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

Rebecca J Benson; Bruce S Hostager; Gail A Bishop

doi:10.1002/eji.200535483

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

Journal article

Open access

Peer reviewed

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

Rebecca J Benson, Bruce S Hostager and Gail A Bishop

European journal of immunology, Vol.36(9), pp.2535-2543

09/2006

DOI: 10.1002/eji.200535483

PMID: 16897814

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Abstract

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-kappaB 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.

Immunoprecipitation

Caspases - immunology

Immunoblotting

TNF Receptor-Associated Factor 6 - immunology

Phosphatidylinositol 3-Kinases - metabolism

fas Receptor - metabolism

Enzyme Activation - immunology

Phosphatidylinositol 3-Kinases - immunology

fas Receptor - immunology

Lymphocyte Activation - immunology

CD40 Antigens - metabolism

TNF Receptor-Associated Factor 1 - deficiency

B-Lymphocytes - metabolism

TNF Receptor-Associated Factor 2 - deficiency

Receptors, Tumor Necrosis Factor - metabolism

Cell Line

TNF Receptor-Associated Factor 3 - deficiency

TNF Receptor-Associated Factor 6 - deficiency

Animals

Apoptosis - immunology

B-Lymphocytes - immunology

TNF Receptor-Associated Factor 2 - immunology

TNF Receptor-Associated Factor 3 - immunology

Mice

Receptors, Tumor Necrosis Factor - immunology

TNF Receptor-Associated Factor 1 - immunology

CD40 Antigens - immunology

Details

Title: Subtitle: Rapid CD40-mediated rescue from CD95-induced apoptosis requires TNFR-associated factor-6 and PI3K
Creators: Rebecca J Benson - Medical Scientist Training Program and Immunology Graduate Program, University of Iowa and Veterans Affairs Medical Center, Iowa City 52245, USA
Bruce S Hostager
Gail A Bishop
Resource Type: Journal article
Publication Details: European journal of immunology, Vol.36(9), pp.2535-2543
Publisher: Germany
DOI: 10.1002/eji.200535483
PMID: 16897814
ISSN: 0014-2980
eISSN: 1521-4141
Grant note: AI49993 / NIAID NIH HHS GM07337 / NIGMS NIH HHS AI28847 / NIAID NIH HHS AI07485 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS CA099997 / NCI NIH HHS AI07511 / NIAID NIH HHS
Language: English
Date published: 09/2006
Academic Unit: Microbiology and Immunology; President; Stead Family Department of Pediatrics; General Pediatrics and Adolescent Medicine
Record Identifier: 9984001128702771

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