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

Nadezhda N. Logunova, Valeriia V. Kriukova, Pavel V. Shelyakin, Evgeny S. Egorov, Alina Pereverzeva, Nina G. Bozhanova, Mikhail Shugay, Dmitrii S. Shcherbinin, Mikhail V. Pogorelyy, Ekaterina M. Merzlyak, Vasiliy N. Zubov, Jens Meiler, Dmitriy M. Chudakov, Alexander S. Apt, Olga V. Britanova

    Research output: Contribution to journalArticlepeer-review

    11 Citations (Scopus)

    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 (Tconv) and naïve regulatory CD4+ T (Treg) cells. Compared with tuberculosis-resistant C57BL/6 (H2-Ab) 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 Tconv and was compensated for by peripheral reconstitution for Treg. We show that H2-Aj 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-MHCII context. H2-Aj and H2-Ab 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.

    Original languageEnglish
    Pages (from-to)13659-13669
    Number of pages11
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume117
    Issue number24
    DOIs
    Publication statusPublished - 16 Jun 2020

    Keywords

    • MHC-II
    • Naïve CD4 T cells
    • Regulatory T cells
    • TCR repertoire landscape

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