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 naive 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. Author summary Following vaccination or resolution of viral infection, three distinct populations of virus-specific memory CD8(+) T cells are generated. Central memory cells (T-CM) circulate between blood and lymph nodes and are able to rapidly enter non-lymphoid tissues in response to infection or tissue injury. In contrast, effector memory (T-EM) are largely restricted to the blood and tissue-resident memory cells (T-RM) are primarily confined within non-lymphoid tissues. In this study, we set out to interrogate the functionality and lineage relationship of these memory populations following a secondary viral skin infection. Circulating memory CD8(+) T cells rapidly infiltrated the skin following viral infection and used cytolysis to provide robust protective immunity. T-CM, but not T-EM, trafficked into the skin and differentiated into functional T-RM following resolution of viral infection and this occurred independent of the ability of these cells to home into and survey peripheral lymph nodes. Altogether, our findings demonstrate that a defined lineage of circulating memory CD8(+) T cells are the principle responders against viral skin infection and also the precursors to secondary T-RM CD8(+) T cells that then form, which are important considerations for understanding host defense mechanisms against recurring viral infections and tissue-specific vaccine development.