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 TCRα and -β 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 naïve T cells. We established two mouse strains carrying distinct allelic variants of H2-A and analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4⁺ T (T_conv) and naïve regulatory CD4⁺ T (T_reg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-A^b) mice, the tuberculosis-susceptible H2-A^j 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 CDR3α and CDR3β, suggesting more stringent selection against a narrower peptide-MHC-II context. H2-A^j and H2-A^b mice have prominent reciprocal differences in CDR3α and CDR3β 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 naïve CD4⁺ T cell CDR3 landscape, which essentially defines adaptive response to infections and self-antigens.

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