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.