Central memory CD8+ T cells become CD69+ tissue-residents during viral skin infection independent of CD62L-mediated lymph node surveillance

Memory CD8+ T cells in the circulation rapidly infiltrate non-lymphoid tissues following infection and provide protective immunity in an antigen-specific manner. However, the subsequent fate of memory CD8+ T cells after entering non-lymphoid tissues such as the skin during a secondary infection is largely unknown. Furthermore, because expression of CD62L is often used to identify the central memory (TCM) CD8+ T cell subset, uncoupling the physical requirement for CD62L-mediated lymph node homing versus other functional attributes of TCM CD8+ T cells remains unresolved. Here, we show that in contrast to naïve CD8+ T cells, memory CD8+ T cells traffic into the skin independent of CD62L-mediated lymph node re-activation and provide robust protective immunity against Vaccinia virus (VacV) infection. TCM, but not effector memory (TEM), CD8+ T cells differentiated into functional CD69+/CD103- tissue residents following viral clearance, which was also dependent on local recognition of antigen in the skin microenvironment. Finally, we found that memory CD8+ T cells expressed granzyme B after trafficking into the skin and utilized cytolysis to provide protective immunity against VacV infection. Collectively, these findings demonstrate that TCM CD8+ T cells become cytolytic following rapid infiltration of the skin to protect against viral infection and subsequently differentiate into functional CD69+ tissue-residents.

循环中的记忆CD8+ T细胞可在感染后快速浸润非淋巴组织，并以抗原特异性方式介导保护性免疫。然而，二次感染过程中，记忆CD8+ T细胞进入皮肤等非淋巴组织后的后续命运，目前仍尚未明确。此外，由于CD62L的表达常被用于鉴定中枢记忆（TCM）CD8+ T细胞亚群，因此要解耦CD62L介导的淋巴结归巢的必要条件与中枢记忆CD8+ T细胞的其他功能属性，仍是尚未解决的科学难题。本研究发现，与初始CD8+ T细胞不同，记忆CD8+ T细胞可不依赖CD62L介导的淋巴结再活化而浸润皮肤，并能为抵御痘苗病毒（VacV）感染提供高效的保护性免疫。在病毒清除后，中枢记忆（而非效应记忆（TEM））CD8+ T细胞可分化为具有功能的CD69+/CD103-组织驻留细胞，这一过程同样依赖于皮肤微环境中的局部抗原识别。最后，本研究发现，记忆CD8+ T细胞浸润皮肤后可表达颗粒酶B，并通过细胞溶解作用为抵御痘苗病毒（VacV）感染提供保护性免疫。综上，本研究结果表明，中枢记忆CD8+ T细胞可在快速浸润皮肤后获得溶细胞活性以抵御病毒感染，并随后分化为具有功能的CD69+组织驻留细胞。