PROJECT SUMMARY Project 2: Genesis and dynamics of human endometrial resident memory T cells revealed by uterus transplant recipients Most T cells in the human body are located within individual tissues as antigen-experienced, resident memory T cells (TRM). However, much of the scientific knowledge about human T cells has been generated from studies of peripheral blood and secondary lymphoid organs where most T cells are naive. Unfortunately, many of the lessons learned from T cells in peripheral blood may therefore not apply to tissue resident immune cells because tissue environments shape immune cell differentiation and responses in ways that do not occur in other anatomic compartments. We therefore lack the knowledge necessary to manipulate tissue resident cells to our advantage to treat a variety of diseases and patient populations. Tissue resident memory T cells are an antigen-experienced, adaptive immune population that play a critical role in protective immunity to pathogens. We address this knowledge gap in this proposal through the study of TRM in the human uterine endometrium. Notably, TRM recruitment, composition, and longevity may be distinctly different in the human endometrium versus other tissues because the endometrium undergoes hundreds of cycles of coordinated tissue loss and regeneration over the course of a lifetime. We have combined cutting-edge next generation sequencing methodologies with access to the endometrium of healthy control volunteers and human uterus transplant recipients to answer questions about TRM trafficking and differentiation that will advance our understanding of human tissue immunity. We expect that this proposal will have particular impact for women's health and transplant recipients but may also inform vaccine strategies and cancer therapeutics as well. In summary, we expect that the knowledge generated by this proposal can be used to expand our capabilities to modulate the human immune system and treat a variety of human diseases.