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 (T_CM) CD8⁺ T cell subset, uncoupling the physical requirement for CD62L-mediated lymph node homing versus other functional attributes of T_CM 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. T_CM, but not effector memory (T_EM), 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 T_CM CD8⁺ T cells become cytolytic following rapid infiltration of the skin to protect against viral infection and subsequently differentiate into functional CD69+ tissue-residents.