MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4 + T cells

Significance The landscape of naïve T cell receptors (TCRs) essentially determines the ability of the host to respond to vaccination, infection, and cancer and to control autoimmunity and inflammation. The diversity of naïve T cells is generated by semirandom recombination, followed by tight shaping during thymic selection against individual pools of self-peptide major histocompatibility complexes (MHCs). We characterize TCR repertoires of naïve conventional and regulatory CD4+ T cells produced in two different MHC-II contexts. We reveal profound differences in the diversity, convergence, and physicochemical properties of their antigen-interacting regions that indicate the distinct mode of TCR interaction with peptide–MHC-II. Such differences are likely to influence individual susceptibility to infections and autoimmunity and have implications for the future development of TCR-based diagnostics and therapies.