Action and Traction: Cytoskeletal Control of Receptor Triggering at the Immunological Synapse

Abstract

It is well known that F-actin dynamics drive the micron-scale cell shape changes required for migration and immunological synapse (IS) formation. In addition, recent evidence points to a more intimate role for the actin cytoskeleton in promoting T cell activation. Mechanotransduction, the conversion of mechanical input into intracellular biochemical changes, is thought to play a critical role in several aspects of immunoreceptor triggering and downstream signal transduction. Multiple molecules associated with signaling events at the IS have been shown to respond to physical force, including the TCR, costimulatory molecules, adhesion molecules, and several downstream adapters. In at least some cases, it is clear that the relevant forces are exerted by dynamics of the T cell actomyosin cytoskeleton. Interestingly, there is evidence that the cytoskeleton of the antigen-presenting cell also plays an active role in T cell activation, by countering the molecular forces exerted by the T cell at the IS. Since actin polymerization is itself driven by TCR and costimulatory signaling pathways, a complex relationship exists between actin dynamics and receptor activation. This review will focus on recent advances in our understanding of the mechanosensitive aspects of T cell activation, paying specific attention to how F-actin-directed forces applied from both sides of the IS fit into current models of receptor triggering and activation.

Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration

“…3a, in the orientation shown in the figure, flow at the top of cell is largely towards the bottom (yellow), flow on the right of the cell is largely toward the left (red), and flow on the left of the cell is largely toward the right (green). Actin flow in migrating lymphocytes is thus centripetal, as previously found in lymphocyte immune synapses 19,31 .…”

“…Actin flow is known to be retrograde and normal to the leading edge in migrating fibroblasts and epithelial cells 17,18,30 . Much less is known about actin flow in migrating lymphocytes, although it is known to be retrograde within the immunological synapse in non-migrating T cells 19,31 . We measured actin dynamics in migrating T cells expressing lifeact-mNeonGreen using the superresolution capabilities of structured illumination microscopy (SIM).…”

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

“…Consistent with this, significant activation of the small GTPase Rap1 in T cells overexpressing TAGLN2 suggested that TAGLN2, together with vinculin, talin, and RapL, is a protein contained in the cytoplasmic signalosomes of LFA-1. 30 These data further suggested that TAGLN2 directly controls LFA-1 avidity rather than indirectly controls it by upregulation of actin contents.…”

Novel Insights into the Role of the Cytoskeleton in Cancer

“…In patients with Alzheimer's disease (AD), actin ilaments play a central role in maintaining and modifying synaptic connections [37]. As the key mediator between receptor activation during learning and a protein involved in regulating spine morphology [38,39], actin not only plays a role in the nervous system but also has functions in the immune system [40]. For example, F-actin can mediate signaling in B cells and T cells [41,42].…”

“…For example, F-actin can mediate signaling in B cells and T cells [41,42]. The dynamics of the actin cytoskeleton regulate adhesion and signal transduction in T cells/APCs [40]. SWAP-70 and HS1 are important downstream components of the TCR signaling pathway and are regulated by actin [43,44].…”