Roles of the NF- B Pathway in Lymphocyte Development and Function

Gerondakis, Steve; Siebenlist, Ulrich

doi:10.1101/cshperspect.a000182

Cited by 275 publications

(309 citation statements)

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“…2 C and D). These data show that canonical NF-κB signals are essential for the functional activity of follicular B cells, and complement a large body of evidence for the multifaceted role of this pathway in the control of humoral immunity (5,17,19).…”

Section: Significancementioning

confidence: 73%

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Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

Derudder

Herzog

Labi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although canonical NF-κB signaling is crucial to generate a normal mature B-cell compartment, its role in the persistence of resting mature B cells is controversial. To resolve this conflict, we ablated NF-κB essential modulator (NEMO) and IκB kinase 2 (IKK2), two essential mediators of the canonical pathway, either early on in B-cell development or specifically in mature B cells. Early ablation severely inhibited the generation of all mature B-cell subsets, but follicular B-cell numbers could be largely rescued by ectopic expression of B-cell lymphoma 2 (Bcl2), despite a persisting block at the transitional stage. Marginal zone (MZ) B and B1 cells were not rescued, indicating a possible role of canonical NF-κB signals beyond the control of cell survival in these subsets. When canonical NF-κB signaling was ablated specifically in mature B cells, the differentiation and/or persistence of MZ B cells was still abrogated, but follicular B-cell numbers were only mildly affected. However, the mutant cells exhibited increased turnover as well as functional deficiencies upon activation, suggesting that canonical NF-κB signals contribute to their long-term persistence and functional fitness. Numerous stimuli activate the NF-κB signaling pathways in mature B cells. In mammals, the NF-κB family of transcription factors comprises five members (RelA, RelB, c-Rel, NF-κB1, and NF-κB2) whose activation is initiated by two major signaling pathways (5). The canonical pathway depends on the IκB kinase (IKK) complex, consisting of the structural protein NF-κB essential modulator (NEMO) and the IκB kinases IKK1 and IKK2. This complex triggers the degradation of a specific set of inhibitors of NF-κB and the induction of dimers containing RelA and/or c-Rel. The canonical pathway regulates NF-κB activation downstream of the BCR (5). The stimulation of the alternative pathway, mediated by NF-κB-inducing kinase and IKK1, leads to the partial proteolysis of the inhibitory precursor NF-κB2 and the activation of dimers containing RelB and/or the processed form of NF-κB2 through another set of receptors, including BAFFR (4).There is abundant evidence for a critical role of the canonical pathway in the generation and/or maintenance of mature B cells. The ablation of NEMO or IKK2 in the B-cell lineage, as well as conditional replacement of the latter by a kinase-dead IKK2, impaired the generation of the three mature B subsets and transitional 2 (T2) cells, a developmental stage preceding the mature stage (6-9). In the case of the kinase-dead IKK2, some mutant cells made it into the mature compartment but were completely outcompeted by WT cells over a period of 4 wk, upon blockade of B-cell generation in the bone marrow (6). Mechanistically, tonic BCR signaling could increase the production of NF-κB2 via canonical NF-κB activation in T2 and follicular B cells, sensitizing B cells to the prosurvival effect of BAFFR (10).However, other work suggested that canonical signals downstream of the BCR may not be critical for the maintenance of mature fo...

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Section: Significancementioning

confidence: 73%

“…In contrast, the generation of MZ B and B1 cells was not rescued, possibly due to a role for canonical NF-κB signaling beyond cell survival (17), consistent with the inability of a Bcl2 transgene regulated by vav gene regulatory elements to promote the development of MZ B cells in NF-κB1-deficient mice (18).…”

Section: Significancementioning

confidence: 87%

Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

Derudder

Herzog

Labi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…T cells, in which p105 cannot undergo inducible processing to p50 also fail to proliferate normally [165]. In vitro, c-Rel is needed for production of IL-2 and therefore, for proliferation, but this need is not recapitulated in vivo [166]. Interestingly, c-Reldeficient T cells appear to have a defect in T H 1 proliferation and production of IFNγ, indicating a selective role for NF-κB family members in T H 1/T H 2 differentiation, independent of that mediated by the innate response.…”

Section: T-cell Responses Mediated By Nf-κbmentioning

confidence: 99%

“…Furthermore, B cells from rela −/− , nfkb1 −/− , nfkb2 −/− , and c-rel −/− mice all have increased sensitivity to apoptosis and/or decreased survival ex vivo [67,188,193]. In addition to contributing directly, it is thought that low level NF-κB activation in B cells contributes to survival through upregulation of p100, which is necessary for BAFFR-induced activation of the alternative pathway [67,75,166].…”

Section: Nf-κb and Lymphocyte Longevitymentioning

confidence: 99%

NF-κB in immunobiology

2011

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NF-κB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-κB is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-κB family of transcription factors. Although this is a well-studied area of NF-κB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-κB in mammalian immunobiology.

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“…Moreover, abnormal NF-kB pathway activation initiates the transformation of gastric lymphoid tissue [12]. The transcription factor NF-kB controls B and T cells maturation and survival, exerting an anti-apoptotic effect on these cells [29]. Through CagA and peptidoglycan fragment translocation, H. pylori increases NF-kB activity which results in the host immune response being modulated, hyperproliferation of lymphocytes and the potential induction of GML [2,17,18].…”

Section: Immune Response Modulation By H Pylorimentioning

confidence: 99%