What is the evolutionary mechanism for the TCR-MHC-conserved interaction? We extend Dembic's model (Dembic Z. In, Scand J Immunol e12806, 2019) of thymus positive selection for high-avidity anti-self-MHC Tregs among double (CD4 + CD8+)-positive (DP) developing thymocytes. This model is based on competition for self-MHC (+ Pep) complexes presented on cortical epithelium. Such T cells exit as CD4 + CD25+FoxP3 + thymic-derived Tregs (tTregs). The other positively selected DP T cells are then negatively selected on medulla epithelium removing high-avidity anti-self-MHC + Pep as T cells commit to CD4 + or CD8 + lineages. The process is likened to the competitive selection and affinity maturation in Germinal Centre for the somatic hypermutation (SHM) of rearranged immunoglobulin (Ig) variable region (V[D]Js) of centrocytes bearing antigen-specific B cell receptors (BCR). We now argue that the same direct SHM processes for TCRs occur in post-antigenic Germinal Centres, but now occurring in peripheral pTregs. This model provides a potential solution to a long-standing problem previously recognized by Cohn and others (Cohn M, Anderson CC, Dembic Z. In, Scand J Immunol e12790, 2019) of how co-evolution occurs of species-specific MHC alleles with the repertoire of their germline TCR V counterparts. We suggest this is not by 'blind', slow, and random Darwinian natural selection events, but a rapid structured somatic selection vertical transmission process. The pTregs bearing somatic TCR V mutant genes then, on arrival in reproductive tissues, can donate their TCR V sequences via soma-to-germline feedback as discussed in this journal earlier. (Steele EJ, Lindley RA. In, Scand J Immunol e12670, 2018) The high-avidity tTregs also participate in the same process to maintain a biased, high-avidity anti-self-MHC germline V repertoire.

中文翻译：

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TCR调节性T细胞和等位基因特异性MHC识别的共同进化。

TCR-MHC保守相互作用的进化机制是什么？我们扩展了Dembic的胸腺阳性选择模型（Dembic Z.In，Scand J Immunol e12806，2019），以在双（CD4 + CD8 +）阳性（DP）发育中的胸腺细胞中获得高抗性的自我MHC Treg。该模型基于皮质上皮细胞上自身MHC（+ Pep）复合物的竞争。此类T细胞以CD4 + CD25 + FoxP3 +胸腺来源的Tregs（tTregs）的形式退出。然后，其他阳性选择的DP T细胞在髓质上皮细胞中阴性选择，因为T细胞具有CD4 +或CD8 +谱系，因此去除了高抗性的自身MHC + Pep。这个过程类似于在生殖中心对具有抗原特异性B细胞受体（BCR）的中心细胞的重排免疫球蛋白（Ig）可变区（V [D] Js）的体细胞超突变（SHM）进行竞争性选择和亲和力成熟。我们现在认为，针对TCR的直接SHM过程发生在抗原后的生殖器中心，但现在发生在外周pTreg中。该模型为Cohn等人（Cohn M，Anderson CC，Dembic Z.In，Scand J Immunol e12790，2019）先前认识到的长期存在的问题提供了一种潜在的解决方案，该问题涉及物种特异性MHC等位基因与他们的种系TCR V对应物库。我们建议这不是“盲目”，缓慢和随机的达尔文式自然选择事件，而是快速结构化的体细胞选择垂直传播过程。然后，携带体细胞TCR V突变基因的pTregs到达生殖组织后，可以通过体细胞到种系的反馈捐赠它们的TCR V序列，如本杂志先前所讨论的。（Steele EJ，Lindley RA.In，Scand J Immunol e12670，2018）高亲和力tTreg也参与同一过程，以维持有偏见，高亲和力的反自身MHC生殖系V谱系。