Role of Regulatory T Cell Antigen Specificity in T Cell Tolerance, Autoimmunity, and Self-Nonself Discrimination

Foxp3+ regulatory T (Treg) cells maintain immune tolerance throughout life by preventing the activation of self-reactive CD4+ conventional T (Tconv) cells. T cells recognize protein-derived peptides presented on host MHC-II molecules (pMHC-II antigen complexes) using a unique T cell receptor (TCR). T cell activation is initiated upon TCR recognition of specific pMHC-II ligands. For the large array of self-pMHC-II displayed throughout the body at steady-state, it is unclear whether CD4+ T cell tolerance must be imparted for individual pMHC-II complexes, or if broad mechanisms of suppression maintain immune homeostasis across multiple T cell specificities. During infections, Treg cells must control Tconv cells reactive to self-derived peptide ligands while permitting Tconv cells that recognize pathogen-derived foreign antigens, yet the basis of this selectivity is unknown. Using mice in which T cell selection on a single prostate-specific self-pMHC-II ligand is altered, we demonstrate that tolerance is maintained under homeostatic conditions. In distinct settings of inflammation, including pathogen-associated epitope mimicry or T cell transfer to a lymphopenic environment, mice developed fulminant prostate-specific autoimmunity. Mechanistically, this self-pMHC-II complex directs antigen-specific cells into the Foxp3+ regulatory T cell lineage during development but does not induce clonal deletion to a measurable extent. This single specificity of Treg cells selectively constrains Tconv cell reactive to the same pMHC-II antigen to prevent T cell infiltration of the prostate, but does not impact the concurrent Tconv cell response against multiple foreign pathogen-derived peptides. Our study reveals a two-tiered system of Treg cell-mediated control in which bystander mechanisms of suppression maintain tolerance at steady-state, while self-pMHC-specific Treg cells enforce self-nonself discrimination in settings of inflammation.