The TCR Triggering Puzzle

Despite extensive efforts, the mechanism of TCR triggering remains poorly understood, and there are a number of competing models. There are major difficulties with more traditional models such as those postulating binding-induced conformational change of the TCR or binding induced-multimerization. Newer models, such as the dimer conformational change, raft-association, and kinetic-segregation models, have been proposed that are compatible with the available data, but they have yet to be rigorously tested.There is more consensus on which property of TCR/pep-MHC interactions determines the outcome of binding. Structural consideration and data have ruled out ligand-specific conformational changes as a determinant. The available data are broadly consistent with the hypothesis that there is an optimal half-life or dwell-time for TCR/pep-MHC interactions. Some data are not consistent with this, possibly because the TCR/pep-MHC half-life is different under physiological conditions in which the interaction is subjected to mechanical stress. Measurements of the mechanical properties of TCR/pep-MHC interactions and direct measurement of the kinetics of membrane-tethered TCR/pep-MHC interactions are needed to clarify this question.

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