Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 36, Issue 9, Pages 2535-2543Publisher
WILEY
DOI: 10.1002/eji.200535483
Keywords
apoptosis; B lymphocyte; cellular activation; signal transduction
Categories
Funding
- NCI NIH HHS [CA099997] Funding Source: Medline
- NIAID NIH HHS [AI07511, AI07485, AI49993, AI28847] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007337, GM07337] Funding Source: Medline
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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 auto-immunity. 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 1-2h 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-kappa B activation and was independent of de novo protein synthesis, but was dependent upon active PI3K. 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.
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