Cytoskeletal tension actively sustains the migratory T cell synaptic contact
Posted on: 11 June 2019
Preprint posted on 4 May 2019
Article now published in The EMBO Journal at http://dx.doi.org/10.15252/embj.2019102783
Actin foci establish a tensile network that sustains the immunological synapse formed during T cell activation
Selected by Tim Fessenden
Categories: biophysics, cell biology, immunology
The Context
A T cell’s specificity for a single unique antigen enables massive immune responses against a pathogen while sparing normal tissue. The molecular basis for this specificity lies in the T cell receptor, which recognizes its cognate peptide antigen held in the major histocompatibility (MHC) receptor on an antigen presenting cell (APC). Around these interacting receptors emerges a dynamic contact zone 5-10 microns in diameter called the immunological synapse (IS). The switch in T cell function and fate driven by TCR recognition depends acutely on the collective dynamics of adhesive, structural, and signaling proteins within the IS. It thus serves as a physical and biochemical module whose organization is of deep interest to immunology.
Immunologists have long appreciated a unique role of the actin cytoskeleton in directing IS maturation into a stable structural and signaling platform following TCR activation. In their previous work, the authors identified actin foci that emerge across the IS and spatially organize crucial signaling modules downstream of the TCR1. These foci depend on the regulatory protein WASP and its effector, the Arp2/3 complex, to locally nucleate actin filaments. Wiscott-Aldrich syndrome patients lack functional WASP and suffer from a host of immune deficiencies, indicating the physiologic role of actin foci for T cell activation.
The present work looks closely at the mechanics and biochemical signaling that collaborate to ensure IS stability, and confronts the largely neglected question of IS disassembly following T cell activation.
The Data
Two primary conclusions reached by this work are 1) that WASP-dependent actin foci are fundamental to IS stability and 2) that symmetry breaking in the IS leads to its disassembly.
Kumari et al demonstrate that WASP furnishes the mechanical and biochemical cues that together determine the lifetime and eventual disassembly of the contact zone between a T cell and an APC. They first observe that IS disassembly and T cell motility is preceded by a loss of radial symmetry, which coincides with a loss of WASP-dependent actin foci. As actin foci dissipate, the IS elongates and the T cell initiates motility. Both mechanical and computational methods demonstrate that actin foci support large traction stresses against the opposing surface, which suggest that symmetry breaking and IS dissolution is dominated by actin-driven mechanics. To this end, the authors also rule out any role of adhesion molecules in IS symmetry breaking.
Kumari et al then turn to a computational model to tease out how these dynamic structures are unified to maintain mechanical coherence of the IS. Their simulations confirm a central role of actomyosin clusters, formed by WASP activity that they spatially enforce in their model parameters.
In their final set of experiments, they perturb the mechanical coherence of the IS in cells to address how IS stability relates to actin foci and contractile stresses.
Global inhibition of myosin via blebbistatin induces IS dissolution, a finding that may be explained in two ways: either tension is an intrinsic requirement of IS stability, or relieving inhibition of lamellar protrusions via myosin inhibition permits migration to “win” over IS stability2. Both explanations seem plausible, although this ready prefers the latter. Next the authors ask whether inhibiting a portion of myosin, and inducing mechanical asymmetries thereby, also leads to IS dissolution. Using a UV light-activated derivative of blebbistatin, they can inactivate myosin only on one edge of the IS. The induced asymmetry in contractile machinery caused rapid IS dissolution and T cell migration. These results demonstrate the requirement not only for cytoskeletal tension per se, but also for radially symmetric stresses enabled by actin foci to maintain the IS.
Implications
The authors offer new biophysical details of a unique actin organelle that induces motility arrest in T cells, which count among the most rapidly moving mammalian cell types. Kumari et al describe an actin architecture dependent on WASP and Arp2/3, which form a contractile network of actin-rich nodes. Other investigations have identified a central role of traction stresses in the IS during cytotoxic T cell killing3. With this study, Kumari et al identify common biophysical properties but important differences between these two T cell organelles.
The size of the IS approaches the diameter of the entire T cell, which suggests that actin present in the cell must be incorporated into either the IS or the actin organelles that drive motility such as lamellipodia, but not both. Further, both the IS and lamellipodia are sustained by feed-forward mechanisms, which would enable an irreversible switch between them. Kumari et al find that IS stability is acutely reliant on myosin-driven contractility, and that an asymmetry in myosin activity can drive IS disassembly.
Actin foci such as those identified here emerge in unique circumstances in cells, notably in the absence of both stress fibers and focal adhesions formed in adherent cells4. Why the actin architecture at the IS preferentially adopts the form of a network of nodes remains to be fully elucidated.
References
- Kumari, S. et al. Actin foci facilitate activation of the phospholipase C-γ in primary T lymphocytes via the WASP pathway. eLife 4, (2015).
- Lomakin, A. J. et al. Competition for actin between two distinct F-actin networks defines a bistable switch for cell polarization. Nat. Cell Biol. 17, 1435–1445 (2015).
- Basu, R. et al. Cytotoxic T Cells Use Mechanical Force to Potentiate Target Cell Killing. Cell 165, 100–110 (2016).
- Luo, W. et al. Analysis of the local organization and dynamics of cellular actin networks. J. Cell Biol. 202, 1057–1073 (2013).
doi: https://doi.org/10.1242/prelights.11014
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