T cell receptor β-chains display abnormal shortening and repertoire sharing in type 1 diabetes.
T cell receptor β-chains display abnormal shortening and repertoire sharing in type 1 diabetes.
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DOI：
10.1038/s41467-017-01925-2
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发表时间：
2017-11-27
影响因子：
16.6
通讯作者：
Peakman M
中科院分区：
文献类型：
--
作者：
Gomez-Tourino I;Kamra Y;Baptista R;Lorenc A;Peakman M
T细胞受体（TCR）库的缺陷被认为是自身免疫的易感因素。在这里，我们通过分析来自1型糖尿病患者和健康供体的循环幼稚、中央记忆、调节和干细胞样记忆CD 4 + T细胞亚群的>2 × 108个TCRB序列，表明患者在所有细胞亚群中具有较短的TCRB互补决定区3s（CDR 3），这是由VDJ重排期间增加的缺失/减少的插入引入的。在非生产性TCRB序列中也观察到高频率的短CDR 3，其不经历胸腺剔除，表明较短的CDR 3独立于正/负选择而产生。此外，与抗病毒T细胞和来自健康供体的T细胞相比，由自身抗原特异性CD 4 + T细胞表达的TCRB CDR 3克隆型更短。因此，胸腺T细胞发育和库生成的早期事件在1型糖尿病中是异常的，这表明短CDR 3增加了自我识别的潜力，从而提高了自身免疫性疾病的风险。T细胞受体通过体细胞基因重组产生，并且通常针对自身反应性进行选择。在这里，作者表明，来自自身免疫性1型糖尿病患者的CD 4 T细胞具有较短的TCRβ序列，更广泛的库多样性和更多的库共享比健康个体。
Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2 × 108 TCRB sequences of circulating naive, central memory, regulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T cells are shorter compared with anti-viral T cells, and with those from healthy donors. Thus, early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease. T cell receptors are generated by somatic gene recombination, and are normally selected against autoreactivity. Here the authors show that CD4 T cells from patients with autoimmune type 1 diabetes have shorter TCRβ sequences, broader repertoire diversity, and more repertoire sharing than those from healthy individuals.
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