation of T cells, including diminished intrinsic CD4(+) T cell pathogenicity and the development of CD4(-)Foxp3(-) regulatory populations.

Altered Differentiation, Diminished Pathogenicity, and Regulatory Activity of Myelin-Specific T Cells Expressing an Enhanced Affinity TCR