Tumor Necrosis Factor Receptor-associated Factor 2 (TRAF2)-deficient B Lymphocytes Reveal Novel Roles for TRAF2 in CD40 Signaling

Hostager, Bruce S.; Haxhinasto, Sokol; Rowland, Sarah L.; Bishop, Gail A.

doi:10.1074/jbc.m306708200

Cited by 117 publications

(242 citation statements)

References 55 publications

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“…JNK inhibitor VIII was obtained from Calbiochem Inc. (San Diego, CA). Hi5 insect cells expressing CD154 and controls have previously been described [48]. A Hi5 cell to B cell ratio of 1:10 was used for suboptimal stimulatory conditions of B cells; a 1 : 5 ratio for optimal stimulation.…”

Section: Reagentsmentioning

confidence: 99%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

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During vaccination or infection, adaptive and innate immune receptors of B cells are engaged by microbial antigens/ligands. A better understanding of how innate and adaptive signaling pathways interact could enlighten B lymphocyte biology as well as aid immunotherapy strategies and vaccine design. To address this goal, we examined the effects of TLR stimulation on BCR and CD40-induced B cell activation. Synergistic production of IL-6 was observed in both human and mouse primary B cells stimulated through B cell antigen receptors, CD40 and TLR7, and these two receptors also cooperated independently of BCR signals. The enhanced IL-6 production was dependent upon the activity of c-Jun kinase (JNK) and cFos. Dual stimulation through CD40 and TLR7 markedly enhanced JNK activity. The increased level of active JNK in dual-stimulated cells was accompanied by an increase in the level of active AP-1 monomers cJun and cFos. The stimulation of B cells through both CD40 and TLR7 therefore enhanced the production of cytokines through increased JNK signaling and AP-1 activity. In addition, the dual stimulation increased cFos/AP-1 species in stimulated cells, effectively expanding the repertoire of AP-1 dimers as compared to singly stimulated B cells. IntroductionNatural immune responses to microbes and responses induced by vaccination involve the cooperation of innate and adaptive immunity. B lymphocytes express receptors that allow them to respond to both antigen-specific and innate immune stimuli [1,2]. One of the key receptors involved in adaptive humoral responses is the TNF receptor superfamily member CD40. The interaction of CD40 on B cells with its ligand CD154, expressed by activated T cells, is integral to immunoglobulin production, isotype switching, and the formation of germinal centers [3], important events in the development of long-lived humoral memory. CD40 stimulation also contributes to B cell antigen presentation by the upregulation of T cell co-stimulatory molecules and production of acute phase cytokines such as . Previous studies have shown that dual stimulation of B cells through the BCR and CD40 leads to an enhancement of Ig and cytokine production [7]. However, the effects and mechanisms of interactions between innate immune receptors and BCR or CD40 expressed by B cells are not yet well defined.B cells can be activated through engagement of a variety of innate immune receptors, including Toll-like receptors (TLR). TLR are related to the Drosophila receptor Toll, important for dorsal-ventral patterning in the developing fly as well as resistance to microbes [8]. The TLR in higher organisms act as sensors of infection or 'danger' by recognizing molecular patterns associated with microbes and/or cellular damage. As natural surveyors of environmental stresses, TLR induce immune cell activity and direct the initial stages of immune responses [9]. Of the 13 TLR mammalian genes [11,12]. TLR7 and -8 bind singlestranded RNA as natural ligands, but also confer responsiveness to guanosine derivatives and the imi...

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Section: Reagentsmentioning

confidence: 99%

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Bush

Bishop

2008

Eur J Immunol

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“…Mice conditionally deficient in B cell TRAF2 show enhanced B cell survival and constitutive activation of the non-canonical NF-κB2 pathway, but this may be due to effects on signaling via other TNFR superfamily members (see below); the B cells do show reduced CD40-induced proliferation [10]. Another interesting function of TRAF2 revealed by TRAF2 -/-B cell lines is its role as the "master regulator" of CD40-mediated degradation of both itself and TRAF3 [11,12]. This degradation is an important feedback control mechanism for CD40 signaling [12].…”

Section: Cd40mentioning

confidence: 99%

Roles of TRAF molecules in B lymphocyte function

Xie

Kraus

Stunz

et al. 2008

Cytokine & Growth Factor Reviews

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Tumor necrosis factor receptor associated factors (TRAFs) play a variety of interesting and important roles in the regulation of B lymphocyte function. They act both as cytoplasmic regulatory molecules, and as signal transducers for receptors involved in both innate and adaptive humoral immune responses. In this brief review, we highlight the current state of knowledge of the diverse roles of TRAF molecules in the functions of B lymphocytes. CD40CD40 is the most well-studied member of the TNFR superfamily expressed by B lymphocytes, so its interactions with TRAF molecules have also been intensively investigated. B cell CD40 is important in the induction of B cell survival and expansion, immunoglobulin (Ig) production and isotype switching, upregulation of surface molecules involved in B cell antigen presentation, differentiation to B memory cells, and the production of various cytokines (reviewed in [1]. The TRAF molecules have been shown to contribute to each of these functions (reviewed in [2].In 1994, TRAF3 became the first cytoplasmic molecule demonstrated to associate with CD40 (reviewed in [2]). However, for many years, its roles in CD40 signaling were largely unknown, and are still not completely understood. TRAF3 -/-mice die shortly after birth, but adoptive transfer of fetal liver cells from these mice suggested that their B cells were capable of reconstituting the humoral response [3], implying that TRAF3 is not required to promote CD40-mediated antibody responses. This conclusion was supported by experiments in B cell lines demonstrating that inducible overexpression of TRAF3 inhibits both CD40 responses [4], and cooperation between CD40 and the BCR [5]. Subsequently, B cell lines made completely TRAF3-deficient via gene targeting by homologous recombination show no defects in CD40 signaling overall, and display enhanced CD40-mediated c-jun kinase (JNK) activation and IgM production [6]. Recently, mice made conditionally deficient in TRAF3 only in CD19+ B cells show no deficiencies in CD40 signaling in vitro and have enhanced antibody responses [7]. TRAF2 was initially demonstrated to bind CD40 by exogenous overexpression studies in adenocarcinoma cell lines, in which it promotes JNK activation and the activity of NF-κB reporter genes (reviewed in [2]. Because TRAF2 -/-mice have an early lethal phenotype [8],Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers

