Human memory B and T cells (Bmem, Tmem) can be found in circulation and residing in lymphoid and non- lymphoid tissues. After infection and vaccination, we can follow antigen (Ag)-specific phenotypically-defined memory cells in blood, but we can't easily track Ag-specific clones of memory cells in blood over time and the cells are lost to us if they leave circulation and move into tissues. Our knowledge of the antigen (Ag)-specific Tmem and Bmem compartments in tissues, particularly non-lymphoid tissues, has been largely limited to single timepoint analyses. While we have learned much about the human immune system from these static and serial approaches, at the end of the day, these analyses still only provide us with “immune snapshots” of the Ag-specific memory clones and tissue resident memory cells. This limits us from asking key questions such as which signals facilitate or prevent the recruitment, retention, and survival of specific populations of tissue resident human memory cells. We are also unable to precisely measure the evolution of Ag-specific clones over time or assess whether microenvironment or immune perturbations influences the evolution and durability of these clones of cells. This knowledge gap is the basis for the Cooperative Centers in Human Immunology (CCHI) U19 application entitled “Evolution and Durability of Human T and B cell Responses”. The goal of this Program is to address the knowledge gap by leveraging our access to samples from organ transplant recipients to: (i) monitor cellular trafficking of memory cells from circulation into tissues over time; (ii) study the evolution of memory cells that reside in the tissue or respond to tissue specific Ags; and (iii) assess the durability of these memory populations over time and in response to changes in the environment. The central hypothesis addressed in this program is that the human immune memory compartment is constantly evolving in response to local and systemic signals that influence both the durability and reactivity profile of these cells. We will address this hypothesis in three research Projects that are supported by three scientific service Cores. Project 1 will address the factors that control the evolution and durability of memory B cells and antibody secreting cells that contribute to organ failure and rejection in kidney transplant patients. Project 2 will study the generation and durability of memory T cells that reside in the endometrium of uterus transplant patients. Project 3 will assess B cell and antibody responses in lung transplants. The three science service Cores will support the overarching goals of the Program and will provide the individual projects with the tools needed to track and analyze memory T cells, memory B cells and antibodies. We believe that the studies in this Proposal are important because they are designed to address fundamental questions about the generation, evolution and durability of human memory B and T cells. In the future, ...