Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
Immunity. 2023 Mar 14;56(3):635-652.e6. doi: 10.1016/j.immuni.2023.01.026. Epub 2023 Feb 15.
Human T cell receptors (TCRs) are critical for mediating immune responses to pathogens and tumors and regulating self-antigen recognition. Yet, variations in the genes encoding TCRs remain insufficiently defined. Detailed analysis of expressed TCR alpha, beta, gamma, and delta genes in 45 donors from four human populations-African, East Asian, South Asian, and European-revealed 175 additional TCR variable and junctional alleles. Most of these contained coding changes and were present at widely differing frequencies in the populations, a finding confirmed using DNA samples from the 1000 Genomes Project. Importantly, we identified three Neanderthal-derived, introgressed TCR regions including a highly divergent TRGV4 variant, which mediated altered butyrophilin-like molecule 3 (BTNL3) ligand reactivity and was frequent in all modern Eurasian population groups. Our results demonstrate remarkable variation in TCR genes in both individuals and populations, providing a strong incentive for including allelic variation in studies of TCR function in human biology.
人类 T 细胞受体（TCRs）对于介导对病原体和肿瘤的免疫反应以及调节自身抗原识别至关重要。然而，编码 TCR 的基因的变异仍然定义不足。对来自四个人群（非洲人、东亚人、南亚人和欧洲人）的 45 个供体的表达 TCRα、β、γ和δ基因的详细分析揭示了 175 个额外的 TCR 可变和连接等位基因。这些基因大多数包含编码变化，并且在人群中以广泛不同的频率存在，这一发现通过使用来自 1000 基因组计划的 DNA 样本得到了证实。重要的是，我们鉴定了三个来自尼安德特人的、渐渗的 TCR 区域，包括一个高度分化的 TRGV4 变体，该变体介导了对丁酰膦蛋白样分子 3（BTNL3）配体反应性的改变，并且在所有现代欧亚人群中都很常见。我们的结果表明 TCR 基因在个体和人群中都存在显著的变异，这强烈促使人们在人类生物学中研究 TCR 功能时纳入等位基因变异。
