Modular Immune Organoids with Integrin Ligand Specificity Differentially Regulate Ex Vivo B Cell Activation

Germinal centers are dynamic structures within lymphoid tissues, which develop once B cells receive activating signals from surrounding immune cells. Germinal center B cells are small in number, heterogeneous, and prone to rapid apoptosis unless selected by the body to form memory B cells. Despite extensive research in the B cell differentiation process, the role of the lymphoid niche, in particular integrin ligands, in the development of early germinal center-like phenotype remains unclear. Here, we report a biomaterials-based modular immune organoid that enables development of early germinal-center phenotype in an integrin ligand-specific manner. We demonstrate the differential role of integrin α4β1- and αvβ3-binding ligands in the induction of GL7+ (GC-like) and GL7- (non-GC-like) phenotype in differentiating B cells while in the presence of CD40 ligand and interleukin-4. We further demonstrate the role of integrin ligand specificities in clustering of β3 integrin and B cell receptor on the surface of differentiated B cells in 3D organoids as compared to the classic 2D cocultures. The study demonstrates that biomaterials-based immune organoids represent an ex vivo platform technology, which recapitulates certain aspects of GC biology to understand the process of B cell differentiation and induction of immunological responses. This platform is particularly useful in understanding the role of selective biomolecular signals and the temporal dependency of immune responses to these signals.