Cytoskeletal Control of Antigen-Dependent T Cell Activation

Huw Colin-York,Yousef Javanmardi,Mark Skamrahl,Sudha Kumari,Veronica T Chang,Satya Khuon,Aaron Taylor,Teng-Leong Chew,Eric Betzig,Emad Moeendarbary,Vincenzo Cerundolo,Christian Eggeling,Marco Fritzsche

doi:10.1016/j.celrep.2019.02.074

Abstract

SummaryCytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell receptor and stimulated by a range of antigens, we found that the peak force experienced by the T cell receptor during activation was independent of the unbinding kinetics of the stimulating antigen. Conversely, quantification of the actin retrograde flow velocity at the synapse revealed a striking dependence on the antigen unbinding kinetics. These findings suggest that the dynamics of the actin cytoskeleton actively adjusted to normalize the force experienced by the T cell receptor in an antigen-specific manner. Consequently, tuning actin dynamics in response to antigen kinetics may thus be a mechanism that allows T cells to adjust the lengthscale and timescale of T cell receptor signaling.

Highlights

Cells adapt their biomechanics to fulfill their function in a range of complex, physical environments
Activating Jurkat T Cells Generate Mechanical Force Whose Magnitude Is Independent of Antigen Kinetics To investigate the mechanical force experienced by T cell receptor (TCR) during T cell activation, we used traction force microscopy (TFM)
The elastic 3 kPa polyacrylamide (PAA) gel surface necessary for TFM was loaded with fluorescent beads and functionalized with histocompatibility leukocyte antigen (HLA) A2 molecules loaded with the NY-ESO-1157–165 peptide recognized by the 1G4-TCR expressed by the Jurkat T cells (Figures 1A and S1)

Summary

Introduction

Cells adapt their biomechanics to fulfill their function in a range of complex, physical environments. It is emerging that cells can dynamically regulate their mechanics to meet their physiological needs via a diverse range of feedback mechanisms (Elosegui-Artola et al, 2016; RocaCusachs et al, 2017; Schwarz and Gardel, 2012). In this way, external stimuli may lead to mechanical transitions within the cell, which influence a functional outcome, such as the effector function of T cells. Molecular interactions at the T cell membrane initiate activation, but what follows is likely to involve a complex balance between the kinetics of key receptor-ligand interactions, the dynamics of the actin cytoskeleton, and the level of mechanical force generation. Understanding the nature of feedback between these components is of critical importance in providing a more complete understanding of T cell activation

Results

Discussion

Conclusion