Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Dec 11:14:1185597.
doi: 10.3389/fimmu.2023.1185597. eCollection 2023.

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

Koushik Roy  1 , Mainak Chakraborty  2 , Ashok Kumar  1 , Asit Kumar Manna  1   3 , Neeladri Sekhar Roy  4
Affiliations
Review

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

Koushik Roy et al. Front Immunol. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
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
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 (TFH) cell and receive T cell help mediated by CD40 signaling (Note: TFH 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 TFH 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.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Laidlaw BJ, Cyster JG. Transcriptional regulation of memory B cell differentiation. Nat Rev Immunol (2021) 21:209–20. doi: 10.1038/s41577-020-00446-2 - DOI - PMC - PubMed
    1. Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol (2022) 40:413–42. doi: 10.1146/annurev-immunol-120419-022408 - DOI - PubMed
    1. Kuraoka M, Schmidt AG, Nojima T, Feng F, Watanabe A, Kitamura D, et al. . Complex antigens drive permissive clonal selection in germinal centers. Immunity (2016) 44:542–52. doi: 10.1016/j.immuni.2016.02.010 - DOI - PMC - PubMed
    1. Nakagawa R, Calado DP. Positive selection in the light zone of germinal centers. Front Immunol (2021) 12:661–78. doi: 10.3389/fimmu.2021.661678 - DOI - PMC - PubMed
    1. Nakagawa R, Toboso-Navasa A, Schips M, Young G, Bhaw-Rosun L, Llorian-Sopena M, et al. . Permissive selection followed by affinity-based proliferation of GC light zone B cells dictates cell fate and ensures clonal breadth. Proc Natl Acad Sci USA (2021) 118:e2016425118. doi: 10.1073/pnas.2016425118 - DOI - PMC - PubMed

Publication types

Grants and funding

This study is funded by the Department of Pathology, University of Utah and the American Society of Hematology Scholar Award to KR.

LinkOut - more resources