Activation and trafficking of CD8+ T cells during viral skin infection: immunological lessons learned from vaccinia virus

[Display omitted] •VacV skin infection generates highly functional effector and memory CD8+ T cells.•Both direct and cross-presentation of antigen activates naïve CD8+ T cells.•Effector and memory CD8+ T cells traffic into the skin during VacV infection.•CD8+ T cells migrate toward VacV-infected cells in the skin microenvironment.•Antigen in the skin generates TRM CD8+ T cells following VacV infection. Epicutaneous delivery of vaccinia virus (VacV) by scarification of the skin generates robust and durable protective immunity, which was ultimately responsible for eradicating smallpox from the human race. Therefore, infection of the skin with VacV is often used in experimental model systems to study the activation of adaptive immunity, as well as the development and functional features of immunological memory. Here, we describe recent advances using this viral infection to identify and characterize the mechanisms regulating the activation and trafficking of cytotoxic CD8+ T cells into the inflamed skin, the migratory features of CD8+ T cells within the skin microenvironment, and finally, their subsequent differentiation into tissue-resident memory cells.