The kinetic-segregation model: TCR triggering and beyond
Davis SJ, van der Merwe PA. (2006), Nat Immunol. 7, 803-9
How the T cell receptor engages antigen is known, but not how that ‘triggers’ intracellular signaling. The first direct support for a mechanism based on the spatial reorganization of signaling proteins, proposed 10 years ago and referred to as the ‘kinetic-segregation’ model, is now beginning to emerge, along with indications that it may also apply to the triggering of nonclonotypic receptors. We describe here the development of the model, review new data and suggest how the model fits a broader conceptual framework for receptor triggering. We also consider the capacity of the model, versus that of other proposals, to account for the established features of TCR triggering.
Key figure: The KS model
In a resting T cell (a), random protein interactions in the membrane lead to phosphorylation and dephosphorylation of molecules with tyrosine-phosphorylation motifs by Src kinases and tyrosine phosphatases. Triggering occurs as the local balance of those constitutive processes is altered by the formation of close-contact zones (b–d). This process is ‘nucleated’ by small proteins such as CD2 and results in the local size-dependent exclusion of large proteins such as CD45 from the close-contact zone. The ‘fates’ of the three TCRs here (1, 2, 3) are presented according to the KS model. In the absence of peptide-MHC contact, TCR 1 diffuses from the contact zone. If TCR 1 had been phosphorylated in the close-contact zone or before its formation, rapid dephosphorylation outside the close-contact zone would prevent signaling. TCR 2, phosphorylated before close-contact zone formation, binds cognate MHC-peptide and is thereby ‘held’ in the close-contact zone long enough for ‘downstream’ events to occur. TCR 3, phosphorylated after close-contact zone formation, is phosphorylated by free Lck only, accounting for coreceptor-independent triggering51, 52. Relatively large amounts of phosphorylation of TCR 2 and TCR 3 lead to ‘downstream’ signaling after Zap70 recruitment.