CD8⁺ T cell self-tolerance permits responsiveness but limits tissue damage

Self-specific CD8⁺T cells can escape clonal deletion, but the properties and capabilities of such cells in a physiological setting are unclear. We characterized polyclonal CD8⁺ T cells specific for the melanocyte antigen tyrosinase-related protein 2 (Trp2) in mice expressing or lacking this enzyme (due to deficiency in Dct, which encodes Trp2). Phenotypic and gene expression profiles of pre-immune Trp2/K^b-specific cells were similar; the size of this population was only slightly reduced in wild-type (WT) compared to Dct-deficient (Dct^-/-) mice. Despite comparable initial responses to Trp2 immunization, WT Trp2/K^b-specific cells showed blunted expansion and less readily differentiated into a CD25⁺proliferative population. Functional self-tolerance clearly emerged when assessing immunopathology: adoptively transferred WT Trp2/K^b-specific cells mediated vitiligo much less efficiently. Hence, CD8⁺ T cell self-specificity is poorly predicted by precursor frequency, phenotype, or even initial responsiveness, while deficient activation-induced CD25 expression and other gene expression characteristics may help to identify functionally tolerant cells.