Physiological T cell activation starts and propagates in lipid rafts.

Lipid rafts are plasma membrane compartments enriched in key signaling molecules. We have previously shown that in T lymphocytes anti-CD3 stimulation is insensitive to cholesterol extraction by methyl-beta-cyclodextrin (MbetaCD), suggesting that anti-CD3 induced signal transduction is independent of raft integrity. Here we show that, in contrast to T cell stimulation by anti-CD3 antibodies, T cell activation by a physiological ligand is mediated by signaling events taking place in lipid raft. Indeed, cholesterol depletion by MbetaCD resulted in reduced T cell activation in response to Epstein Barr Virus (EBV)-transformed B cells pulsed with a bacterial superantigen. Moreover, T cell stimulation by pulsed EBV-B cells, but not by anti-CD3 antibodies, induced recruitment of active Lck in detergent-resistant membranes, where the signal transduction is organized and amplified.