CD40/CD40 homodimers are required for CD40-induced phosphatidylinositol 3-kinase-dependent expression of B7.2 by human B lymphocytes.
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.
Reyes-Moreno
Carlos
C
Centre de Recherche en Rhumatologie et Immunologie (CRRI), Centre Hospitalier de l'Université Laval, Montreal, Quebec, Canada.
Girouard
Julie
J
Lapointe
Rejean
R
Darveau
André
A
Mourad
Walid
W
D015703:Antigens, CD / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism*; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D023201:CD40 Ligand / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D004854:Herpesvirus 4, Human; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D004220:Disulfides; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases