T cell migration from blood to, and within lymphoid organs and tissue, as well as, T cell activation rely on complex biochemical signaling events. But T cell migration and activation also take place in distinct mechanical environments and lead to drastic morphological changes and reorganization of the acto-myosin cytoskeleton. In this review we discuss how adhesion proteins and the T cell receptor act as mechanosensors to translate these mechanical contexts into signaling events. We further discuss how cell tension could bring a significant contribution to the regulation of T cell signaling and function.

Significance: T-cell activation requires the translation of antigen binding to the T-cell receptor (TCR) into intracellular signaling. However, how antigen recognition and signal transduction are mechanistically linked is poorly understood. Here, we used single-molecule localization microscopy to link TCR clustering to signaling. We found that the likelihood of a single receptor to initiate signaling upon ligand binding depended on receptor-to-receptor spacing, with TCRs in dense clusters having the highest signaling efficiency. This means that antigen recognition must first be translated into a spatial reorganization of receptors into dense, signaling-competent clusters before signaling can begin. Thus, the quality of an antigen in terms of signaling is given by its ability to densely cluster receptors.

T cell signaling begins with the ligation of the T cell antigen receptor (TCR) by a cognate peptide and the phosphorylation of the receptor’s immunoreceptor tyrosine-based activation motif domains by the kinase Lck. However, the canonical receptor model is insufficient to explain how the constitutively active kinase Lck can discriminate between non-ligated and ligated TCRs. Here, we discuss the factors that are thought to regulate the spatial distribution of the TCR and Lck, and therefore critically influence TCR signaling initiation.