Project summary We face an unprecedented time in human history. There has never been a greater need to understand immunity in our barrier tissues (e.g. skin, lung, and gut). Peripheral memory T cells maintain protective long- term immunity to infections in tissue (including CoV2, influenza, herpes, and smallpox) and survey against primary cancers and metastases. Tissue specific memory is needed for long-lived protective immunity, including tissue immunization strategies, targeting infections and cancers of the tissue. This proposal tests how our long-lived memory T cells that reside in the skin are formed, maintained, and governed through a single regulatory axis and by cross-talk with local tissue Dendritic Cells. Our goal is foundational: to understand the basic principles by which barrier immunity is generated and shaped. We apply our findings to important and relevant in vivo models for infection and test the consequences for tissue inflammation, autoimmunity and protective memory recall. Establishing a mechanistic groundwork and robust preclinical modeling is needed to later test interventions. This work is also likely to offer insight into the pathophysiology of class of agents in clinical use driving tissue-specific toxicities in the skin and other peripheral organs known as as immune related adverse events (iRAEs).