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J. Biol. Chem., Vol. 279, Issue 9, 7799-7806, February 27, 2004

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CD40/CD40 Homodimers Are Required for CD40-induced Phosphatidylinositol 3-Kinase-dependent Expression of B7.2 by Human B Lymphocytes^*

Carlos Reyes-Moreno, Julie Girouard, Rejean Lapointe, André Darveau¶, and Walid Mourad, Recipient of a scientist award from the Arthritis Society of Canada||

From the Centre de Recherche en Rhumatologie et Immunologie (CRRI), Centre Hospitalier de l'Université Laval and the ^¶Département de Biochimie et Microbiologie, Université Laval, Quebec City, Quebec G1V 4G2, Canada and the Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Quebec H2W 1T8, Canada

Preformed CD40/CD40 homodimers were initially observed on human Burkitt lymphoma cell lines, normal B cells, and transitional bladder carcinoma cell lines. However, the nature and the biological relevance of these homodimers have not yet been investigated. In the present study, we demonstrated that Epstein-Barr virus-transformed B cells and CD40-transfected HEK 293 cells constitutively expressed disulfide-linked CD40/CD40 homodimers at low levels. Oligomerization of CD40 leads to a rapid and significant increase in the disulfide-linked CD40/CD40 homodimer formation, a response that could be prevented using a thiol-alkylating agent. Formation of CD40/CD40 homodimers was found to be absolutely required for CD40-mediated activation of phosphatidylinositol 3-kinase, which, in turn regulated B7.2 expression. In contrast, CD40 monomers provided the minimal signal emerging from CD40, activating p38 MAP kinase and inducing homotypic B cell adhesion. CD40/CD40 homodimer formation was totally independent of TRAF1/2/3/5 associations with the threonine at position 254 in the cytoplasmic tail of the CD40 molecules. This finding may be vital to better understanding the molecular mechanisms that govern cell signaling triggered by CD40/CD154 interactions.

Received for publication, December 12, 2003

^* This work was supported by grants from the Canadian Institutes of Health Research, the Arthritis Society of Canada, and the Canadian Arthritis Network. 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: CRRI, Centre Hospitalier de l'Université Laval, 2705 Blvd. Laurier, T-121, Quebec City, Quebec G1V 4G2, Canada. Tel.: 418-654-2772; Fax: 418-654-2765; E-mail: walid.mourad{at}crchul.ulaval.ca.

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