Controversy and consensus regarding myosin II function at the immunological synapse

Highlights

• F-actin and myosin II form arcs at the immunological synapse.

• IS domains correspond to the lamellipodium and lamellum of other cells.

• Researchers disagree about the magnitude of myosin II's role in IS formation and T cell signaling.

• The magnitude of myosin II's contribution may be context dependent.

Regulated actin dynamics play a central role in modulating signaling events at the immunological synapse (IS). Polymerization of actin filaments at the periphery of the IS, coupled to depolymerization near the center, generates a centripetal flow of the actin network and associated movement of signaling molecules. A recent flurry of papers addresses the role of myosin II in facilitating these events. Investigators agree that myosin II is present at the IS, where it forms actomyosin arcs within the peripheral supramolecular activation cluster, a region corresponding to the lamellum of migrating cells. However, there is substantial disagreement about the extent to which myosin II drives IS formation and signaling events leading to T cell activation.

Introduction

Upon contact with an antigen presenting cell (APC), a T cell undergoes a series of rapid cytoskeletal rearrangements that culminate in formation of an immunological synapse (IS) [1, 2]. The most notable of these is the initiation of robust actin polymerization at the outermost edges of the contact [3, 4]. Given the radial symmetry of the contact, this polymerization, coupled with depolymerization near the center of the interface, creates a dramatic centripetal flow of actin just under the T cell's plasma membrane in the plane of the IS. Actin flow is widely thought to provide much of the motive force for the centripetal movement of signaling microclusters (MCs) [5, 6, 7]. This leads, over a period of several minutes, to the formation of a mature IS containing an outer ring rich in integrins (termed the peripheral supramolecular activation cluster or pSMAC [8]) and an inner region rich in TCRs and associated signaling molecules (the central supramolecular activation cluster or cSMAC [9]).

At the leading edge of other cell types, the pushing force of actin polymerization-driven retrograde flow is coupled with a pulling force generated by myosin II-dependent actin arc contraction [10, 11, 12, 13]. These two forces reside in structurally distinct zones, with actin polymerization in the outer lamellipodium (LP) and actomyosin II arc contraction behind the LP, in the lamellum (LM). The LP is composed largely of a branched actin network created by Arp2/3-dependent nucleation at the plasma membrane cytoplasm interface [14, 15]. The LM, on the other hand, is composed of linear actin arcs or fibers aligned roughly parallel to the leading edge. These are probably created by formin-dependent nucleation and the rearrangement of LP actin [11, 16, 17, 18]. Dynamic imaging of GFP-actin in Jurkat T cells engaged on planar stimulatory surfaces reveals robust Arp2/3-dependent actin retrograde flow principally in a ring surrounding the pSMAC, termed the distal SMAC (dSMAC) [3, 19, 20, 21, 22]. Based partly on these observations, Dustin hypothesized that the IS might represent a radially symmetric version of the leading edge of a fibroblast, with the dSMAC corresponding to the LP and the pSMAC corresponding to the LM [23, 24] (Figure 1). In comparison with these outer regions of the IS, the cSMAC is F-actin-poor, albeit not devoid of F-actin [25, 26]. Importantly, the LM is a zone of actomyosin II arc contraction, raising the possibility that the centripetal transport of TCR and other signaling MCs is driven not only by the pushing force of actin retrograde flow, but also by the pulling force of myosin II-dependent contraction. Here, we briefly review a series of recent studies that provide evidence for and against the existence of this latter mechanism and its contribution to MC transport, IS formation and T cell signaling.