Recognition of peptide presented by the major histocompatibility complex (pMHC) molecule by the T cell receptor (TCR) determines T cell selection, development, differentiation, fate and function. Despite intensive studies on the structures, thermodynamic properties, kinetic rates and affinities of TCR�pMHC interactions in the past two decades, questions regarding the functional outcome of these interactions, i.e., how binding of the a� TCR heterodimer with distinct pMHCs triggers different intracellular signals via the adjacent CD3 components to produce different T cell responses, remain unclear. Most kinetic measurements have used surface plasmon resonance, a three-dimensional (3D) technique in which fluid-phase receptors and ligands are removed from their cellular environment. Recently, several two-dimensional (2D) techniques have been developed to analyze molecular interactions on live T cells with pMHCs presented by surrogate antigen presenting cells or supported planar lipid bilayers. The insights from these in situ analyses have provided a sharp contrast of the 2D network biology approach to the 3D reductionist approach and prompted rethinking of our current views of T cell triggering. Based on these insights, we propose a mechanochemical coupled triggering hypothesis to explain why the in situ kinetic parameters differ so much from their 3D counterparts yet correlate so much better with T cell functional responses.

Insights from in situ analysis of TCR–pMHC recognition: Response of an interaction network

245th National Meeting (2013)

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