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

T cell maturation and activation depend upon T cell receptor (TCR) interactions with a wide variety of antigenic peptides displayed in a given major histocompatibility complex (MHC) context. Complementarity-determining region 3 (CDR3) is the most variable part of the TCR alpha and -beta chains, which govern interactions with peptide-MHC complexes. However, it remains unclear how the CDR3 landscape is shaped by individual MHC context during thymic selection of naive T cells. We established two mouse strains carrying distinct allelic variants of H2-A and analyzed thymic and peripheral production and TCR repertoires of naive conventional CD4(+) T (T-conv) and naive regulatory CD4(+) T (T-reg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-A(b)) mice, the tuberculosissusceptible H2-Aj mice had fewer CD4(+) T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for T-conv and was compensated for by peripheral reconstitution for T-reg. We show that H2-A(j) favors selection of a narrower and more convergent repertoire with more hydrophobic and strongly interacting amino acid residues in the middle of CDR3 alpha and CDR3 beta, suggesting more stringent selection against a narrower peptide-MHC-II context. H2-A(j) and H2-A(b) mice have prominent reciprocal differences in CDR3 alpha and CDR3 beta features, probably reflecting distinct modes of TCR fitting to MHC-II variants. These data reveal the mechanics and extent of how MHC- II shapes the naive CD4(+) T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.