Role of Mechanotransduction and Tension in T Cell Function

Abstract

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.

Keywords: T cell; TCR; actin cytoskeleton; adhesion; mechanotransduction; migration; signaling; tension.

Figure 1

Mechanotransduction during the adhesion cascade. The proteins that mediate rolling and arrest of T cells on endothelial cells during the adhesion cascade are mechanosensors, which are sensitive to and relies on the force of the shear flow. (A) During the early steps of the adhesion cascade, selectins at the tip of microvilli of T cells interact with their ligands at the surface of endothelial cells to mediate tethering and rolling. Shear force impose a tension on this bond and thereby induces a conformational change in the selectin headpiece, which gives to the selectin-ligand bond a catch-bond characteristic. (B) Integrins mediate arrest after rolling and firm adhesion to the endothelium. Shear force also plays an essential role in this multistep process. Inside-out signaling from selectins of from chemokine receptors induces a first conformational change that increases the affinity of integrins for ICAMs and anchors them to the cytoskeleton through the recruitment of talin. Shear force pulls ligand-bond integrins into a high affinity, open conformation and increases the life-time of the bond through a catch-bond process.

Figure 2

Mechanotransduction during T cell activation. (A) TCRs at the tip of microvilli are subjected to specific forces while T cells migrate on or form a kinapse with antigen-presenting cells. It is not yet determined if tensions are “absorbed” due to the elastic nature of microvilli, or if on the contrary, microvilli push against the antigen-presenting cells, thereby increasing the tension on TCR (B) During and after the formation of an immunological synapse with a cell presenting a cognate antigen, migration-related, and acto-myosin-mediated tensions drive integrins into a full affinity state, similarly to what happens during the adhesion cascade (Figure 1B). These forces also lead to passive mechanosensing by TCR. Additionally, TCR itself further engages in active mechanosensing, by pulling and pushing on pMHC molecules. Non-stimulatory ligands form slip-bonds under tension and fail to trigger TCR signaling. By contrast, stimulatory ligands engage in a catch-bond with TCR, which leads to a conformational change and in turn promotes TCR signaling. Binding to a stimulatory ligand also increase the density of F-actin around the TCR to further anchor it to the underlying cytoskeleton. All in all, tensions through the TCR-pMHC bond contribute to TCR triggering and antigen discrimination.

Figure 3

How cell tension could regulate cellular processes essential to T cell activation. Cell tension, either generated by external forces (such as the blood flow), or resulting from intracellular mechanisms (molecular motors, actin flow, modification of the linkage between membrane and the cytoskeleton) can regulate: (a) Ca²⁺ flux, through MS ion channels, (b) cell proliferation and differentiation, through the opening of the nuclear pore complex or modification of chromatin compaction, (c) endo- and exocytosis, via membrane tension and d) actin polymerization, through the activity of the small GTPase Rac or the binding and unbinding of BAR domain proteins.