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J. Biol. Chem., Vol. 278, Issue 46, 45382-45390, November 14, 2003

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

Bruce S. Hostager, Sokol A. Haxhinasto, Sarah L. Rowland, and Gail A. Bishop¶||**

From the Department of Pediatrics, Interdisciplinary Program in Immunology, and the ^¶Departments of Microbiology, Internal Medicine, University of Iowa, Iowa City and the ^||Veterans Affairs Medical Center, Iowa City, Iowa 52242

CD40 function is initiated by tumor necrosis factor (TNF) receptor-associated factor (TRAF) adapter proteins, which play important roles in signaling by numerous receptors. Characterizing roles of individual TRAFs has been hampered by limitations of available experimental models and the poor viability of most TRAF-deficient mice. Here, B cell lines made deficient in TRAF2 using a novel homologous recombination system reveal new roles for TRAF2. We demonstrate that TRAF2 participates in synergy between CD40 and B cell antigen receptor signals, and in CD40-mediated, TNF-dependent IgM production. We also find that TRAF2 participates in the degradation of TRAF3 associated with CD40 signaling, a role that may limit inhibitory actions of TRAF3. Finally, we show that TRAF2 and TRAF6 have overlapping functions in CD40-mediated NF-B activation and CD80 up-regulation. These findings demonstrate previously unappreciated roles for TRAF2 in signaling by TNF receptor family members, using an approach that facilitates the analysis of genes critical to the viability of whole organisms.

Received for publication, June 24, 2003 , and in revised form, August 15, 2003.

^* This work was supported by grants from the American Heart Association (to B. S. H.), by National Institutes of Health Grants AI28847 and AI49993, and by Veterans Affairs Merit Review 383 (to G. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Dept. of Microbiology, University of Iowa, 3-570 Bowen Science Bldg., 51 Newton Rd., Iowa City, IA. 52242. Tel.: 319-335-7945; Fax: 319-335-9006; E-mail: gail-bishop{at}uiowa.edu.

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