PROJECT SUMMARY Given the recent SARS CoV2 pandemic, and monkeypox outbreak, there is an urgent unmet need to understand immunity in our barrier tissues (e.g. skin, lung, and gut) where viruses are encountered. Tissue specific memory is needed for long-lived protective immunity, including immunization strategies that target infections and cancers of the tissue. T resident memory cells are long-lived memory populations generated by infections, cancers, and vaccines. Tissue resident memory T cells maintain long-term protective immunity to re-encountered pathogens (which include CoV2 and influenza in lung, and herpes, monkeypox, and smallpox in skin). Tissue resident memory T cells also survey against primary cancers and metastases. However, in pathogenic contexts tissue resident memory cells drive autoimmune memory recall. This proposal tests intervenable regulatory mechanisms when skin-specific T resident memory cells are formed, maintained, and governed, and a regulatory axis with local tissue Dendritic Cells. Our goal is foundational: to understand the basic principles by which barrier immunity, and T cell receptor repertoire is generated and shaped in the tissues, like skin. We apply our findings to important and relevant in vivo mouse 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 basic insight into the foundational mechanisms by which specific immune-modulatory drugs drive tissue-specific toxicities in the skin and other peripheral organs of patients, known as immune-related adverse events (irAEs).

PUBLIC HEALTH RELEVANCE Infections and tumors evade early immune detection in barrier tissues such as the skin, lung, and gut. The application offers foundational insight into how tissue-specific immunity is generated, and maintained in our, for which there is a current urgent need, given the SARSCoV2 pandemic (lung) and Monkeypox (skin) outbreak. We predict mechanisms being investigated in this application are central to modeling better vaccine immunizations, to understanding the efficacy and toxicity from immune based drugs being used in patients, to generating better adoptive cell therapies, and to therapeutically limit autoimmunity.