Thymocytes bearing αβ T cell receptors (TCRαβ) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8αα-expressing intraepithelial lymphocytes (CD8αα IELs). The factors that influence the choice between negative selection versus CD8αα IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8αα IEL development, we show that the affinity threshold for CD8αα IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.

带有对自肽-MHC 复合物具有高亲和力的 αβ T 细胞受体 (TCRαβ) 的胸腺细胞会经历负选择或转向替代 T 细胞谱系，这一过程称为激动剂选择。在携带仅限于 I 类 MHC 的 TCR 的胸腺细胞中，激动剂选择可导致前体细胞的发育，这些前体细胞可归巢于肠道并产生表达 CD8αα 的上皮内淋巴细胞 (CD8αα IEL)。影响负选择与 CD8αα IEL 发展之间选择的因素仍然很大程度上未知。使用支持负选择和 CD8αα IEL 发育的同步胸腺组织切片模型，我们表明 CD8αα IEL 发育的亲和力阈值高于负选择。我们还研究了肽呈递细胞和细胞因子的影响，以及与这些替代细胞命运相关的迁移模式。我们的数据强调了 TCR 亲和力和胸腺微环境对 T 细胞命运的作用。