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Full CD3/TCR activation through cholesterol-depleted lipid rafts.

Rouquette-Jazdanian AK, Pelassy C, Breittmayer JP, Aussel C

Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 576, IFR 50, Hôpital de l'Archet I, 151 Route de Saint Antoine de Ginestière, B.P. 79, 06202 Nice Cedex 3, France.

Exogenous bacterial sphingomyelinase (SMase) and C6-Ceramides (C6-Cer) considerably lower buoyant cholesterol on sucrose density-gradient (at least 55% less cholesterol). In opposition, short C2-Cer fails to displace buoyant cholesterol. Note that neither SMase nor C6-Cer delocalize raft markers (Lck, LAT, CD55, and GM1). They are still anchored in ceramides-rich/cholesterol-poor domains, demonstrating that cholesterol is not necessary for their buoyancy. SMase-treated cells, i.e. cells exhibiting cholesterol-depleted rafts, optimally transmit CD3-induced phosphorylations (tyrosine, threonine, and serine). SMase, that extracts and partially displaces buoyant cholesterol, does not inhibit PLCgamma1-LAT interaction, Vav 1 phosphorylation, the actin polymerization, IL-2 and NF-kappaB (EMSA and luciferase assays) activation, and CD25 up-regulation (RT-PCR and cytometry) at all. Nevertheless, Ca(2+) influx and diacylglycerol (palmitoyl-DAG and arachidonoy-DAG) production are lowered. The drop of CD3-induced Ca(2+) influx is due to a strong plasma membrane depolarization because of Cer. The decreased DAG level is a consequence of the drop of intracellular Ca(2+) that is a cofactor for the PLCgamma1. In conclusion, our study challenges the real role of cholesterol-rich rafts in CD3/TCR signaling and suggests that other membrane domains than cholesterol-rich rafts can optimally transmit CD3/TCR signals.

Published 4 June 2007 in Cell Signal, 19(7): 1404-18.
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