TCR triggering: co-receptor-dependent or -independent?
Davis SJ, van der Merwe PA. (2003), Trends Immunol. 24, 624-6
Key figure: Co-receptor involvement in T-cell receptor (TCR) triggering according to the kinetic-segregation model
(a) Random interactions of membrane inner leaflet- or co-receptor-associated p56lck and CD45 with the TCR results in constitutive TCR phosphorylation–dephosphorylation cycles in resting T cells [e.g. red spot in TCR 2 in (a)]. (b) On encounter with an antigen-presenting cell (APC), the proteins segregate according to size, excluding the phosphatase CD45 and extending the half-life of phosphorylated species within many small close-contact zones, such as that represented in (b) and (c). Specific TCR–MHC–peptide interactions hold the TCR in such zones long enough either for co-receptor recruitment to pre-existing phosphorylated TCRs [e.g. TCR 2 in (b)] or the phosphorylation of new TCRs [e.g. TCR 3 in (b)]. (c) Phosphorylation of properly engaged TCRs is amplified by the recruited co-receptor [e.g. TCR 2 in (c)], leading to full signal transduction. Specificity results from the rapid diffusion from the close-contact zone of TCRs that fail to engage MHC bearing appropriate peptide, prior to their initiation of signal transduction [e.g. TCR 1 in (b)]. Less efficiently, TCRs will also be hyper-phosphorylated by free p56lck [e.g. TCR 3 in (c)], giving co-receptor independent signalling. Crucially, the model is not dependent on any ligand-induced effects beyond simple binding.