Figure 3. The non-canonical NF-κB pathway regulates GC reactions in multiple steps.

Immune responses to protein antigens involve the formation of germinal centres (GCs) within B cell follicles, in which activated B cells undergo clonal expansion and a series of differentiation events, which leads to the generation of antibody-secreting plasma cells or memory B cells. The initial step of GC formation involves interactions between antigen-primed T cells and B cells on the border of the T cell zone and the B cell follicle, which are required for differentiation of the CD4⁺ T cells into follicular helper T (T_FH) cells. The T cell–B cell interaction is initiated through TCR interaction with the MHC–antigen complex and also requires the ICOS–ICOSL interaction. Ligation of CD40 and BAFFR by their ligands, CD40L and BAFF, induces non-canonical NF-κB signalling in B cells, which is important for maintaining high levels of ICOSL expression and, thus, T_FH cell differentiation. T_FH cells, in turn, promote the clonal expansion and differentiation of B cells in the subsequent steps of GC reactions. Non-canonical nuclear factor-κB (NF-κB) signalling regulates GC reactions through promoting the survival of naive B cells, the differentiation of T_FH cells by inducing the expression of inducible co-stimulator ligand (ICOSL) in B cells, GC cell expansion, GC B cell survival, immunoglobulin (Ig) class switching, somatic hypermutation (SHM) and plasma cell survival^{60,62,76,117–119,121}. In addition, non-canonical NF-κB signalling also functions in stromal cells to mediate the induction of chemokines required for the formation of B cell follicles and the follicular dendritic cell network, which in turn are crucial for GC formation¹¹⁴ (not shown in Figure). BAFF, B cell activating factor; BAFFR, BAFF receptor; BCR, B cell receptor; CXCR5, CXC-chemokine ligand 5; DC, dendritic cell; FDC, follicular dendritic cell; TCR, T cell receptor.