Clustering of the T-cell receptor complex may facilitate T-cell activation by stretching of CD3ζ cytoplasmic tails

Motivated by experimental observations that T-cells can activate as a consequence of clustering of T-cell receptors, we hypothesize that steric confinement between the intracellular chains of the TCR could play a role. Using coarse-grained simulations, we show that steric interactions between TCRs are sufficient to induce appreciable stretch of the intracellular domains of CD3ζ chains. We propose a model, in which the difference in membrane distances between the phosphatase CD45 and the kinases lck and fyn is able to sense the clustering-induced CD3ζ stretch: we estimate a 1.5- to 2-fold increase in phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) at CD3ζ upon TCR clustering.