PROJECT SUMMARY – Project 1 COVID remains a major killer and disruptor worldwide. We made fundamental contributions to the understanding of COVID and T and B cell immune memory after SARS2 infection and COVID vaccines. Those studies predominantly examined human blood. In Project 1 we now aim to complement those fundamental findings with studies of T and B cell memory of URT lymphoid tissue and nasal epithelium. Mechanistic studies, particularly in humans, are essential to inform on URT immune memory and the roles of long GCs in adaptive immune responses, but are currently sparse or nonexistent given the complexities for such experiments. Here we address these important knowledge gaps, synergizing with Project 2 and 3. We will do so through a series of experiments. Additionally, there are striking data demonstrating that (1) long GCs can exist after acute SARS2 infection, (2) long GCs can exist after a protein immunization, and (3) long GCs can exist after mRNA vaccination. The recent recognition of these long GCs to acute antigens significantly changes our understanding of immune responses, and long GCs appear to have great value for protective immunity and immune memory. We hypothesize that long GCs have broad impacts on adaptive immunity, including memory B cell affinity maturation, memory B cell functional properties, the functionality and durability of memory follicular helper T (TFH) cells, and characteristics of mucosal immunity in the upper airways. All of those attributes are directly examined in this Project. In both components (analyses of long GCs and analyses of URT immune memory), we will study multiple human cohorts, with particular focus on COVID-19 breakthrough infections and COVID-19 vaccinations.