Advances in Human and Animal Germinal Center Models In Vitro: New Approaches to Studying Immune Responses

Germinal centers (GCs) are dynamic structures in secondary lymphoid organs where B cells undergo antigen-driven clonal selection, affinity maturation by somatic hypermutation (SHM), and class switch recombination (CSR), resulting in the generation of high-affinity antigen-specific long-lived plasma cells and memory B cells. Reconstructing these processes in vitro is critical for mechanistic studies and for advancing translational applications in vaccinology and immunotherapy. This review examines human and murine approaches to in vitro models of GC-like reactions, including conventional cultures, three-dimensional (3D) scaffolds, organoids, and microfluidic systems. We summarize the stimuli and culture conditions used across studies, highlighting common requirements, as well as model-specific strategies. Most models effectively induced B cell proliferation, CSR, and plasma cell differentiation. In contrast, SHM and clonal selection, key features of the GC, were less frequently shown, reflecting the technical complexity of reproducing these events in vitro. Finally, we outline the main challenges in recreating a fully functional GC and suggest future directions for refining these models to more closely mimic the secondary lymphoid organ environment.