Targeting T follicular helper cells for rejuvenating the aging germinal center

PROJECT SUMMARY As humans age, their immune systems become dysfunctional. Specifically, aging impacts adaptive immunity leading to a decline in vaccine induced secretion of high-affinity antibodies. We know a lot about cellular responses to vaccines in aged individuals from investigating their blood. However, antibody responses evolve in germinal centers (GCs) of secondary lymphoid organs, where T follicular helper cells (Tfh) facilitate the selection of plasma cells that produce high-affinity antibodies. Limited access to human tissues has prevented us from fully understanding how aging and age-associated frailty influences Tfh function in tissue and how they contribute to a concomitant decline in antibody responses. The overarching hypothesis of this proposal is that age- related changes in Tfh frequencies, positioning, and function in human lymphoid tissues contributes to reduced vaccine efficacy in older adults. To address this, I have developed a research plan, spanning both my training during the mentored K99 and independent R00 phase. Using a systems immunology approach, integrating orthogonal transcriptomic, epigenomic, and phenotypic readouts, I will quantify age-associated changes in Tfh heterogeneity in secondary lymphoid organs. I hypothesize that Tfh in secondary lymphoid organs accumulate epigenetic changes with age, resulting in a transcriptional state of reduced metabolic plasticity and muted cytokine responses, which is reminiscent of immune senescence. Next, using a novel in vitro human tonsil organoid model and with the help of training proposed in this application, I will identify features of Tfh that correlate with declining quality of antibodies following influenza vaccination in older adults. I hypothesize that vaccination in older adults will result in poor Tfh differentiation, limited clonal expansion, diminished phenotypic plasticity in GCs and consequently poor B cell help. Furthermore, I anticipate that Tfh- focused immune modulation will improve quality of the antibody response in older adults. To test this mechanistically, in the R00 phase, I will determine how Tfh frequencies and function contribute to poorly cross- reactive antibody responses in older adults. Finally, I will test strategies to rejuvenate the aging GC, by using immune modulatory agents targeting Tfh to overcome suboptimal influenza vaccine responses in older adults. Gaining insight into the factors influencing diminished Tfh responses as individuals age will lay the groundwork for enhancing vaccine effectiveness in older populations. The diverse scope of research outlined in this proposal and an assembled team of mentors, co-mentors, and collaborators will provide me with training in aging biology, microscopy, and antibody assays, which will complement my existing background in systems immunology. Collectively, this training will facilitate my progression towards establishing an independent research program at the nexus of immunology and aging.