MHC heterozygosity limits T cell receptor variability in CD4 T cells

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2024-07-12 DOI:10.1126/sciimmunol.ado5295

Alexander J. Brown, Janice White, Laura Shaw, Jimmy Gross, Andrei Slabodkin, Ella Kushner, Victor Greiff, Jennifer Matsuda, Laurent Gapin, James Scott-Browne, John Kappler, Philippa Marrack

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Abstract

αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this, we compared the TCR repertoires of naïve CD4 T cells in mice expressing one or two MHC alleles. Unexpectedly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes.

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MHC 杂合性限制了 CD4 T 细胞中 T 细胞受体的变异性。

αβ T 细胞受体（TCR）V(D)J 基因编码数十亿种 TCR 组合。然而，在任何个体的外周 T 细胞中，只有一部分会出现，因为胸腺细胞要成熟，必须与胸腺表达的主要组织相容性（MHC）/肽发生低亲和力而非高亲和力的反应。MHC 蛋白具有很强的多态性。不同的等位基因结合不同的肽。因此，任何个体都可能表达许多不同的 MHC 等位基因，以确保入侵者的某些肽与 MHC 结合并激活 T 细胞。然而，大多数个体表达的 MHC 等位基因数量有限。为了探究这个问题，我们比较了表达一种或两种 MHC 等位基因的小鼠的幼稚 CD4 T 细胞的 TCR 重排。出乎意料的是，杂合子小鼠的 TCR 种类少于其 MHC 等位基因亲属的 TCR 种类总和。我们的研究结果表明，胸腺负选择抵消了MHC杂合子中胸腺正选择增加的优势。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.