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Cell Rep. 2019 Mar 19;26(12):3369-3379.e5. doi: 10.1016/j.celrep.2019.02.074.

Cytoskeletal Control of Antigen-Dependent T Cell Activation.

Author information

1
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford OX3 9DS, UK.
2
Department of Mechanical Engineering, University College London, London WC1E 7JE, UK.
3
Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
5
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA.
6
Department of Mechanical Engineering, University College London, London WC1E 7JE, UK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford OX3 9DS, UK; Kennedy Institute for Rheumatology, University of Oxford, Roosevelt Drive, Oxford OX3 7LF, UK. Electronic address: marco.fritzsche@rdm.ox.ac.uk.

Abstract

Cytoskeletal 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.

KEYWORDS:

T cell activation; TCR cluster; TFM; actin dynamics; immunological synapse; mechanosensation; mechanosensitivity

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