Local antigen in non-lymphoid tissue promotes resident memory CD8+ T cell formation during viral infection.

Abstract

Abstract Tissue-resident memory (TRM) CD8+ T cells are functionally distinct from their circulating counterparts and are potent mediators of host protection against re-infection. One largely accepted paradigm is that activated CD8+ T cells are able to freely migrate to non-lymphoid tissues and differentiate into TRM independent of local antigen recognition. In contrast, using skin infections with Vaccinia virus (VacV) expressing model antigens, we found that local antigen recognition had a profound impact on TRM formation. Activated CD8+ T cells trafficked to VacV-infected skin in an inflammation-dependent, but antigen-independent manner. However, following viral clearance, there was a subsequent ~50-fold increase in CD103+/CD69+ TRM formation when antigen was present in the tissue microenvironment. Secondary antigen stimulation in non-lymphoid tissue caused CD8+ T cells to rapidly express CD69 and be retained at the site of infection. Finally, TRM CD8+ T cells that formed during VacV infection in an antigen-dependent manner became potent stimulators of localized antigen-specific inflammatory responses in the skin. Thus, our studies indicate that the presence of antigen in the non-lymphoid tissue microenvironment plays a critical role in the formation of functional TRM CD8+ T cell populations, a finding with relevance for both vaccine design and prevention of inflammatory disorders.