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

Vaccine adjuvant-elicited CD8+ T cell immunity is co-dependent on T-bet and FOXO1

Summary: T-bet and FOXO1 are transcription factors canonically associated with effector and memory T cell fates, respectively. During an infectious response, these factors direct the development of CD8+ T cell fates, where T-bet deficiency leads to ablation of only short-lived effector cells, while FOXO1 deficiency results in selective loss of memory. In contrast, following adjuvanted subunit vaccination in mice, both effector- and memory-fated T cells are compromised in the absence of either T-bet or FOXO1. Thus, unlike responses to challenge with Listeria monocytogenes, productive CD8+ T cell responses to adjuvanted vaccination require coordinated regulation of FOXO1 and T-bet transcriptional programs. Single-cell RNA sequencing analysis confirms simultaneous T-bet, FOXO1, and TCF1 transcriptional activity in vaccine-elicited, but not infection-elicited, T cells undergoing clonal expansion. Collectively, our data show that subunit vaccine adjuvants elicit T cell responses dependent on transcription factors associated with effector and memory cell fates