Logunova Nadezhda N, Kriukova Valeriia V, Shelyakin Pavel V, Egorov Evgeny S, Pereverzeva Alina, Bozhanova Nina G, Shugay Mikhail, Shcherbinin Dmitrii S, Pogorelyy Mikhail V, Merzlyak Ekaterina M, Zubov Vasiliy N, Meiler Jens, Chudakov Dmitriy M, Apt Alexander S, Britanova Olga V
Laboratory for Immunogenetics, Central Institute for Tuberculosis, Moscow, 107564, Russia.
Department of Genomics of Adaptive Immunity, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, 117997, Russia.
Proc Natl Acad Sci U S A. 2020 Jun 16;117(24):13659-13669. doi: 10.1073/pnas.2003170117. Epub 2020 Jun 1.
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 and analyzed thymic and peripheral production and TCR repertoires of naïve conventional CD4 T (T) and naïve regulatory CD4 T (T) cells. Compared with tuberculosis-resistant C57BL/6 (H2-A) mice, the tuberculosis-susceptible H2-A mice had fewer CD4 T cells of both subsets in the thymus. In the periphery, this deficiency was only apparent for T and was compensated for by peripheral reconstitution for T We show that H2-A 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 and H2-A 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.
T细胞的成熟和激活取决于T细胞受体（TCR）与在特定主要组织相容性复合体（MHC）背景下展示的多种抗原肽的相互作用。互补决定区3（CDR3）是TCRα和β链中变化最大的部分，它决定了与肽-MHC复合物的相互作用。然而，在幼稚T细胞的胸腺选择过程中，CDR3图谱如何由个体MHC背景塑造仍不清楚。我们建立了两个携带不同等位基因变体的小鼠品系，并分析了幼稚常规CD4 T（T）细胞和幼稚调节性CD4 T（T）细胞的胸腺和外周产生情况以及TCR库。与抗结核的C57BL/6（H2-A）小鼠相比，易感结核的H2-A小鼠胸腺中两个亚群的CD4 T细胞都较少。在外周，这种缺陷仅在T细胞中明显，而T细胞通过外周重建得到补偿。我们发现，H2-A有利于选择更窄且更趋同的库，在CDR3α和CDR3β中间具有更多疏水且相互作用强烈的氨基酸残基，这表明针对更窄的肽-MHC-II背景进行了更严格的选择。H2-A和H2-A小鼠在CDR3α和CDR3β特征上存在显著的相互差异，这可能反映了TCR与MHC-II变体结合的不同模式。这些数据揭示了MHC-II塑造幼稚CD4 T细胞CDR3图谱的机制和程度，而CDR3图谱本质上定义了对感染和自身抗原的适应性反应。
