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Review
. 2014 Feb;1838(2):546-56.
doi: 10.1016/j.bbamem.2013.05.004. Epub 2013 May 14.

T cell antigen receptor activation and actin cytoskeleton remodeling

Sudha Kumari  1 , Silvia Curado  1 , Viveka Mayya  1 , Michael L Dustin  2
Affiliations
Review

T cell antigen receptor activation and actin cytoskeleton remodeling

Sudha Kumari et al. Biochim Biophys Acta. 2014 Feb.

Abstract

T cells constitute a crucial arm of the adaptive immune system and their optimal function is required for a healthy immune response. After the initial step of T cell-receptor (TCR) triggering by antigenic peptide complexes on antigen presenting cell (APC), the T cell exhibits extensive cytoskeletal remodeling. This cytoskeletal remodeling leads to the formation of an "immunological synapse" [1] characterized by regulated clustering, segregation and movement of receptors at the interface. Synapse formation regulates T cell activation and response to antigenic peptides and proceeds via feedback between actin cytoskeleton and TCR signaling. Actin polymerization participates in various events during the synapse formation, maturation, and eventually its disassembly. There is increasing knowledge about the actin effectors that couple TCR activation to actin rearrangements [2,3], and how defects in these effectors translate into impairment of T cell activation. In this review we aim to summarize and integrate parts of what is currently known about this feedback process. In addition, in light of recent advancements in our understanding of TCR triggering and translocation at the synapse, we speculate on the organizational and functional diversity of microfilament architecture in the T cell. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Hervé.

Keywords: Actin; Activation; Cytoskeleton; Lymphocytes; Myosin.

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Figures

Figure 1
Figure 1
Actin polymerization and remodeling at the synapse is critical for TCR microcluster movement to the cSMAC. The mature radially symmetrical synapse exhibits three spatially distinct zones of actin organization. The outermost ring of rapid polymerization zone - dSMAC-involves feedback between TCR triggering and actin dynamics. Actin polymerization aids in TCR signaling and microcluster formation via an unknown mechanism, and TCR triggering in turn potentiates actin polymerization. Actin polymerization then drives movement of TCR microclusters from the dSMAC, towards the pSMAC, and is the onset site of fast actin centripetal flow (0.1µm/sec). The pSMAC is the middle zone that undergoes contractions guided by actomyosin network, and actin retrograde flow. Actin flow occurs at slower speed in the pSMAC (0.04µm/sec), and is achieved majorly via actin polymerization and possibly with contribution from myosinII activity. The contractile network is visible as F-actin “arcs” in Jurkat T cell system (shown as interrupted network in pSMAC). TCR microclusters exhibit kinetic coupling with actin flow all across the synapse interface; sometimes translocating slower than the flow due to occasional slippage, and sometimes exhibiting similar translocation rate as F-actin speckles. At the inner boundary of the pSMAC, there is rapid decline and collapse of F-actin flow, generating a sharp boundary of the F-actin-rich pSMAC and F-actin-poor cSMAC. Actin polymerization appears to be a major driving force for microcluster movement, however the myosinII activity and actomyosin contraction provides directional persistence to reduce meandering and efficient delivery of microclusters to the cSMAC. In addition, TCR microclusters are capable of interacting with microtubular motor protein dynein, thus utilizing microtubular tracks for navigating the synaptic interface, and eventual delivery to the cSMAC.
Figure 2
Figure 2
Schematic view of integration of TCR signal transduction with diverse components of the actin polymerization machinery. TCR ligation with the pMHC complex on APC leads to Lck-mediated phosphorylation of cytosolic ITAM motifs in the CD3 zeta chain, which then serve as docking sites for ZAP70 kinase and it is accompanied by ZAP70 phosphorylation. From this initial step, TCR signaling diversifies to trigger a variety of signaling modules that yield actin polymerization. ZAP70 can activate NPF WASp via WIP-CrkL pathway (1), or via recruitment of Nck and thus of WASp. ZAP70-mediated recruitment of LAT and SLP76 complex, which then recruits Vav1, can activate Rho GTPase Cdc42, which in turn can release WASp auto-inhibition. Alternatively, WASp can be activated by PIP2-dependent-, Fyn-dependent or PST-PIP pathway (2). Activated WASp then recruits Arp2/3 complex and initiates actin polymerization. HS1, another NPF with cortactin activity, is recruited in an ITK-dependent manner and interacts with WASp, or can independently bind Arp2/3 and stabilize F-actin. WASP and HS1 activation in response to TCR engagement promotes release of Ca2+ from intracellular stores. In addition to Vav1, Lck-dependent activation of another GEF - SLAT - causes Rac GTPase activation, which in turn causes Abi/WAVE complex-dependent Arp2/3 recruitment to generate lamellipodial spreading and Ca2+ entry from the extracellular milieu. SLAT also activates Cdc42. Activation of WASH (3), a WASp-family NPF, causes the binding of WASH regulatory complex (SHRC) with endosomes, Arp2/3 complex recruitment and subsequent actin polymerization at the endosomes. SHRC also interacts with microtubules, and regulates endocytic recycling of cell surface receptors. Apart from the actin nucleating factor Arp2/3, the formin family proteins respond to TCR activation, and act to elongate the actin filaments linearly. These proteins localize to filopodia, as well as the perinuclear centrosomal area, where they regulate MTOC polarization to the synapse. (NPFs in the signaling cascades shown in red).
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