Membrane Compartmentation Is Required for Efficient T Cell Activation

Abstract

The plasma membrane of mammalian cells contains detergent-resistant membrane rafts enriched in glycosphingolipids and cholesterol. Although several important signaling molecules have been found in such rafts, evidence documenting a functional role for their localization has been scarce. Using a fractionation scheme that preserves tyrosine phosphorylation, we show that T cell activation leads to a striking compartmentation in the rafts of activated T cell receptor and associated signal-transducing molecules. Conditions that reversibly disrupt raft structure either by dispersing their contents or by forcing their internalization reversibly disrupt the earliest steps of T cell activation. Thus, raft integrity is a prerequisite for efficient T cell receptor signal transduction.

Defect of CD8+ Memory T Cells Developed in Absence of IL-12 Priming for Secondary Expansion

“…However, there are points related to the potential mechanism which should be considered for future investigation. For example, rapid responses to external stimuli are facilitated by the organization of signaling molecules downstream of the TCR in distinct lipid rafts (15) leading to impairment of further stimulatory responses. Bcl-6 is essential for memory B cell development in germinal center (16).…”

Modifications and intracellular trafficking of FADD/MORT1 and caspase-8 after stimulation of T lymphocytes

“…Some reports have indicated that rafts play a critical role in TCR signalling. [24][25][26] These studies should, however, be viewed with caution as the amount of TCR/CD3 and their signal transducers recovered with rafts depends on the type of detergent used. 27 Recently, it was suggested that activation of Fas leads to the recruitment of FADD and caspase-8 into lipid rafts in mouse thymocytes, 28 human CD4 þ T cells 29 and in a human lymphoblastoid cell line, 30 indicating that such intracellular trafficking might also play a role in 'death receptor'-induced apoptosis.…”

Constitutive activation of the Ras/MAP kinase pathway and enhanced TCR signaling by targeting the Shc adaptor to membrane rafts

“…TCR signal transduction has been recently shown to be dependent on receptor recruitment to lipid rafts (Montixi et al, 1998;Xavier et al, 1998). These are detergent resistant plasma membrane microdomains highly enriched in cholesterol and glycosphingolipids, where key signaling molecules posttranslationally modi®ed by addition of a lipid moiety, such Ras and Src family PTKs, reside (reviewed in Simons and Ikonen, 1997;Magee and Marshall, 1999).…”

“…These are detergent resistant plasma membrane microdomains highly enriched in cholesterol and glycosphingolipids, where key signaling molecules posttranslationally modi®ed by addition of a lipid moiety, such Ras and Src family PTKs, reside (reviewed in Simons and Ikonen, 1997;Magee and Marshall, 1999). Following ligand binding, the activated TCR colocalizes in lipid rafts together with ZAP-70 and Syk, which are recruited to the tyrosine phosphorylated ITAMs from their otherwise cytosolic localization (Montixi et al, 1998;Xavier et al, 1998). Also the Shc adaptor inducibly localizes in the rafts following TCR triggering (Xavier et al, 1998), suggesting that raft localization might be required for Shc activity.…”

“…Following ligand binding, the activated TCR colocalizes in lipid rafts together with ZAP-70 and Syk, which are recruited to the tyrosine phosphorylated ITAMs from their otherwise cytosolic localization (Montixi et al, 1998;Xavier et al, 1998). Also the Shc adaptor inducibly localizes in the rafts following TCR triggering (Xavier et al, 1998), suggesting that raft localization might be required for Shc activity. Here we show that addition to Shc of the membrane localization sequence from Ras resulted in constitutive Shc localization at the plasma membrane, with a distribution largely con®ned to lipid rafts.…”