The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells

Abstract

Memory B cells and antibody-secreting cells are the two prime effector B cell populations that drive infection- and vaccine-induced long-term antibody-mediated immunity. The antibody-mediated immunity mostly relies on the formation of specialized structures within secondary lymphoid organs, called germinal centers (GCs), that facilitate the interactions between B cells, T cells, and antigen-presenting cells. Antigen-activated B cells may proliferate and differentiate into GC-independent plasmablasts and memory B cells or differentiate into GC B cells. The GC B cells undergo proliferation coupled to somatic hypermutation of their immunoglobulin genes for antibody affinity maturation. Subsequently, affinity mature GC B cells differentiate into GC-dependent plasma cells and memory B cells. Here, we review how the NFκB signaling system controls B cell proliferation and the generation of GC B cells, plasmablasts/plasma cells, and memory B cells. We also identify and discuss some important unanswered questions in this connection.

Keywords: B cell; NFκB; and cell signaling; memory B cell; plasma cell.

Figure 1

Schematic of canonical and non-canonical NFκB activation in B cell. TLR and IgM-mediated BCR signaling activate the canonical NFκB pathway (15, 35). IgD-mediated BCR signaling may activate both the canonical and non-canonical NFκB pathway (41, 42). CD40 and BAFF activate the canonical and non-canonical NFκB pathways (15). The canonical signaling activates NEMO and IKK1/2 containing complex. The activated IKK1/2 phosphorylates members of the IκBs (IκBα, IκBβ, and IκBε here referred as IκBα/β/ε) bound with NFκB, leading to the degradation of IκBα/β/ε. The degradation of IκBα/β/ε releases IκB-bound NFκB, which translocates to the nucleus. The activated IKK1/2 phosphorylates IκB-like molecule p105, and ubiquitin-mediated degradation of p105 generates p50 with the formation of RelA:p50, cRel:p50 and p50:p50 (15, 22, 35). RelA:p50 and cRel:p50 dimers are transcriptional activators. p50:p50 dimer may function as a transcriptional inhibitor and are present in naïve mature B cell (35). B cell activation by canonical pathway replaces p50:p50 with RelA:p50 and cRel:p50 (15, 35). The non-canonical signaling stabilizes NIK and subsequent activation of IKK1. The activated IKK1 phosphorylates IκB-like molecule p100 and generates p52. The degradation of RelB-bound p100 generates RelB:p52 dimer, and its nuclear translocation (15). The multimeric association of p100 generates IκBδ. IκBδ remains predominantly bound with cRel:p50 and RelA:p50 dimers. The activated IKK1 degrades IκBδ and releases cRel:p50 and RelA:p50 dimers to the nucleus (16, 43).

Figure 2

Antigen-specific naïve B cells following antigen binding activate and grow in size. cRel:p50 dimer control activation/B cell growth (58, 59). Activated B cells proliferate in the extrafollicular foci or differentiate in GC B cells. cRel is required for B cell proliferation (15, 58, 60, 61). Whether cRel is required in B cells for GC initiation or formation is not yet clear (62). Proliferating B cells in the extrafollicular foci differentiated into memory B cells and plasmablast. cRel inhibits plasmablast differentiation (21), and BAFF signaling needed for GC-independent memory B cell generation suggests NFκB could control GC-independent memory B cell generation (63). GC has anatomically two distinct zones: dark and light zone. Activated B cells that enter GC and differentiate into GC B cells undergo proliferation coupled with somatic hypermutation in the dark zone. GC B cells in the dark zone rapidly proliferate and undergo somatic hypermutation of B cell receptors. GC B cells in the light zone acquire antigen from follicular dendritic cell (FDC). Light zone B cells present the antigen to the T follicular helper (T_FH) cell and receive T cell help mediated by CD40 signaling (Note: T_FH cell also provides other modes of help such as IL21, IL4, etc. Here, we emphasize only the CD40 signal). Long-lived plasma cells are generated from affinity-selected GC B cells. It is controversial whether affinity-based selection is required for the generation of GC-derived memory B cells. cRel is required for GC maintenance and likely control the light to dark zone transition (20). cRel may control BCR-mediated GC survival as BCR-activated light zone B cells show NFκB target gene expression (64). RelA is required, but cRel inhibits, for GC-derived plasma cell generation (20). RelB:p52 is required for cell cycle entry of GC B cells and likely control the interaction of GC B cells with T_FH cells (19). Thus, RelB:p52 control re-entry of GC B cells from light to dark zone. Both cRel and RelA control GC-derived memory B cell generation (65), and the conclusion is based on an induced GC-B cells culture system.