Research Programs Unit, Translational Immunology, and Medicum, University of Helsinki, Haartmaninkatu 3, 00290, Helsinki, Finland.
Department of Computer Science, Aalto University, Konemiehenkatu 2, 02150, Espoo, Finland.
J Autoimmun. 2021 May;119:102616. doi: 10.1016/j.jaut.2021.102616. Epub 2021 Feb 27.
The T-cell receptor (TCR) repertoire is generated in a semistochastic process of gene recombination and pairing of TCRα to TCRβ chains with the estimated total TCR diversity of >10. Despite this high diversity, similar or identical TCR chains are found to recur in immune responses. Here, we analyzed the thymic generation of TCR sequences previously associated with recognition of self- and nonself-antigens, represented by sequences associated with autoimmune diabetes and HIV, respectively. Unexpectedly, in the CD4 compartment TCRα chains associated with the recognition of self-antigens were generated in significantly higher numbers than TCRα chains associated with the recognition of nonself-antigens. The analysis of the circulating repertoire further showed that these chains are not lost in negative selection nor predominantly converted to the regulatory T-cell lineage. The high abundance of self-reactive TCRα chains in multiple individuals suggests that the human thymus has a predilection to generate self-reactive TCRα chains independently of the HLA-type and that the individual risk of autoimmunity may be modulated by the TCRβ repertoire associated with these chains.
T 细胞受体 (TCR) 库是通过基因重组和 TCRα 与 TCRβ 链的配对的半随机过程产生的，估计 TCR 的总多样性超过 10。尽管存在这种高度多样性，但在免疫反应中发现类似或相同的 TCR 链反复出现。在这里，我们分析了先前与自身和非自身抗原识别相关的 TCR 序列在胸腺中的产生，这些序列分别代表与自身免疫性糖尿病和 HIV 相关的序列。出乎意料的是，在 CD4 区室中，与自身抗原识别相关的 TCRα 链的生成数量明显高于与非自身抗原识别相关的 TCRα 链。对循环库的分析进一步表明，这些链不会在阴性选择中丢失，也不会主要转化为调节性 T 细胞谱系。多个个体中高丰度的自身反应性 TCRα 链表明，人类胸腺具有独立于 HLA 类型产生自身反应性 TCRα 链的倾向，并且与这些链相关的 TCRβ 库可能会调节个体自身免疫的风险。
