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Abstract：
How T-cell receptor (TCR) characteristics determine subset commitment during T-cell development is still unclear. Here, we addressed this question for innate-like T cells, mucosal-associated invariant T (MAIT) cells, and invariant natural killer T (iNKT) cells. MAIT and iNKT cells have similar developmental paths, leading in mice to two effector subsets, cytotoxic (MAIT1/iNKT1) and IL17-secreting (MAIT17/iNKT17). For iNKT1 vs iNKT17 fate choice, an instructive role for TCR affinity was proposed but recent data argue against this model. Herein, we examined TCR role in MAIT and iNKT subset commitment through scRNAseq and TCR repertoire analysis. In our dataset of thymic MAIT cells, we found pairs of T-cell clones with identical amino acid TCR sequences originating from distinct precursors, one of which committed to MAIT1 and the other to MAIT17 fates. Quantitative in silico simulations indicated that the number of such cases is best explained by lineage choice being independent of TCR characteristics. Comparison of TCR features of MAIT1 and MAIT17 clonotypes demonstrated that the subsets cannot be distinguished based on TCR sequence. To pinpoint the developmental stage associated with MAIT sublineage choice, we demonstrated that proliferation takes place both before and after MAIT fate commitment. Altogether, we propose a model of MAIT cell development in which noncommitted, intermediate-stage MAIT cells undergo a first round of proliferation, followed by TCR characteristics-independent commitment to MAIT1 or MAIT17 lineage, followed by an additional round of proliferation. Reanalyzing a published iNKT TCR dataset, we showed that this model is also relevant for iNKT cell development.
摘要：
T细胞受体（TCR）特征如何决定T细胞发育过程中的亚组分类仍不清楚。这里,我们解决了先天样T细胞的问题，粘膜相关不变T（MAIT）细胞，和不变的自然杀伤T（iNKT）细胞。MAIT和iNKT细胞具有相似的发育路径,在小鼠中导致两个效应子子集，细胞毒性（MAIT1/iNKT1）和IL17分泌（MAIT17/iNKT17）。对于iNKT1vsiNKT17命运选择，提出了TCR亲和力的指导作用，但最近的数据反对这一模型。在这里，我们通过scRNAseq和TCR谱分析研究了TCR在MAIT和iNKT亚群承诺中的作用。在我们的胸腺MAIT细胞数据集中，我们发现一对T细胞克隆具有相同的氨基酸TCR序列，源自不同的前体，其中一个致力于MAIT1，另一个致力于MAIT17的命运。定量计算机模拟表明，这种情况的数量最好通过谱系选择与TCR特征无关来解释。MAIT1和MAIT17克隆型的TCR特征的比较表明，不能基于TCR序列来区分子集。为了确定与MAIT亚谱系选择相关的发育阶段，我们证明，扩散发生在MAIT命运承诺之前和之后。总之,我们提出了一个MAIT细胞发育模型，其中非承诺，中期MAIT细胞经历第一轮增殖，其次是TCR特征-对MAIT1或MAIT17谱系的独立承诺，随后又一轮扩散。重新分析已发布的iNKTTCR数据集，我们表明该模型也与iNKT细胞发育有关。
