Conditional Deletion of NF-κB–Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation

Brightbill, Hans; Jackman, Janet; Suto, Eric; Kennedy, H. A.; Jones, Charles; Chalasani, Sreedevi; Lin, Zhonghua; Tam, Lucinda; Roose-Girma, Meron; Balázs, Mercedesz; Austin, Cary D.; Lee, Wyne P.; Wu, Lawren C.

doi:10.4049/jimmunol.1401514

Cited by 56 publications

(74 citation statements)

References 76 publications

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“…The aim of this study was to investigate the B-cell intrinsic role of NIK by generating a new mouse strain harboring a conditional allele of NIK. By using CD19-Cre to delete NIK during B-cell development, we were able to show a significant reduction in the number of PP, which is consistent with the phenotype of NIK aly/aly and NIK-deficient mice [21]. Whereas NIK alyaly and NIK-deficient mice lack LN, the number and size of LN in NIK BKO mice was unchanged compared with control animals.…”

supporting

confidence: 78%

“…In addition, NIK-deficient and NIK aly/aly mice have deficits in immunoglobulin (Ig) production and germinal center formation. Recently, it was shown that deletion of NIK in mature cells leads to similar phenotypes, such as reduced B-cell populations and serum IgA levels [21]. To better understand the role of NIK in B-cell homeostasis, we generated mice that lack NIK specifically in B cells, either at an early stage of their development, or when these cells attempt to class switch.…”

Section: Introductionmentioning

confidence: 99%

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NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

et al. 2015

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NF-κB-inducing kinase (NIK) isAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe nuclear factor-κB (NF-κB) family of transcription factors is composed of a collection of structurally related proteins that modulate multiple physiological processes, ranging from immune responses to cell death or survival [1][2][3]. The five members include: p65 (RelA), p105/p50, RelB, p100/p52, and c-Rel. Activation of NF-κB signaling is mediated by two distinct pathways: the canonical and the noncanonical signaling pathways. NF-κB-inducing kinase (NIK) is a key regulator of the noncanonical pathway. It transduces signals from distinct members of the TNFR family and induces, via phosphorylation of IκB-specific kinase α, the procession of p100/RelB to p52/RelB, which then translocate as a heterodimer into the nucleus [4][5][6]. Although p52/RelB is the main complex induced by the noncanonical NF-κB pathway, the activation of other members of the NF-κB family might also be induced [7]. NIK, a member of the mitogen-activating protein 3 (MAP3) kinases, is continuously synthesized but protein levels are Correspondence: Dr. Nadine Hövelmeyer e-mail: hoevelme@uni-mainz.de undetectable in resting cells due to constitutive degradation [8,9]. However, following receptor activation, the degradation of NIK is inhibited, leading to its accumulation and downstream signaling. Unlike the canonical NF-κB pathway, which responds to diverse stimuli, the noncanonical pathway is activated by a small subset of ligands. In B cells, these include the CD40 ligand (CD40L), B-cell-activating factor belonging to the TNF family (BAFF), ligands of the lymphotoxin-β receptor (LT-βR) and TNF-related weak inducer of apoptosis (TWEAK) [10][11][12][13].It is well established that mice harboring a spontaneous mutation in the nik gene (NIK aly/aly mice), which prevents the association of NIK with IKKα, cannot activate the noncanonical NF-κB pathway [14]. Similar results have been obtained from NIK knockout mice [15]. Both mouse strains are devoid of lymph nodes (LNs) and Peyer's patches (PP), similarly to LT-βR-deficient mice [16]. Effective NIK activation is critical for BAFF receptor signaling, which, in turn, is critical for B-cell survival. As a consequence, mice lacking BAFF or BAFF receptor show a dramatic reduction in * These authors contributed equally to this work. Results B-cell-specific deletion of NIK leads to fewer B cells in BM, lymphoid organs, and peritoneumMice deficient in NIK and NIK aly/aly mice suffer from multiple deficiencies in the immune system including the lack of lymph nodes (LNs) and dramatic reductions in B-cell numbers [14,15]. This compound phenotype makes it difficult to determine whether the observed defects result from abnormal bone marrow (BM) derived cells such as B cells or from abnormalities in other cells of the body. In order to investigate the role of NIK in B cells, we generated mice in which exons 4-6 of the nik gene were flanked by loxP sites (N...

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confidence: 78%

Section: Introductionmentioning

confidence: 99%

NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

et al. 2015

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“…It is clear that continuous or periodic signals are required for the maintenance of mature GCs, as the involution of established GCs has been observed upon inhibition of CD40 signaling (41). Via specific conditional gene deletion within GC B cells, it has been shown that c-MYC, c-REL, and NF-κB-induced kinase, an upstream regulator of the alternative NF-κB pathway that can also activate the canonical pathway (42,43), are all required for the maintenance of established GCs (20,(44)(45)(46)(47). We here demonstrated that RELB and NF-κB2 have a similarly critical role in this process.…”

Section: Discussionmentioning

confidence: 65%

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

Silva

Anderson

Carette

et al. 2016

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

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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

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Section: Methodsmentioning

confidence: 99%

“…CD11c-Cre transgenic mice were obtained from Boris Reizis (Columbia University, New York) and were bred with NIK flox transgenic mice (33). NIK and Cre allele status was positively confirmed in all progeny by exon-specific genomic PCR as described elsewhere (33). All mice were housed under specific pathogen-free conditions, and all experiments were conducted in accordance with NIH Guide for the Care and Use of Laboratory Animals (34) using protocols approved by the Genentech Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

Dendritic cells require NIK for CD40-dependent cross-priming of CD8 ⁺ T cells

Katakam¹,

Brightbill²,

Franci³

et al. 2015

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

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Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB-inducing kinase) remains unclear. Because NIKdeficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c + cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8+ T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8+ DCs in vitro, namely antigen cross-presentation to CD8+ T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4 + T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.NIK | dendritic cells | CD8 T cells | cross-priming | antigen cross-presentation

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Conditional Deletion of NF-κB–Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation

Cited by 56 publications

References 76 publications

NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

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

Dendritic cells require NIK for CD40-dependent cross-priming of CD8 ⁺ T cells

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Conditional Deletion of NF-κB–Inducing Kinase (NIK) in Adult Mice Disrupts Mature B Cell Survival and Activation

Cited by 56 publications

References 76 publications

NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

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

Dendritic cells require NIK for CD40-dependent cross-priming of CD8 + T cells

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Dendritic cells require NIK for CD40-dependent cross-priming of CD8 ⁺ T cells