Impact of aging on human B cell vaccine responses

PROJECT SUMMARY As humans age, their immune systems become dysfunctional. Specifically, aging impacts adaptive immunity leading to reduced response to vaccines. A productive immune response to vaccines is characterized by high affinity antibodies and an increase in antigen-specific memory B and T cells. Intense research efforts have determined the role of T cells in aging; however the role of B cells is less clear. We hypothesize that humans, like mice, have age-related B cells (ABCs) in blood that can be tracked by clonal expansion, and in within tissue, outcompete important tissue specific B cell types, therefore limiting the capacity of older adults to respond to vaccines. We have assembled a team that span topic areas and technical expertise to address difficult questions of human B cell dysfunction with age. We utilize longitudinal and cross-sectional design to assess B cell aging in blood and lymphoid tissues. Further, we leverage a novel in vitro human tonsil organoid model we developed that allows mechanistic testing of age-induced B cell decline of vaccine responses, a feat previously impossible. In Aim 1, we will identify human ABCs by mapping dysregulation of phenotypic and functional B cell signatures over time. We hypothesize that ABCs are memory B cells that accumulated epigenetic changes, leading to a transcriptional program consisting of muted BCR responsiveness, dysregulated expansion, and defective function. We will analyze peripheral blood B cells and serum from a healthy aged longitudinal cohort using high-parameter flow cytometry and bulk RNA sequencing and multiplexing to track changes in B cell subsets, transcriptional profiles, BCR repertoires, and cytokine and antibody secretion. In Aim 2, we will target age-related mechanisms of lymphoid tissue B cell dysfunction to improve effective flu vaccine responses. ABCs are thought to derive from expansion of memory B cells. Therefore, we hypothesize that lymphoid tissues with high antigen exposure will have higher prevalence of ABCs and increased signatures of aging. Furthermore, we anticipate that targeting ABCs using a human tonsil organoid platform will improve flu vaccine responses. With unparalleled access to multiple post-mortem lymphoid tissues, we will compare B cells from young and older adults. We will use high parameter flow cytometry to enumerate B cell populations and perform single cell RNA sequencing on sorted B cells across human blood and tissues. Additionally, we will assess metabolism and cytokine secretion of aging B cells across tissues using extracellular flux analysis and multiplex cytokine profiling. Lastly, we will use a novel in vitro human tonsil organoid model to determine the cellular and molecular mediators of impaired vaccine responses. Understanding how age impacts B cell function will allow for improvement of vaccine design to increase B cell antibody responses, and therefore better protect the aging population of the world.