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.