Frontiers in Immunology (Nov 2016)
TCR/pMHC interaction: phenotypic model for an unsolved enigma
Abstract
TCR-pMHC interaction is the keystone of the adaptive immune response.This process exhibits animpressive capacity of speed, sensitivity and discrimination thatallows to detect foreign pMHCs at very low concentration amongmuch more abundant self-pMHC ligands.However, and despite over three decades of intensive research,the mechanisms by which this remarkablediscrimination and sensitivity is attained remain controversial.In kinetic proofreading mechanisms (KPR)an increase of specificity occurs by reducing thesensitivity. To overcome this difficulty more elaborate modelsincluding feedback processes or induced rebinding have beenincorporated into the KPR scheme.Here a new approach based on the assumptionthat the proofreading chain behaves differently forforeign and self pMHCs has been integrated into aphenotypic model in which the complexes responsible for T cell activationstabilize (for foreign peptides), or weaken (for foreign peptides),resulting in a dramatic increase in sensitivity andspecificity. Stabilization and destabilizationof complexes may be caused by conformational changes, rebinding, orany other process leading to variations in the dissociation rateconstants of the complexes transmitting the activation. Thenumerical solution and the analytical expression for the steadystate response as a function of k off (i)(i=0,1,..,N, where C0, C1,..,CN are the complexes inthe proofreading chain) are provided. The activation chain speedsup and larger increases in sensitivity and discrimination areobtained if the rate of activation along the proofreading chainincreases for foreign pMHCs and decreases for self ligands.Experimental implications and comparison with current models are discussed.
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