SUMMARY Since 1998, this grant has funded a body of work on skin immunology that most recently has focused on “skin resident” memory T cells, or TRM. Our work with Vaccinia virus (VACV) taught us a great deal about the biology of CD8 TRM, and their critical role in host defense against viral infection in peripheral tissues. While the VACV work elucidated CD8 TRM biology, more recent work has helped define the behavior and function of skin CD4 TRM. Additional work has contributed to understanding the lineage development of TRM, and showed that TRM and TCM derive from a common naïve T cell precursor. The corollary to this observation is that every TRM clone in peripheral tissue is mirrored by a TCR identical TCM clone in peripheral blood/secondary lymphoid tissue, suggesting that there are two compartments of adaptive immune memory—one in tissue, which is “backed up” in secondary lymphoid tissue. While the benefit of TRM is the maintenance of superior host defense in peripheral tissues, there is a “dark side” to TRM. Growing evidence suggests that pathogenic TRM mediate tissue-specific immune-mediated diseases as diverse as psoriasis and vitiligo, asthma, inflammatory bowel disease, rheumatoid and spondylo-arthritis, and insulin-dependent diabetes. We hypothesize that the difficulty in achieving durable remission in these diseases is because the genetic program of TRM is focused on maintaining their indefinite survival in tissues. While TRM’s disease-causing activity can be transiently blocked with immune suppressive drugs, there is currently no means of dislodging these pathogenic cells from tissue. As a result, these diseases are chronic and relapsing. In 2017, we reported that CD8 TRM in skin depend upon uptake of exogenous free fatty acids (FFA), which they use for mitochondrial oxidation and ATP generation. If either free fatty acid uptake or mitochondrial oxidation are blocked, CD8 TRM do not survive in peripheral tissue. We believe that blocking TRM lipid uptake and metabolism may dislodge pathogenic TRM from tissue, which is the overarching premise of this proposal. Accordingly, we seek to more fully characterize the evolution of TRM in tissue at the single cell level, extend and better characterize the dependence of CD8 TRM on exogenous lipid and lipid metabolism, test the lipid dependence of CD4 TRM , and test the hypothesis that blocking TRM lipid uptake and metabolism can dislodge them from tissue. This may forge a path towards more durable treatment of TRM-mediated disorders of skin and other tissues.