Resident-Memory CD8 T Cells and mTOR: Generation, Protection, and Clinical Importance

Tissues such as the lung, skin, intestinal epithelium, and reproductive tract serve as a barricade against pathogen exposure for the entire body. Specifically within the skin and mucosal tissues, a population of resident CD8 T cells plays a salient role in the protection against infection. Resident-memory CD8 T cells (TRM) are a long-lived subset of memory CD8 T cells that do not re-circulate after taking up residence in the tissues. Traditionally memory CD8 T cells were conceptually divided into two subsets central (TCM) and effector (TEM) memory where TCM preferentially localized within secondary lymphoid tissues (SLO) and TEM circulated throughout the peripheral tissues. While the concept of TCM and TEM has been considerably explored, memory CD8 T cells found within barrier tissues do not totally fit within the TCM/TEM paradigm. Through the study of circulating CD8 T cells, our understanding of memory CD8 T cells has grown tremendously in the last 25 years. We now understand that it is not sufficient to simply generate large numbers of circulating memory CD8 T cells in order to enhance protection against localized infection. Developing clinical strategies that can enhance protection against mucosal pathogens will require a clear understanding of how memory CD8 T cells are generated and maintained within barrier tissues at the sites of initial pathogen exposure. We will outline our current understanding of TRM in respect to their generation, functional importance, and how future studies must shed light on how we can exploit TRM to develop the next generation of effective vaccines. GENERATION OF TISSUE-RESIDENTMEMORY CD8 T CELLS CD8 T cells are primed within tissue draining lymph nodes and lymphoid tissues. Once primed, CD8 T cells receive tissuespecific signals that allow them entry into tissues, which at steady-state are normally non-permissive to T cell migration (1). Upon entry into mucosal or skin tissues CD8 T cells take up residence and do not recirculate (2, 3). For T cells to enter the small intestine the integrin α4β7 and chemokine receptor CCR9 are important (4, 5). α4β7 and CCR9 expression is induced by dendritic cell-derived signals like the vitamin A metabolite retinoic acid (6). α4β7 is transiently expressed and the timing of its expression correlates with the window of opportunity for T cell migration into the small intestine (2, 4, 5). Primed T cells that enter mucosal tissues differentiate into TRM in response to tissue-derived signals, not limited to but including TGF-β and IL-15 (5, 7). Tissue-derived signals like TGF-β and IL-15 are not uniquely confined to barrier tissues, as their availability is also important for circulating CD8 T cells. TRM originate from KLRG1 effector cells, are not terminally differentiated, however, express lower levels of CD127 and CD122 than circulating memory CD8 T cells (7, 8). While TRM share a common naïve precursor with blood and SLO memory cells they are inherently different from their circulating counterparts (9). Unlike circulating memory CD8 T cells, TRM maintain expression of CD69 and elevated levels of Granzyme B, attributes akin to effector cells (2, 10, 11). Generation of TRM is dependent on CD69 as overexpression S1pr1 or deletion of CD69 in CD8 T cells limits TRM formation (7, 12). TRM also upregulate the integrin subunit CD103 whereas circulating memory CD8 T cells remain CD103 (2, 8). A qualitative feature that distinguishes circulating TCM and TEM from TRM is that regardless of infection or anatomical location TRM share a signature of core gene transcripts (7). Within this signature are genes involved in chemotaxis, adhesion, and co-stimulation. Expression of some genes associated with circulating memory cells are decreased, e.g., Eomes, S1pr1, and Ly6C. The signaling events that regulate the transcriptional programing of TRM is unknown.