The role of T-cell receptor recognition of peptide:MHC complexes in the formation and activity of Foxp3⁺ regulatory T cells.

Foxp3(+) regulatory T (Treg) cells are required to prevent the immune system from spontaneously mounting a severe autoaggressive lymphoproliferative disease and can modulate immune responses in a variety of settings, including infections. In this review, we describe studies that use transgenic mice to determine how signals through the T-cell receptor (TCR) contribute to the development, differentiation, and activity of Treg cells in in vivo settings. By varying the amount and quality of the self-peptide recognized by an autoreactive TCR, we have shown that the interplay between autoreactive thymocyte deletion and Treg cell formation leads to a Treg cell repertoire that is biased toward low abundance agonist self-peptides. In an autoimmune disease setting, we have demonstrated that diverse TCR specificities can be required in order for Treg cells to prevent disease in a mouse model of autoimmune inflammatory arthritis. Lastly, we have shown that Treg cells initially selected based on specificity for a self-peptide can be activated by TCR recognition of a viral peptide, and that they can acquire a specialized phenotype and suppress antiviral effector cell activity at the site of infection. These studies provide insights into the pivotal role that TCR specificity plays in the formation and activity of Treg cells.