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Review
. 2010 Sep;2(9):a002444.
doi: 10.1101/cshperspect.a002444. Epub 2010 Aug 11.

Mediation of T-cell activation by actin meshworks

Peter Beemiller  1 , Matthew F Krummel
Affiliations
Review

Mediation of T-cell activation by actin meshworks

Peter Beemiller et al. Cold Spring Harb Perspect Biol. 2010 Sep.

Abstract

Although the actin cytoskeleton and T-cell receptor (TCR) signaling complexes are seemingly distinct molecular structures, they are tightly integrated in T cells. The signaling pathways initiated by TCRs binding to peptide MHC complexes are extensively influenced by the actin cytoskeletal activities of the motile phase before TCR signaling, the signalosome scaffolding function of the cytoskeleton, and the translocation of signaling clusters that precedes the termination of signaling at these complexes. As these three successive phases constitute essentially all the steps consequent to immune synapse formation, it has become clear that the substantial physical forces and signaling interactions generated by the actin cytoskeleton dominate the signaling life cycle of TCR signalosomes. We discuss the contributions of the actin cytoskeleton to TCR signaling phases and model some remaining questions about how specific cytoskeletal factors regulate TCR signaling outcomes.

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Figures

Figure 1.
Figure 1.
The actin meshwork of the motile T cell establishes a mechanical regime of TCR triggering. (A) T cells (TC) display various modes of motility depending on the adhesive properties of their microenvironment. To achieve high velocities, T cells create series of small, short-lived contacts with substrates. The pseudopod sequences are generated by cycles of actin polymerization followed by myosin generated contractility. When T cells encounter the adhesion promoting surface of an APC, such as a dendritic cell (DC), integrin ligation causes the T cells to spread more extensively, maximizing surface interactions between the cells. Cell body motion does not completely stop, though, and T cells continue to drift over the surface of the APC as they scan for their cognate pMHC. (B) The actin cytoskeletal remodeling induced by integrin ligation during T-APC coupling assists TCR-pMHC interactions. Branched actin network formation (brown), initiated from ligated LFA1 (purple), presses the cell surfaces together (1) to a length scale that allows pMHC (gold) binding to TCRs (blue). (See facing page for legend.)By pressing the cell membranes into close proximity, actin polymerization drives bulky, inhibitory phosphatases, such as CD45 (green), from the zone of pMHC-TCR ligation (2). (C) T-cell motility places continuous stress of molecules interaction across the T cell-APC junction. In the receptor deformation model, actin cytoskeletal movements introduce shear force that can break TCR-pMHC interactions. When a perpendicular force is applied (1), TCRs bound to pMHCs that are not bearing the T cells agonist ligand (left) rupture, freeing the TCR to scan another pMHC. When a TCR binds a pMHC bearing the agonist ligand (purple, at right), shear force (2) induces a conformational change, triggering the receptor and recruitment of signalosome factors (yellow).
Figure 2.
Figure 2.
Actin meshwork scaffolding stabilizes signaling clusters and promotes rapid signalosome assembly. (A) Association of TCRs with actin filaments holds receptors in place following triggering, and places the receptors in proximity to actin-associated effectors that can be rapidly recruited to stabilize the triggered TCR on the cytoskeleton (left, red and green). This can increase the lifetime of intermolecular interactions to allow diffusion of soluble effectors (yellow) to signalosomes and microcluster coalescence. Additionally, costimulatory receptors signal through many of the same effectors as TCRs. CD2 has been observed to colocalize with TCRs following stimulation, and can assemble TCR signaling factors into a signalosome resembling a TCR signalosome even before TCR triggering. By sharing effectors, association of CD2 and TCR microdomains allows rapid coalescence of a signalosome around a triggered TCR. (B) TCRs transiently associate with the actin meshwork, either directly or through an intermediate binding partner (yellow). Functional signalosomes can be quickly assembled following receptor triggering by concatenating actin-dependent TCR membrane microdomains (1) with prescaffolded, LAT-enriched membrane microdomains (2). To terminate signaling, TCRs can be separated from signalosome factors by myosin based actin filament movement (in gold) that pulls TCRs from the signaling supportive periphery into the center of the immune synapse (3).
Figure 3.
Figure 3.
Friction applied by the actin meshwork regulates T-cell activation through actin retrograde flow. (A) TCR microclusters (cyan circles) stream centripetally toward the cSMAC boundary (indicated by the dashed purple semi-circle). Receptors couple to retrograde actin flow (brown arrows) generated by actin-associated myosin motor proteins (gold) and by actin polymerization at the periphery of the interface. Because of the density of the actin meshwork in the periphery, receptors need not travel along filaments, but rather can be forced inward nonspecifically (shown at top). Alternatively, differential binding to an actin-associated signaling factor (yellow) could determine the extent to which a receptor centralizes. A generic coupling mechanism is suggested by recent work that indicates that both LFA1 (red circles) and TCRs couple to the centripetal actin flow. The extent to which receptors centralize is controlled by the size of clusters, with larger TCR microclusters consistently sorting to the interior of smaller integrin microclusters (shown at bottom). In a “clutched” mechanism, the larger TCR microclusters (cyan) generate more links to actin filaments than smaller intergrin clusters (red). As a result, TCR signaling clusters show increased centralization. (B) Some costimulation receptors (purple) may function by increasing the time that TCR microclusters spend in the signaling factor enriched periphery of the synapse. By creating a series of frictional barriers (shown at left), ligated costimulation receptors generate forces (purple arrows) that counteract retrograde flow of the cytoskeletal meshwork, increasing the length of the path (cyan line) that microclusters follow to reach the cSMAC. This increases the residence time of the TCR microcluster in the signaling effector enriched pSMAC. In the absence of ligated coreceptors, TCRs quickly pass through the pSMAC, decreasing their residence time in the signal generating region of the synapse (shown at right).
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