Tracking CD8+ T cell memory differentiation across different immune compartments in humans

Human CD8+ T cells are essential for control and clearance of viral infections. Following infection with most viral pathogens, effector CD8+ T cells undergo rapid clonal expansion to mediate viral control and limit disease progression. Upon antigen clearance, long-lived memory CD8+ T cells develop in order to launch an effective secondary response against future viral infections. Human immunological memory has so far been studied almost exclusively in the blood. However, recent studies from Prof. Marcus Buggert have demonstrated that blood is populated with unique memory CD8+ T cell subsets that do not recirculate through tissues at steady-state1. These data provide a conceptual advance in our understanding of human T cell biology and underscore that blood and tissues are anatomically comprised of different memory CD8+ T cell populations, which can rapidly execute different functions to limit viral spread after viral re-exposure.The goal of the proposed project is to characterize CD8+ T cell memory trajectories across different immunological compartments upon infection with a live attenuated virus. To do this end, I will take advantage of state-of-the-art single cell technologies such as multi-parameter flow cytometry, single cell RNA sequencing (scRNAseq) and TCR sequencing to study the primary and longitudinal CD8+ T cell response to yellow fever virus (YFV) vaccination in the blood, draining and non-draining lymph nodes of healthy volunteers. Furthermore, I will assess the role of genetic factors in this process by examining YFV-specific responses in pairs of homozygotic twins and, finally, identify cytokine signatures present in the lymph node and blood during the acute phase correlating to specific memory differentiation programs. By characterizing memory populations in the blood and lymph nodes during the primary response, at steady state, and during recall responses, our project will provide new insights on the respective role of blood vs. lymphoid memory pools in immunological memory. This will not only advance the current knowledge on protective immunity in infectious diseases, bringing about a significant advancement in basic human immunology, but also inform translation research strategies in immunization and immune modulation.