MHC-II alleles shape the CDR3 repertoires of conventional and regulatory naïve CD4 <sup>+</sup> T cells
Н. Н. Логунова, Valeriia Kriukova, Pavel V. Shelyakin, Evgeny S. Egorov, Alina R. Pereverzeva, Nina G. Bozhanova, Mikhail Shugay, D. P. Shcherbinin, Mikhail V. Pogorelyy, Ekaterina M. Merzlyak, Vasiliy N. Zubov, Jens Meiler, Dmitriy M. Chudakov, Alexander Apt, Olga V. Britanova
Abstract
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.