Tissue-Resident Memory T Cells: Sheltering-in-Place for Host Defense

A silent revolution has occurred in our understanding of how T cell-mediated immunity protects the host from recrudescent pathogens and how it fits into occurrences of autoimmunity and allergies. Under the new paradigm, the hitherto unknown noncirculatory, tissue-resident memory T cells (T-RM) constitute the host defense sentinels posted in diverse anatomic compartments and they are the key actors in protection against reinfection, tissue surveillance, cancer, and in many cases in autoimmunity and allergy in both animal models and humans. This contrasts with the previously held view that circulating memory T cells (T-circM) transitioning through the peripheral tissue are the main defenders against reinfection and are underlying agents in autoimmune reactions. T-RM, elicited after primary pathogen encounter in a given tissue, are now known to be stably positioned in the respective bather (skin, lungs, gut, female reproductive tract mucosa, liver, etc.) or nonbanier (brain, kidneys, etc.) peripheral tissues. T-RM represent a rapid, tissue-autonomous, first line of robust adaptive immune defense against recurring infections. Following a discussion on the defining characteristics of T-RM, this review will focus on how T-RM seeding and induction at the site of recurrent pathogen invasion is now, and must continue to be, the governing principle in new vaccine designs. The review will also elaborate on the role of T-RM in relapsing and remitting autoimmunity by being prepositioned in the tissue as potent effectors. Many infectious disease vaccines targeted to establish and activate T-RM at the infection site in animal models are robustly more effective at host protection relative to their traditional, parenterally administered counterparts that only activate systemic T-circM. Likewise, T-RM-centered remedies are being successful in ameliorating T cell mediated autoimmunity in cases in which approaches based on circulatory T cells failed. Thus, the current and emerging T-RM discoveries are piloting a new era of T-RM-driven strategies focused on activation or inactivation of tissue-localized immunity in vaccines and therapies targeting infectious disease, cancer, autoimmunity, and allergies.