How specificity for self-peptides shapes the development and function of regulatory T cells

The cataclysmic disease that develops in mice and humans lacking CD4(+) T cells expressing the transcription factor Foxp3 has provided abundant evidence that Foxp3(+)CD4(+) Tregs are required to suppress a latent autoreactivity of the immune system. There is also evidence for the existence of tissue-specific Tregs that can act to suppress regional autoimmune responses, suggesting that Tregs exert their effects, in part, through responding to self-peptides. However, how the immune system generates a repertoire of Tregs that is designed to recognize and direct regulatory function to self-peptides is incompletely understood. This review describes studies aimed at determining how T cell recognition of self-peptide(s) directs Treg formation in the thymus, including discussion of a modified avidity model of thymocyte development. Studies aimed at determining how TCR specificity contributes to the ability of Tregs to suppress autoimmune diseases are also discussed. J. Leukoc. Biol. 88: 1099-1107; 2010.