Co-stimulation and counter-stimulation: lipid raft clustering controls TCRsignaling and functional outcomes

T cell receptor (TCR) antigen recognition induces the formation of a specia lized 'immunological synapse' at the T cell:antigen presenting cell (APC) j unction. This junction is generated by the recruitment and exclusion of par ticular proteins from the contact area and is required for T cell activatio n. We and others have hypothesized that lipid raft/non-raft partitioning pr ovides a molecular basis for protein sorting which organizes the TCR, co-st imulators, signal transducers and the actin cytoskeleton at the T cell:APC interface. Here we discuss the emerging paradigm that co-stimulators induce the directional transport and clustering of lipid rafts at the T cell:APC interface, thus generating platform(s) specialized for processive and susta ined TCR signal transduction and T cell activation. We also discuss recent data implicating the involvement of 'counter-stimulators' and other negativ e regulators which prevent optimal raft clustering at the TCR contact site and, thus, facilitate T cell inactivation and tolerance induction.