Cytokine regulation of recirculating and tissue-resident memory CD8+ T cells in homeostasis and inflammation - Project Summary/Abstract Memory CD8+ T cells are seeded throughout lymphoid and non-lymphoid tissues in the aftermath of acute infection. During this process, differentiation occurs into functionally distinct circulating and tissue-resident subsets which can then persist for years, decades, or even life. However, our understanding of this remarkable longevity is largely confined to studying circulating populations in homeostasis, neglecting the preponderance of tissue-resident memory T cells in non-lymphoid tissues and frequent perturbations caused by infection, inflammation, physiological and metabolic changes, etc. Through the proposed studies, the applicant will begin to address this knowledge gap by establishing how preexisting bystander memory CD8+ T cell subsets are maintained during homeostasis and infection via flexible use of cytokines, as addressed with infection models and cytokine therapy. Despite variable requirements for IL-15 between different memory CD8+ T cell populations, the applicant recently published that IL-15 sensitivity is a shared feature across memory subsets that operates within subset- and tissue-specific constraints. Dr. Jarjour proposes that as part of the memory CD8+ T cell program, memory cells gain the capacity to promiscuously utilize many different cytokines, thereby gaining resilience to stark alterations in availability during infection and other perturbations. This flexibility appears to operate within the confines of tissue- and subset-specific regulation, which the applicant will elucidate using his expertise in studying resident immune cells. Beyond revealing a key mechanism supporting durability of memory CD8+ T cells, these studies have implications for immunotherapies to expand memory CD8+ T cell populations, including during vaccination and cancer. The data generated through this proposal will form the basis for an R01 application and will position Dr. Jarjour for an independent career in basic immunology research, with long-term repercussions for human therapies.
