Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus
Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus
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DOI：
10.1126/scitranslmed.aao2966
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发表时间：
2018-09-05
影响因子：
17.1
通讯作者：
Toubert, Antoine
中科院分区：
文献类型：
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作者：
Clave, Emmanuel;Araujo, Itaua Leston;Toubert, Antoine
胸腺是原始T细胞产生的主要淋巴器官；然而，除了年龄之外，控制其在健康人体内功能的参数仍然未知。我们利用外周血T细胞中的T细胞受体切除环（trec）作为胸腺功能的替代标记物，对1000名按年龄和性别分层的健康成人胸腺功能的变异性进行了表征。年龄和性别是唯一确定的影响胸腺功能的非遗传因素。TREC含量随着年龄的增长而下降，女性的TREC含量高于男性。此外，一项全基因组关联研究显示，在T细胞受体TCRA-TCRD位点（位于DD2和DD3基因段之间）存在一种与TREC数量相关的常见变异（rs2204985）。引人注目的是，将rs2204985 GG基因型的人造血干细胞移植到免疫缺陷小鼠体内，可以产生更高的trec、胸腺细胞计数和更高的TCR库多样性的胸腺。我们的群体免疫学方法揭示了影响健康成人胸腺功能的遗传位点，在精准医学中具有潜在的广泛意义。
The thymus is the primary lymphoid organ where naive T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age - and sex-stratified healthy adults of the Milieu Interieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.