CD40 signaling in human dendritic cells is initiated within membrane rafts |
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Authors: | Vidalain P O Azocar O Servet-Delprat C Rabourdin-Combe C Gerlier D Manié S |
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Affiliation: | Immunité et infections virales, Faculté de médecine Laennec, VPV-CNRS-UCBL UMR 5537, 69 372 Lyon cedex 08 and Immunobiologie Fondamentale et Clinique, INSERM U503, IFR 74, ENS Lyon, 69 364 Lyon cedex 07, France Corresponding author e-mail: |
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Abstract: | Despite CD40's role in stimulating dendritic cells (DCs) for efficient specific T-cell stimulation, its signal transduction components in DCs are still poorly documented. We show that CD40 receptors on human monocyte-derived DCs associate with sphingolipid- and cholesterol-rich plasma membrane microdomains, termed membrane rafts. Following engagement, CD40 utilizes membrane raft-associated Lyn Src family kinase, and possibly other raft-associated Src family kinases, to initiate tyrosine phosphorylation of intracellular substrates. CD40 engagement also leads to a membrane raft-restricted recruitment of tumor necrosis factor (TNF) receptor-associated factor (TRAF) 3 and, to a lesser extent, TRAF2, to CD40's cytoplasmic tail. Thus, the membrane raft structure plays an integral role in proximal events of CD40 signaling in DCs. We demonstrate that stimulation of Src family kinase within membrane rafts initiates a pathway implicating ERK activation, which leads to interleukin (IL)-1alpha/beta and IL-1Ra mRNA production and contributes to p38-dependent IL-12 mRNA production. These results provide the first evidence that membrane rafts play a critical role in initiation of CD40 signaling in DCs, and delineate the outcome of CD40-mediated pathways on cytokine production. |
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