Transcription factors of the alternative NF-κB pathway are required for germinal center B-cell development

Abstract

The NF-κB signaling cascade relays external signals essential for B-cell growth and survival. This cascade is frequently hijacked by cancers that arise from the malignant transformation of germinal center (GC) B cells, underscoring the importance of deciphering the function of NF-κB in these cells. The NF-κB signaling cascade is comprised of two branches, the canonical and alternative NF-κB pathways, mediated by distinct transcription factors. The expression and function of the transcription factors of the alternative pathway, RELB and NF-κB2, in late B-cell development is incompletely understood. Using conditional deletion of relb and nfkb2 in GC B cells, we here report that ablation of both RELB and NF-κB2, but not of the single transcription factors, resulted in the collapse of established GCs. RELB/NF-κB2 deficiency in GC B cells was associated with impaired cell-cycle entry and reduced expression of the cell-surface receptor inducible T-cell costimulator ligand that promotes optimal interactions between B and T cells. Analysis of human tonsillar tissue revealed that plasma cells and their precursors in the GC expressed high levels of NF-κB2 relative to surrounding lymphocytes. Accordingly, deletion of nfkb2 in murine GC B cells resulted in a dramatic reduction of antigen-specific antibodysecreting cells, whereas deletion of relb had no effect. These results demonstrate that the transcription factors of the alternative NF-κB pathway control distinct stages of late B-cell development, which may have implications for B-cell malignancies that aberrantly activate this pathway.germinal center B cell | plasma cell | NF-κB transcription factors

The non-canonical NF-κB pathway in immunity and inflammation

“…3). It has also been shown that simultaneous deletion of Nfkb2 and RelB in GC B cells causes the collapse of established GCs 119 . Interestingly, NIK is also important for the survival of B cells that have undergone class switching, as well as the survival of fully differentiated plasma cells 118 .…”

“…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 formation 114 (not shown in Figure).…”

Plasma cell differentiation during the germinal center reaction

“…4,28 Previous immunohistochemical analyses of GCs demonstrated that IRF4 + , Bcl6 − , or Blimp-1 + cells are present within GCs, 29 suggesting that plasma cell-like cells can be already generated in the GC. 4,28 Previous immunohistochemical analyses of GCs demonstrated that IRF4 + , Bcl6 − , or Blimp-1 + cells are present within GCs, 29 suggesting that plasma cell-like cells can be already generated in the GC.…”

Mediation of transitional B cell maturation in the absence of functional Bruton’s tyrosine kinase

“…CD40 on B cells is known to provide pro-survival signals, possibly via the induction of anti-apoptotic members of the Bcl-2 family77, and while Btk has been argued to be involved downstream of CD40 as well80, there is also evidence for a Btk-independent TRAF2 recruitment step. Further, both canonical3377 and non-canonical pathways7888 of NF-kappaB activation have been shown downstream of CD40 signalling.…”