Investigating the local and systemic coordination of antiviral immunity by tissue-resident memory CD8 T cells in the skin

Project Summary/Abstract Cutaneous viral infections, including vector-borne viruses, cause significant morbidity and mortality. Vector-borne viruses are transmitted first to the skin through mosquito bites, then disseminate, causing a broad spectrum of frequently devastating disease. Yet, strategies to thwart cutaneous viruses remain elusive. Resident memory T cells (TRM) represent a promising target due to their potent effector functions and localization at barrier tissues including the skin. In contrast to recirculating memory T cells, TRM stably occupy nonlymphoid tissues (NLT) where they rapidly detect pathogen reinfection and initiate protective anamnestic immune responses. In fact, skin TRM can provide complete protection against cutaneous challenge through direct killing of infected cells and innate-like effector functions that establish an antiviral state. Extensive preliminary data supports the broad range of TRM functions that can be leveraged therapeutically. It is unknown, however, if skin TRM can be directed to limit viral spread in acute infection after targeted immunization. By focusing on antiviral CD8 TRM populations in the skin, this proposal will identify TRM functions in host immunity that may be harnessed against skin-borne infectious diseases. Building on preliminary data, Aim 1 will determine whether CD8 TRM reactivation orchestrates immune cells in the skin. Aim 2 will determine the extent to which skin TRM influence distal immunity. TRM must function from a fixed location, yet it is unclear if they are to serve as a local alarm or one that is amplified to enhance immunity at other sites. Observations that local inflammation has far-reaching effects on other tissues, creating a cascade of responses that heighten immunity at an organismal level lend credence to the idea TRM provoke systemic immune effects. By understanding how we can utilize TRM through TCR-dependent processes, we may be able to wield this population in a more broad manner. Given the many parallels between mouse and human TRM, findings in my studies using reductionist mouse models may readily be applied to clinical therapeutics.