B-cell antigens and cytokines targeted by biologics in clinical development. Schematic representation of B-cell/T-cell interaction and differentiation of activated B cells into antibody secreting plasma cells. B cells presenting antigen to T cells via HLA receive co-stimulatory signals from T-cell-expressed CD40 ligand (CD40L). CD4 T cells, in particular T follicular helper (TFH) cells, in turn receive activating signals from the B-cell-expressed ICOS ligand B7RP-1. Class switch recombination by B cells and plasma cell differentiation are critically dependent on IL-21 and co-stimulation through the CD40/CD40L pathway. The two TNF family members B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) provide survival signals by triggering their respective receptors expressed on B cells (BAFF receptor BR3 and transmembrane activator and calcium-modulating ligand interactor (TACI) on memory B cells) and plasma cells (BAFF/APRIL receptors B-cell maturation (BCMA) and TACI). B cells can also be directly targeted by antibodies against B-cell restricted antigens, such as CD20, CD22, and CD19. See text for additional details. BCR, B-cell receptor; TCR, T-cell receptor.