Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection
David E. J. Klawon, Nicole Pagane, Matthew T. Walker, Nicole K. Ganci, Christine H. Miller, Eric Gai, Donald M. Rodriguez, Bridgett K. Ryan-Payseur, Ryan K. Duncombe, Erin J. Adams, Mark Maienschein‐Cline, Nancy E. Freitag, Ronald N. Germain, Harikesh S. Wong, Peter A. Savage
Abstract
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.