Expansion or Elimination of B Cells In Vivo: Dual Roles for CD40- and Fas (CD95)-Ligands Modulated by the B Cell Antigen Receptor

Rathmell, Jeffrey C.; Townsend, Sarah E.; Xu, Jialin; Flavell, Richard A.; Goodnow, Christopher C.

doi:10.1016/s0092-8674(00)81349-5

Cited by 382 publications

(261 citation statements)

References 69 publications

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“…[21][22][23] Our results show that mitogenstimulated, c-Myc-deficient B lymphocytes are more resistant to CD95-induced cell death, and express low surface levels of CD95 and CD95L when compared to control cells (Figure 4a and b). Noteworthy is the fact that c-Myc-deficient B cells express normal surface levels of activation markers like CD69 or CD25, showing that they are capable of receiving Same numbers of sorted B lymphocytes were activated with either anti-CD40 antibody (10 mg/ml) or anti-CD40 plus interleukin 4 (20 ng/ml).…”

Section: Discussionmentioning

confidence: 68%

“…[18][19][20] Anti-CD40 stimulation of B lymphocytes induces the surface expression of CD95 and makes them susceptible to cell death by this receptor. [21][22][23] Furthermore, addition of interleukin 4 to anti-CD40-activated B lymphocytes renders these cells more resistant to CD95-induced cell death. 24 Inactivation of c-myc gene in the germ line results in embryonic lethality at day 9.5.…”

Section: Introductionmentioning

confidence: 99%

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c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

2003

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C-myc gene is a member of the myc family of protooncogenes involved in proliferation, differentiation, and apoptosis. Overexpression of c-myc in fibroblasts causes apoptosis under low serum conditions in a process that requires the interaction of CD95 and CD95L on the surface. We have previously reported an in vivo conditional model to inactivate the c-myc gene in B lymphocytes. Here, we show that c-Myc-deficient primary B lymphocytes are resistant to different apoptotic stimuli. Nonactivated c-Myc-deficient B cells are resistant to spontaneous cell death. Upon activation, c-Myc-deficient B lymphocytes express normal surface levels of activation markers, and show resistance to staurosporine and CD95-induced cell death.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

2003

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“…This paradigm is supported by subsequent reports of in vitro experiments in the human system, and of in vivo experiments in the murine system [38][39][40][41]. Thus, the outcome of B cell stimulation with respect to Fas signaling is regulated on the basis of particular environmental cues as interpreted by specific receptor binding.…”

Section: Inroductionmentioning

confidence: 80%

Inducible resistance to Fas-mediated apoptosis in B cells

Rothstein

2000

Cell Res

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Apoptosis produced in B cells through Fas (APO-1, CD95) triggering is regulated by signals derived from other surface receptors: CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas-induced cell death, whereas antigen receptor engagement, or IL-4R engagement, inhibits Fas killing and in so doing induces a state of Fas-resistance, even in otherwise sensitive, CD40-stimulated targets. Surface immunoglobulin and IL-4R utilize at least partially distinct pathways to produce Fas-resistance that differentially depend on PKC and STAT6, respectively. Further, surface immunoglobulin signaling for inducible Fas-resistance bypasses Btk, requires NF-κB, and entails new macromolecular synthesis. Terminal effectors of B cell Fas-resistance include the known anti-apoptotic gene products, Bcl-xL and FLIP, and a novel anti-apoptotic gene that encodes FAIM (Fas Apoptosis Inhibitory Molecule). faim was identified by differential display and exists in two alter-

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“…Severalstudies have shown that CD40 ligationprotects B cells from CD95-inducedapoptosis [2,44,45]; however, theearlysignaling pathwaysinvolvedin CD40 rescuehave not been elucidated. We here describe a novel mechanism of rapid CD40 rescue.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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Expansion or Elimination of B Cells In Vivo: Dual Roles for CD40- and Fas (CD95)-Ligands Modulated by the B Cell Antigen Receptor

Cited by 382 publications

References 69 publications

c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

c-Myc-deficient B lymphocytes are resistant to spontaneous and induced cell death

Inducible resistance to Fas-mediated apoptosis in B cells

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

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