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“…5A), so rescue was independent of CD40 binding to TRAF1, TRAF2, and TRAF3. To further test whether cytoplasmic, unbound TRAF are required for CD40-mediated apoptosis rescue, we examined subclones of A20 and CH12.LX made TRAF-deficient using gene targeting by homologous recombination [24,27]. CD40 rescue from CD95-induced apoptosis was unchanged in B cells deficient in TRAF1, TRAF2, or TRAF3 (data not shown).…”

Section: Effect Of Cd40 Signals On Early Events In the Cd95 Pathwaymentioning

confidence: 99%

“…These were maintained in BCM supplemented with 400 lg/mL G418 disulfate (Research Products International, Mount Prospect, IL) and/or 200 lg/mL hygromycin B (Calbiochem, La Jolla, CA). TRAF6 -/-A20 cells were generated using a gene targeting protocol and transfected with WT or delTRAF TRAF6 mutants as described previously [24]. Hi5 insect cells infected with WT baculovirus (BV) or BV expressing mCD154 were described previously [50].…”

Section: Cellsmentioning

confidence: 99%

“…TRAF are important for transmitting a variety of pro-survival signals including activation of several families of kinases and transcription factors [21,22]. TRAF6 has been shown to be important in B cells for CD40-mediated IL-6 production, Ig secretion, and CD80 up-regulation, but its role in NF-jB activation may be partially redundant with TRAF2 [23,24]. It is not known which TRAF molecules are required for CD40 rescue from CD95 apoptosis.…”

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confidence: 99%

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Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

Benson

Hostager²,

Bishop

2006

Eur J Immunol

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The activation molecule CD40 and the death receptor CD95/Fas play important roles in regulating B cells so that effective antimicrobial immunity occurs without autoimmunity. CD40 signaling increases CD95 expression, sensitizing cells to apoptosis, but sustained CD40 signals rescue B cells from CD95 killing. Here we describe a mechanism of early CD40-mediated rescue from CD95-induced apoptosis in B cells. Maximal rescue was achieved when CD40 signals were given within 1-2 h of initiating CD95 apoptosis. CD40 signaling did not block association of Fas-associated death domain-containing protein with CD95, but decreased CD95-induced activation of caspases 3 and 8. Rapid CD40 rescue did not require NF-jB activation and was independent of de novo protein synthesis, but was dependent upon active PI3 K. Signaling via a CD40 mutant that does not bind TNFR-associated factor (TRAF)1, TRAF2, and TRAF3 rescued B cells from CD95-induced apoptosis. TRAF1/2/3-independent rescue was confirmed in B cell lines made deficient in these TRAF molecules by gene targeting. In contrast, CD40 rescue was completely abrogated in TRAF6-deficient B cells, which showed reduced activation of Akt in response to CD40 engagement. These results reveal a new rapid mechanism to balance B cell activation and apoptosis. IntroductionB cells integrate many signals that direct proliferation and differentiation into Ig-secreting plasma cells or longlived memory cells. Ultimately, activated B cells can be eliminated through apoptosis, which is important for maintaining immune tolerance and homeostasis [1,2]. Molecules of the TNFR family play critical roles in regulating the balance between B cell activation and apoptosis. CD40 signals allow B cells to proliferate, differentiate, switch isotype, form GC, and become memory cells [3][4][5]. CD40 stimulation also induces upregulation of other members of the TNFR family, including the death receptor CD95/Fas [6].The importance of CD95 in maintaining lymphocyte homeostasis and tolerance is highlighted by the human disease autoimmune lymphoproliferative syndrome (ALPS), caused by mutations in the CD95 signaling pathway [7,8] autoantibodies are produced, and systemic autoimmunity develops [9]. Expression of the CD95 transgene exclusively in T cells of lpr/lpr mice is sufficient to decrease lymphadenopathy, splenomegaly, and the accumulation of abnormal T cells, but these mice still produce autoantibodies, causing deposition of immune complexes in kidney glomeruli [10]. In contrast, expression of the CD95 transgene in both B and T cells reduces the levels of serum Ig, autoimmune symptoms, and mortality [11]. Thus, CD95 signaling in B cells is crucial for maintaining peripheral tolerance and preventing autoimmunity. When CD95 is oligomerized, either by binding to its ligand on T cells (CD95L) or by Ab against its extracellular domain, it recruits the adaptor molecule Fas-associated death domain-containing protein (FADD) and procaspase 8 into a complex called the deathinducing signaling complex (DISC) that cleaves pro...

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Tumor Necrosis Factor Receptor-associated Factor 2 (TRAF2)-deficient B Lymphocytes Reveal Novel Roles for TRAF2 in CD40 Signaling

Cited by 117 publications

References 55 publications

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

TLR7 and CD40 cooperate in IL‐6 production via enhanced JNK and AP‐1 activation

Roles of TRAF molecules in B lymphocyte function

Rapid CD40‐mediated rescue from CD95‐induced apoptosis requires TNFR‐associated factor‐6 and PI3K

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