Bioengineered organoid models of human germinal centers

Abstract

Abstract B cells undergo affinity maturation to T cell-dependent antigens within specialized microenvironments in secondary lymphoid organs termed germinal centers (GCs) resulting in the selective proliferation and differentiation of high-affinity B cells. Selection is driven by the ability of antigen-specific GC B cells to extract antigen presented on follicular dendritic cells and subsequently recruit stimuli from T follicular helper cells. Successful GC B cells ultimately differentiate into plasma cells that secrete large amounts of antigen-specific antibody, or memory B cells that contribute to long-term immunity. However, the factors that influence selection and differentiation of GC B cells in humans are not yet well understood. One challenge arises from the rapid loss of viability of human primary GC B cells ex vivo under conventional cell culture conditions. To overcome this, we bioengineered organoids using a customizable matrix along with modified feeder cell lines. When encapsulated in these organoids, primary human GC B cells exhibit enhanced viability similar to that of B cells in GCs in vivo. The low auto-fluorescent properties of these organoids allow for imaging of cellular interactions and migration. Furthermore, the customizable chemistry of the organoid matrix allows us to screen for factors that influence the differentiation and fate of human GC B cells. Improving our understanding of these processes may provide important insights in areas such as therapeutics and vaccine development.