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 (TRM ) constitute the host defense sentinels posted in diverse anatomic compartments and they are the key actors in protection against reinfections, 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 (TcircM) transitioning through the peripheral tissue are the main defenders against reinfections and are underlying agents in autoimmune reactions. TRM, elicited after primary pathogen encounter in a given tissue, are now known to be stably positioned in the respective barrier (skin, lungs, gut, female reproductive tract mucosa, liver, etc.) or nonbarrier (brain, kidneys, etc.) peripheral tissues. TRM represent a rapid, tissue-autonomous, first line of robust adaptive immune defense against recurring infections. Following a discussion on the defining characteristics of TRM, this review will focus on how TRM 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 TRM in relapsing and remitting autoimmunity by being prepositioned in the tissue as potent effectors. Many infectious disease vaccines targeted to establish and activate TRM 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 TcircM. Likewise, TRM-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 TRM discoveries are piloting a new era of TRM-driven strategies focused on activation or inactivation of tissue-localized immunity in vaccines and therapies targeting infectious disease, cancer, autoimmunity, and allergies.