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
Affiliations
Huw Colin-York
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford OX3 9DS, UK
Yousef Javanmardi
Department of Mechanical Engineering, University College London, London WC1E 7JE, UK
Mark Skamrahl
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford OX3 9DS, UK
Sudha Kumari
Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Veronica T. Chang
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK
Satya Khuon
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA
Aaron Taylor
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA
Teng-Leong Chew
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA
Eric Betzig
Janelia Research Campus, Howard Hughes Medical Institute, 19700 Helix Drive, Ashburn, VA 20147, USA
Emad Moeendarbary
Department of Mechanical Engineering, University College London, London WC1E 7JE, UK; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Vincenzo Cerundolo
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford OX3 9DS, UK
Christian Eggeling
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Headley Way, Oxford OX3 9DS, UK
Marco Fritzsche
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; Corresponding author
Summary: 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. : T cell activation relies on a dynamic actin cytoskeleton. Here, Colin-York et al. show how the kinetics of the stimulating antigen influence the dynamics of actin. This feedback mechanism influences the mechanics at the immune synapse, allowing T cells to orchestrate the length scale and timescale of signaling. Keywords: TFM, actin dynamics, TCR cluster, immunological synapse, mechanosensation, mechanosensitivity, T cell activation
