BCR Engagement Induces Fas Resistance in Primary B Cells in the Absence of Functional Bruton’s Tyrosine Kinase

Tumang, Joseph R.; Negm, Robert S.; Solt, Laura A.; Schneider, Thomas J.; Colarusso, Thomas P.; Hastings, William D.; Woodland, Robert T.; Rothstein, Thomas L.

doi:10.4049/jimmunol.168.6.2712

Cited by 14 publications

(9 citation statements)

References 64 publications

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“…Our results demonstrate that this requirement is malleable, as we found that CD40 engagement provides the means to circumvent the block in BCR signaling produced by Btk mutation. This was evident on a molecular scale in terms of NF-B induction, and in a more complex outcome such as cellular proliferation, and is consistent with our previous results showing anti-Ig-induced up-regulation of two NF-B-dependent Bcl-2 family members in xid B cells previously stimulated through CD40 (16). These effects of CD40 engagement were specific, inasmuch as in the presence of MR-1 anti-CD40L antagonistic Ab (31) (kindly provided by Dr. R. Noelle (Dartmouth Medical Center, Hitchcock, NH)), CD40L failed to create conditions allowing BCR induction of NF-B in xid B cells (data not shown).…”

Section: Discussionsupporting

confidence: 92%

“…However, we found that the ability of anti-Ig to produce Fas resistance was not substantially affected by mutation or deletion of Btk (16). In light of recent reports indicating that Btk is absolutely required for NF-B activation (8,9), these two results, indicating that induction of Fas resistance depends on NF-B but occurs independently of Btk, would seem to be at odds with one another.…”

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confidence: 39%

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Cutting Edge: CD40 Engagement Eliminates the Need for Bruton’s Tyrosine Kinase in B Cell Receptor Signaling for NF-κB

Mizuno

Rothstein

2003

The Journal of Immunology

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The Tec kinase Bruton’s tyrosine kinase (Btk) represents a key intermediary for B cell receptor (BCR) signaling. Btk mutation produces B cell deficiency in mice with X-linked immunodeficiency (xid), and surface Ig-mediated responses of mature B cells are seriously deranged. The central role that Btk plays in directing downstream events produced by BCR engagement is demonstrated by the complete failure of NF-κB induction and cellular proliferation following anti-Ig treatment of B cells obtained from xid mice. In this study, we report that the block in BCR signaling produced by Btk mutation is reversed by CD40 engagement. Prior treatment with CD40 ligand normalized subsequent responses of xid B cells to BCR cross-linking, so that typical outcomes of BCR signaling such as NF-κB activation and cell cycle progression occurred in a Btk-independent fashion. These results demonstrate that a specific genetic lesion interrupting BCR-mediated intracellular signaling is circumvented through stimulation of CD40.

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Section: Discussionsupporting

confidence: 92%

contrasting

confidence: 39%

Cutting Edge: CD40 Engagement Eliminates the Need for Bruton’s Tyrosine Kinase in B Cell Receptor Signaling for NF-κB

Mizuno

Rothstein

2003

The Journal of Immunology

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“…Signals through the BCR protect B cells from CD95-induced apoptosis through both transcriptionally dependent and independent mechanisms [25,[41][42][43]. In our studies, we found that stimulating B cells through CD40 after BCR activation substantially increased the percentage of cells rescued from CD95-induced apoptosis.…”

Section: Discussionmentioning

confidence: 64%

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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“…Results with actinomycin D and cycloheximide indicate that new gene expression and new protein synthesis are required for induction of Fas resistance (29), and several gene products have been implicated in this process, including Bcl-x L , FLIP, and Fas apoptosis inhibitory molecule (30 -35). However, the signaling pathways leading from surface Ig (sIg) to induction of Fas resistance have not been clarified beyond the level of protein kinase C (29,36).…”

Section: T He Fas Death Receptor Is a Member Of The Tnf Receptor Famimentioning

confidence: 99%

NF-κB Is Required for Surface Ig-Induced Fas Resistance in B Cells

Schram

Rothstein

2003

The Journal of Immunology

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The susceptibility of primary murine B cells to Fas-mediated apoptosis is regulated in a receptor-specific fashion. Whereas CD40 engagement produces marked sensitivity to Fas killing, engagement of the B cell Ag receptor blocks Fas signaling for cell death in otherwise Fas-sensitive, CD40-stimulated targets and thus induces Fas resistance. The signaling pathway that leads from B cell Ag receptor to Fas resistance has not been fully characterized, but has been shown to depend on new gene expression. NF-κB is activated following B cell Ag receptor engagement and is associated with antiapoptosis; thus, it would seem a likely candidate to mediate transcriptional activation for inducible Fas resistance. Inhibition of B cell Ag receptor signaling for NF-κB activation completely blocked induction of Fas resistance by anti-Ig, and this same phenotype was observed both with chemical inhibitors such as lactacystin and pyrrolidinedithiocarbamate as well as with an IκBα dominant negative TAT fusion protein. Antiapoptotic, NF-κB-responsive transcripts include two gene products previously implicated in mediating anti-Ig-induced Fas resistance, Bcl-xL and FLIP. B cell Ag receptor-induced up-regulation of both these gene products was blocked by NF-κB inhibition, suggesting a mechanism by which the loss of nuclear NF-κB alters the sensitivity of B cell Ag receptor-stimulated B cells to Fas-mediated apoptosis. These results indicate that activation of NF-κB plays a key role in mediating Fas resistance produced by B cell Ag receptor engagement.

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BCR Engagement Induces Fas Resistance in Primary B Cells in the Absence of Functional Bruton’s Tyrosine Kinase

Cited by 14 publications

References 64 publications

Cutting Edge: CD40 Engagement Eliminates the Need for Bruton’s Tyrosine Kinase in B Cell Receptor Signaling for NF-κB

Cutting Edge: CD40 Engagement Eliminates the Need for Bruton’s Tyrosine Kinase in B Cell Receptor Signaling for NF-κB

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

NF-κB Is Required for Surface Ig-Induced Fas Resistance in B Cells

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