Lipid rafts in T cell receptor signalling

Abstract

The molecular events and the protein components that are involved in signalling by the T cell receptor (TCR) for antigen have been extensively studied. Activation of signalling cascades following TCR stimulation depends on the phosphorylation of the receptor by the tyrosine kinase Lck, which localizes to the cytoplasmic face of the plasma membrane by virtue of its post-translational modification. However, the precise order of events during TCR phosphorylation at the plasma membrane, remains to be defined. A current theory that describes early signalling events incorporates the function of lipid rafts, microdomains at the plasma membrane with distinct lipid and protein composition. Lipid rafts have been implicated in diverse biological functions in mammalian cells. In T cells, molecules with a key role in TCR signalling, including Lck, localize to these domains. Importantly, mutant versions of these proteins which fail to localise to raft domains were unable to support signalling by the TCR. Biochemical studies using purified detergent-resistant membranes (DRM) and confocal microscopy have suggested that upon stimulation, the TCR and Lck-containing lipid rafts may come into proximity allowing phosphorylation of the receptor. Further, there are data suggesting that phosphorylation of the TCR could depend on a transient increase in Lck activity that takes place within lipid rafts to initiate signalling. Current results and a model of how lipid rafts may regulate TCR signalling are discussed.

Figure 1

Two-dimensional reconstruction of confocal Z-series recorded from a Jurkat T cell that was stained with FITC-CTB for 15 min on ice, and fixed with 4% paraformaldehyde. Images were obtained with a Zeiss LSM510META confocal microscope. Scale bar = 10 μm.

Figure 2

A model describing the initial steps that lead to phosphorylation of the TCR in lipid rafts. In resting T cells, the TCR may weakly interact with lipid rafts. Also, Lck in these domains has low activity due to the action of the PAG/Cbp-Csk inhibitory complex. Antigen presentation by APCs strengthens the association of the TCR with lipid rafts and induces a transient redistribution of CD45 to these domains. Dephosphorylation of Lck-Y505 and of PAG/Cbp by CD45 and dissociation of Csk, increases the activity of Lck resulting in ITAM phosphorylation and signalling. This Figure is reproduced in colour in Molecular Membrane Biology online.