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J. Biol. Chem., Vol. 279, Issue 4, 2575-2582, January 23, 2004

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Synergistic B Cell Activation by CD40 and the B Cell Antigen Receptor

ROLE OF B LYMPHOCYTE ANTIGEN RECEPTOR-MEDIATED KINASE ACTIVATION AND TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED FACTOR REGULATION^*

Sokol A. Haxhinasto and Gail A. Bishop¶||**

From the Departments of Microbiology and ^¶Internal Medicine, the Interdisciplinary Graduate Program in Immunology, University of Iowa, and the ^||Veteran's Affairs Medical Center, Iowa City, Iowa 52242

Optimal activation of B-lymphocytes depends both upon expression of various cell surface receptors and adequate integration of signaling pathways. This requires signals generated upon recognition of antigen by the B lymphocyte antigen receptor (BCR) as well as additional signals provided by cognate interaction with T helper cells, including the CD40-CD154 interaction. Engagement of both the BCR and CD40 results in synergistic activation of B cells. Previous studies identified tumor necrosis factor receptor-associated factor (TRAF)-2 and TRAF3 in the CD40-signaling pathway together with BCR-activated protein kinase D (PKD) as important cooperative factors in this synergy. To better understand the role of these factors in bridging the BCR and CD40 signaling pathways, BCR signal regulation of TRAF function was examined. Results show that phosphorylation of TRAF2 is increased upon BCR but not CD40 engagement and that of the potentially phosphorylated residues of TRAF2, tyrosine 484 is crucial for BCR-CD40 synergy. Additionally, wild type or constitutively active Bruton's tyrosine kinase (Btk) enhanced, whereas the xid mutant form of Btk prevented, BCR-CD40 synergy. These effects were dependent upon TRAF2 and PKD activity. These findings suggest a model in which Btk contributes to the enhancement of the CD40 response by TRAF2 in a PKD-dependent manner.

Received for publication, September 25, 2003 , and in revised form, November 5, 2003.

^* This work was supported by National Institutes of Health Grants AI28847, AI49993, and CA099997 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, Iowa City, IA 52242. Tel.: 319-335-7945; Fax: 319-335-9006; E-mail: gail-bishop{at}uiowa.edu.

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