Tissue-engineered Aged B Cell Immune Organoid to Study Antibody Secreting Cell Differentiation Trajectory

Georgia Institute Of Technology, Atlanta GA

Investigators

Abstract

RESEARCH SUMMARY Aged individuals, who are often at higher risk of fatality in life-threatening infectious diseases, do not form high- quality antibodies against new infections. Humoral immunity against infections depends on the germinal center (GC) differentiation process in the B cell follicles of lymph nodes. In GCs, naïve B cells rapidly proliferate in response to T cell-dependent antigens and somatically mutate into high-affinity antibody-secreting cells, i.e., plasma cells. B cells assume heterogeneous cell fates upon stimulation in young mice, with only a fraction differentiating into antibody-secreting cells (ASC). Notably, plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs. Chromatin accessibility changes correlate with gene expression and reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by the histone modification H3 lysine 27 trimethylation (H3K27me3), a Polycomb protein Enhancer of zeste homolog 2 (EZH2) catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and include the essential plasma cell transcription factor Blimp-1. Consequently, chemical inhibition of EZH2 results in enhanced plasma cell formation. A significant concern is that with aging, B cells exhibit a decreased expansion of B cells and GC reaction in response to antigen partly due to immune senescence and a defective follicular T helper cell (TFH) system. As a result, aged mice cannot generate sufficient GCs to provide insight into ASC fate and epigenomic remodeling of GC B cells, necessitating the development of a tissue-engineered model of an aged lymph node. Therefore, the long term goal of this R01 is to develop an ex vivo “aged B cell follicle” organoid technology capable of inducing early GC programming of aged B cells from both mice and humans and enabling the study of plasma cell fate and regulation of the epigenome of B cells to identify checkpoint targets that can be suppressed to boost GC response in aged B cells. The R01 brings together a multidisciplinary team of experts in GC organoids, vaccine, adjuvants, and lymphoid tissue engineering (Ankur Singh, PI, Georgia Tech) and GC immunology, ASC fate mapping and epigenomics (Jeremy Boss, Co-I, Emory Medicine), and microenvironment spatial omics (Ahmet Coskun, Co-I, Georgia Tech).