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Transient protein accumulation at the center of the T cell antigen presenting cell interface drives efficient IL-2 secretion

Danielle J. Clark, Laura E. McMillan, Sin Lih Tan, Gaia Bellomo, Clémentine Massoué, Harry Thompson, Lidiya Mykhaylechko, Dominic Alibhai, Xiongtao Ruan, Kentner L. Singleton, Minna Du, Alan J. Hedges, Pamela L. Schwartzberg, Paul Verkade, Robert F. Murphy, Christoph Wülfing
doi: https://doi.org/10.1101/296616
Danielle J. Clark
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Laura E. McMillan
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Sin Lih Tan
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Gaia Bellomo
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Clémentine Massoué
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Harry Thompson
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Lidiya Mykhaylechko
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Dominic Alibhai
2School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom
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Xiongtao Ruan
3Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Kentner L. Singleton
4Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Minna Du
4Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Alan J. Hedges
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
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Pamela L. Schwartzberg
5Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
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Paul Verkade
2School of Biochemistry, University of Bristol, Bristol BS8 1TD, United Kingdom
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Robert F. Murphy
3Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
6Departments of Biological Sciences, Biomedical Engineering and Machine Learning, Carnegie Mellon University, Pittsburgh, PA 15213, USA
7Freiburg Institute for Advanced Studies and Faculty of Biology, Albert Ludwig University of Freiburg, 79104 Freiburg, Germany
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Christoph Wülfing
1School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, United Kingdom
3Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA 15213, USA
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Abstract

Supramolecular signaling assemblies are of interest for their unique signaling properties. A µm scale signaling assembly, the central supramolecular signaling cluster (cSMAC), forms at the center of the interface of T cells activated by antigen presenting cells. We have determined that it is composed of multiple complexes of a supramolecular volume of up to 0.5µm3 and associated with extensive membrane undulations. To determine cSMAC function, we have systematically manipulated the localization of three adaptor proteins, LAT, SLP-76, and Grb2. cSMAC localization varied between the adaptors and was diminished upon blockade of the costimulatory receptor CD28 and deficiency of the signal amplifying kinase Itk. Reconstitution of cSMAC localization restored IL-2 secretion which is a key T cell effector function as dependent on reconstitution dynamics. Our data suggest that the cSMAC enhances early signaling by facilitating signaling interactions and attenuates signaling thereafter through sequestration of a more limited set of signaling intermediates.

Footnotes

  • ↵* Email: Christoph.Wuelfing{at}bristol.ac.uk

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 04, 2019.
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Transient protein accumulation at the center of the T cell antigen presenting cell interface drives efficient IL-2 secretion
Danielle J. Clark, Laura E. McMillan, Sin Lih Tan, Gaia Bellomo, Clémentine Massoué, Harry Thompson, Lidiya Mykhaylechko, Dominic Alibhai, Xiongtao Ruan, Kentner L. Singleton, Minna Du, Alan J. Hedges, Pamela L. Schwartzberg, Paul Verkade, Robert F. Murphy, Christoph Wülfing
bioRxiv 296616; doi: https://doi.org/10.1101/296616
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Transient protein accumulation at the center of the T cell antigen presenting cell interface drives efficient IL-2 secretion
Danielle J. Clark, Laura E. McMillan, Sin Lih Tan, Gaia Bellomo, Clémentine Massoué, Harry Thompson, Lidiya Mykhaylechko, Dominic Alibhai, Xiongtao Ruan, Kentner L. Singleton, Minna Du, Alan J. Hedges, Pamela L. Schwartzberg, Paul Verkade, Robert F. Murphy, Christoph Wülfing
bioRxiv 296616; doi: https://doi.org/10.1101/296616

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