Cytoskeletal tension actively sustains the migratory T-cell synaptic contact.

Sudha Kumari,Darrell J Irvine,Michael Dustin,Nicki Watson,Mariane Melo,Michael Mak,Erin Janssen,Raif Geha,Mira Tohme,Yeh‐Chuin Poh

doi:10.15252/embj.2019102783

Abstract

When migratory T cells encounter antigen‐presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T‐cell immunity. While the cellular processes underlying synapse formation have been well characterized, those that maintain the symmetry, and thereby the stability of the synapse, remain unknown. Here we identify an antigen‐triggered mechanism that actively promotes T‐cell synapse symmetry by generating cytoskeletal tension in the plane of the synapse through focal nucleation of actin via Wiskott–Aldrich syndrome protein (WASP), and contraction of the resultant actin filaments by myosin II. Following T‐cell activation, WASP is degraded, leading to cytoskeletal unraveling and tension decay, which result in synapse breaking. Thus, our study identifies and characterizes a mechanical program within otherwise highly motile T cells that sustains the symmetry and stability of the T cell–APC synaptic contact.

Highlights

During an immune response, T cells form specialized junctions with cognate antigen-presenting cells (APCs) termed “immunological synapses” (Negulescu et al, 1996; Grakoui et al, 1999)
As T cells formed synapses with an antigen-presenting surface (APS), the key integrin adaptor protein talin accumulated rapidly at the periphery of the interface and talin levels remained constant at later times as cells began polarizing (Fig 1D)
Activating integrins using MnCl2 (Dransfield et al, 1992) after a stable synapse was established did not affect subsequent polarization/synapse breaking at 20 min, and inhibiting LFA-1/ICAM interactions using the small molecule inhibitor A286982 (Liu et al, 2000) blocked T-cell polarization, indicating that integrin activation is not necessary to sustain synapse symmetry and may be required for symmetry breaking (Fig 1F and G)

Summary

Introduction

T cells form specialized junctions with cognate antigen-presenting cells (APCs) termed “immunological synapses” (Negulescu et al, 1996; Grakoui et al, 1999). F-actin along with the activated integrin lymphocyte function-associated antigen-1 (LFA-1) is organized into a ring-like structure in the early synapse, and this ring-like pattern is thought to promote synaptic junctional stability (Wulfing et al, 1998; Kaizuka et al, 2007; Babich et al, 2012). This F-actin/integrin ring undergoes continuous fluctuations and is amenable to symmetry breaking

Methods

Results

Conclusion