Heterogeneity in Thymic Emigrants: Implications for Thymectomy and Immunosenescence

The development of mature, antigen-inexperienced (naive) T cells begins in the thymus and continues after export into the periphery. Post-thymic maturation of naive T cells, in humans, coincides with the progressive loss of markers such as protein tyrosine kinase 7 (PTK7) and platelet endothelial cell adhesion molecule-1 (CD31). As a consequence, subpopulations of naive T cells can be recognised raising questions about the processes that give rise to the loss of these markers and their exact relationship to recent thymic emigrants (RTE). Here, we combine a mathematical survival analysis approach and data from healthy and thymectomised humans to understand the apparent persistence of populations of ‘veteran’ PTK7+T cells in thymectomised individuals. We show that a model of heterogeneity in rates of maturation, possibly linked to natural variation in TCR signalling thresholds or affinity for self-antigens, can explain the data. This model of maturation predicts that the average post-thymic age of PTK7+T cells will increase linearly with the age of the host suggesting that, despite the immature phenotype, PTK7+cells do not necessarily represent a population of RTE. Further, the model predicts an accelerated increase in the average post-thymic age of residual PTK7+T cells following thymectomy and may also explain in part the prematurely aged phenotype of the naive T cell pool in individuals thymectomised early in life.

成熟的抗原未接触初始T细胞（antigen-inexperienced (naive) T cells）的发育始于胸腺，并在迁出至外周循环后仍持续进行。在人类中，初始T细胞的胸腺后成熟过程，与蛋白酪氨酸激酶7（protein tyrosine kinase 7, PTK7）、血小板内皮细胞黏附分子-1（platelet endothelial cell adhesion molecule-1, CD31）等标志物的进行性丢失同步发生。因此可通过上述标志物识别初始T细胞的亚群，这也引发了相关科学问题：究竟是哪些过程介导了这些标志物的丢失，以及这些亚群与近期胸腺迁出细胞（recent thymic emigrants, RTE）之间的确切关系如何。本研究结合数学生存分析方法与健康及胸腺切除人群的实验数据，旨在解析胸腺切除个体中“资深”PTK7阳性T细胞群体持续存在的现象。研究表明，成熟速率存在异质性的模型——该异质性可能与T细胞受体（T cell receptor, TCR）信号阈值或自身抗原亲和力的自然变异相关——能够合理解释上述实验数据。该成熟模型预测，PTK7阳性T细胞的平均胸腺后年龄会随宿主年龄呈线性增长，这提示尽管PTK7阳性细胞呈现未成熟表型，但其未必属于近期胸腺迁出细胞群体。此外，该模型还预测，胸腺切除术后残留的PTK7阳性T细胞的平均胸腺后年龄会加速升高，这也可在一定程度上解释早年接受胸腺切除术的个体中，初始T细胞池呈现早衰表型的现象。