Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection.

During infections, CD4(+) Foxp3(+) regulatory T (T(reg)) cells must control autoreactive CD4(+) conventional T (T(conv)) cell responses against self-peptide antigens while permitting those against pathogen-derived "nonself" peptides. We defined the basis of this selectivity using mice in which T(reg) cells reactive to a single prostate-specific self-peptide were selectively depleted. We found that self-peptide-specific T(reg) cells were dispensable for the control of T(conv) cells of matched specificity at homeostasis. However, they were required to control such T(conv) cells and prevent autoimmunity toward the prostate after exposure to elevated self-peptide during infection. Notably, the T(reg) cell response to self-peptide did not affect protective T(conv) cell responses to a pathogen-derived peptide. Thus, self-peptide-specific T(reg) cells promoted self-nonself discrimination during infection by selectively controlling T(conv) cells of shared self-specificity.