Regulatory T cell memory in human tissues

PROJECT SUMMARY T cell memory is stored across heterogeneous subsets with diverse functions in both tissues and circulation. While most studies have focused on the pro-inflammatory and cytotoxic functions of memory T cells, regulatory T cells (Tregs) serve an equally important immunomodulatory role in memory responses, particularly in tissues. While specific roles for Tregs in establishing tolerance and promoting tissue homeostasis have been elucidated in mouse models, the role of human Tregs in healthy immune responses and protective immunity in vivo has been difficult to assess. Moreover, the identity and function of human Tregs in diverse tissues remains unknown. We have established an organ donor tissue resource for human immunology that has allowed us to profile antigen-specific T cells across human tissues. Through these efforts, we found that antigen-specific Tregs are substantially enriched among memory T cells that respond to antigens from multiple viruses, including SARS-CoV-2, influenza, and EBV, and are particularly enriched in lymph nodes, spleen and lungs compared to blood, bone marrow and other sites. In addition, we found that memory Tregs induce an activation program that is distinct from effector memory T cells (TEM) involving CCL17 as a novel Treg-derived cytokine not produced by TEM cells or any other T cell subset. Moreover, tissue memory Tregs exhibit clonal overlap with TEM cells within and between sites. These findings raise the possibility that memory Tregs are generated along with TEM during priming and that they share a common pre-cursor with TEM. In the proposed studies, we will pursue three aims: 1) Determine the role of antigen and tissue in memory Treg induction; 2) Define the clonal and migratory relationships (i.e. tissue distributions) between memory Treg and other memory subsets; 3) Elucidate the functional and spatial interactions of tissue Tregs with immune and structural cells in the lymph node. We will combine state-of-the-art technologies for single-cell and spatial profiling with our unique human tissue resource to elucidate mechanisms for the generation, function, and maintenance of memory Tregs in human tissues. The results from this study will be important for designing strategies to promote immunoregulation and tissue repair for protective immunity and can inform Treg-directed therapies for autoimmunity and transplantation.