Department of Pediatrics, University of Vermont, Burlington, VT 05405, USA.
J Immunol. 2012 Sep 1;189(5):2356-64. doi: 10.4049/jimmunol.1200382. Epub 2012 Aug 1.
The generation of TCR proteins is the result of V(D)J recombinase-mediated genomic rearrangements at recombination signal sequences (RSS) in human lymphocytes. V(D)J recombinase can also mediate rearrangements at nonimmune or "cryptic" RSS in normal and leukemic human peripheral T cells. We previously demonstrated age- and gender-specific developmental differences in V(D)J coding joint processing at cryptic RSS within the HPRT locus in peripheral T cells from healthy children (Murray et al. 2006. J. Immunol. 177: 5393-5404). In this study, we investigated developmentally specific V(D)J recombinase TCRβ immune gene rearrangements and coding joint processing at RSS in peripheral T cells in the same pediatric population. This approach provided a unique opportunity to investigate site-specific V(D)J recombinase rearrangements and coding joint processing at immune and nonimmune genes from the same individual T cell population. We determined the genomic sequence of 244 TCRβ coding junctions from 112 (63 male, 49 female) subjects from the late stages of fetal development through 9 y of age. We observed both age- and gender-specific V(D)J recombinase-mediated TCRβ gene usage and coding joint processing at immune RSS. To the best of our knowledge, these data represent the first description of age- and gender-specific developmental differences in TCR gene usage and coding joint processing that could directly influence TCR diversity and immune specificity. It will be important for future studies to ascertain the mechanistic etiology of these developmental and gender differences in TCR diversity and specificity, as well as their importance with respect to the age and gender risks for infectious and autoimmune diseases in humans.
TCR 蛋白的产生是人类淋巴细胞中重组信号序列（RSS）介导的 V(D)J 重组酶基因座重排的结果。V(D)J 重组酶也可以介导正常和白血病人类外周 T 细胞中非免疫或“隐匿”RSS 的重排。我们之前证明了健康儿童外周 T 细胞中 HPRT 基因座内隐匿 RSS 处 V(D)J 编码连接加工存在年龄和性别特异性的发育差异（Murray 等人，2006 年。J. Immunol. 177：5393-5404）。在这项研究中，我们研究了同一儿科人群外周 T 细胞中 RSS 处发育特异性的 V(D)J 重组酶 TCRβ 免疫基因重排和编码连接加工。这种方法提供了一个独特的机会来研究来自同一个体 T 细胞群体的免疫和非免疫基因的特定部位 V(D)J 重组酶重排和编码连接加工。我们从晚期胎儿发育到 9 岁的 112 名（63 名男性，49 名女性）个体中确定了 244 个 TCRβ 编码连接的基因组序列。我们观察到免疫 RSS 处年龄和性别特异性的 V(D)J 重组酶介导的 TCRβ 基因使用和编码连接加工。据我们所知，这些数据代表了 TCR 基因使用和编码连接加工的年龄和性别特异性发育差异的首次描述，这些差异可能直接影响 TCR 多样性和免疫特异性。未来的研究将确定 TCR 多样性和特异性的这些发育和性别差异的机制病因及其在人类感染和自身免疫性疾病的年龄和性别风险方面的重要性。
