Methyltransferase Nsd2 Ensures Germinal Center Selection by Promoting Adhesive Interactions between B Cells and Follicular Dendritic Cells.

Antibody affinity maturation, which is an antigen-based selection process for B cells, occurs in germinal centers (GCs). GCB cells must efficiently recognize, acquire, and present antigens from follicular dendritic cells (FDCs) to receive positive selection signals from T helper cells. Previous studies showed that GCB cells undergo adhesive interactions with FDCs, but the regulatory mechanisms underlying the cell adhesions and their functional relevance remain unclear. Here, we identified H3K36me2 methyltransferase Nsd2 as a critical regulator of GCB cell-FDC adhesion. Nsd2 deletion modestly reduced GC responses but strongly impaired B cell affinity maturation. Mechanistically, Nsd2 directly regulated expression of multiple actin polymerization-related genes in GCB cells. Nsd2 loss reduced B cell adhesion to FDC-expressed adhesion molecules, thus affecting both B cell receptor (BCR) signaling and antigen acquisition. Overall, Nsd2 coordinates GCB positive selection by enhancing both BCR signaling and T cell help.