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Synthetic Antigen Presenting cells reveal the diversity and functional specialisation of extracellular vesicles composing the fourth signal of T cell immunological synapses

View ORCID ProfilePablo F. Céspedes, Ashwin Jainarayanan, Lola Fernández-Messina, Salvatore Valvo, David G. Saliba, Audun Kvalvaag, Elke Kurz, Huw Colin-York, Marco Fritzsche, Yanchun Peng, Tao Dong, Jesús A. Siller-Farfán, View ORCID ProfileOmer Dushek, Michal Maj, View ORCID ProfileErdinc Sezgin, Ben Peacock, Alice Law, Dimitri Aubert, Simon Engledow, Moustafa Attar, Svenja Hester, Roman Fischer, Francisco Sánchez-Madrid, View ORCID ProfileMichael L. Dustin
doi: https://doi.org/10.1101/2021.05.29.445691
Pablo F. Céspedes
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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  • ORCID record for Pablo F. Céspedes
Ashwin Jainarayanan
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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Lola Fernández-Messina
2Immunology Service, Hospital de la Princesa, Instituto Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Madrid, Spain
3Intercellular communication in the inflammatory response. Vascular Physiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Salvatore Valvo
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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David G. Saliba
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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Audun Kvalvaag
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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Elke Kurz
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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Huw Colin-York
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
4MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford, Oxford, UK
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Marco Fritzsche
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
4MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford, Oxford, UK
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Yanchun Peng
4MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford, Oxford, UK
5Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
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Tao Dong
4MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford, Oxford, UK
5Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK
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Jesús A. Siller-Farfán
6Sir William Dunn School of Pathology, The University of Oxford, Oxford, UK
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Omer Dushek
6Sir William Dunn School of Pathology, The University of Oxford, Oxford, UK
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Michal Maj
6Sir William Dunn School of Pathology, The University of Oxford, Oxford, UK
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Erdinc Sezgin
7Science for Life Laboratory, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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Ben Peacock
8NanoFCM, MediCity, Nottingham, UK
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Alice Law
8NanoFCM, MediCity, Nottingham, UK
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Dimitri Aubert
8NanoFCM, MediCity, Nottingham, UK
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Simon Engledow
9Oxford Genomics Centre, Wellcome Centre for Human Genetics, The University of Oxford, Oxford, UK
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Moustafa Attar
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
9Oxford Genomics Centre, Wellcome Centre for Human Genetics, The University of Oxford, Oxford, UK
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Svenja Hester
10Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, The University of Oxford, Oxford, UK
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Roman Fischer
10Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, The University of Oxford, Oxford, UK
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Francisco Sánchez-Madrid
2Immunology Service, Hospital de la Princesa, Instituto Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Madrid, Spain
3Intercellular communication in the inflammatory response. Vascular Physiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
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Michael L. Dustin
1Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK
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  • ORCID record for Michael L. Dustin
  • For correspondence: michael.dustin@kennedy.ox.ac.uk
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ABSTRACT

The T cell Immunological Synapse (IS) is a pivotal hub for the regulation of adaptive immunity by facilitating the exchange of information between cells engaged in physical contact. Beyond the integration of antigen (signal one), co-stimulation (signal two), and cytokines (signal three), the IS facilitates the delivery of T-cell effector assemblies including supramolecular attack particles (SMAPs) and extracellular vesicles (EVs). How these particulate outputs differ among T-cell subsets and how subcellular compartments and signals exchanged at the synapse contribute to their composition is not fully understood. Here we harnessed bead-supported lipid bilayers (BSLBs) as a tailorable and versatile technology to study synaptic particle biogenesis and composition in different T-cell subsets, including CART. These synthetic antigen-presenting cells (APCs) facilitated the characterisation of synaptic vesicles (SVs) as a heterogeneous population of EVs comprising among others plasma membrane-derived synaptic ectosomes and CD63+ exosomes. We harnessed BSLB to unveil the factors influencing the vesicular release of CD40L, as a model effector, identifying CD40 trans-presentation, T-cell activation, ESCRT upregulation/recruitment, antigen density/potency, co-repression by PD-1 ligands, and its processing by ADAM10 as major determinants. Further, BSLB made possible the comparison of microRNA (miR) species associated with SVs and steadily shed EVs (sEVs). Altogether, our data provide evidence for a higher specialisation of SVs which are enriched not only in effector immune receptors but also in miR and RNA-binding proteins. Considering the molecular uniqueness and functional complexity of the SV output, which is also accompanied by SMAPs, we propose their classification as signal four.

Competing Interest Statement

Ben Peacock, Alice Law, and Dimitri Aubert are employed by NanoFCM Co., Ltd.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Synthetic Antigen Presenting cells reveal the diversity and functional specialisation of extracellular vesicles composing the fourth signal of T cell immunological synapses
Pablo F. Céspedes, Ashwin Jainarayanan, Lola Fernández-Messina, Salvatore Valvo, David G. Saliba, Audun Kvalvaag, Elke Kurz, Huw Colin-York, Marco Fritzsche, Yanchun Peng, Tao Dong, Jesús A. Siller-Farfán, Omer Dushek, Michal Maj, Erdinc Sezgin, Ben Peacock, Alice Law, Dimitri Aubert, Simon Engledow, Moustafa Attar, Svenja Hester, Roman Fischer, Francisco Sánchez-Madrid, Michael L. Dustin
bioRxiv 2021.05.29.445691; doi: https://doi.org/10.1101/2021.05.29.445691
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Synthetic Antigen Presenting cells reveal the diversity and functional specialisation of extracellular vesicles composing the fourth signal of T cell immunological synapses
Pablo F. Céspedes, Ashwin Jainarayanan, Lola Fernández-Messina, Salvatore Valvo, David G. Saliba, Audun Kvalvaag, Elke Kurz, Huw Colin-York, Marco Fritzsche, Yanchun Peng, Tao Dong, Jesús A. Siller-Farfán, Omer Dushek, Michal Maj, Erdinc Sezgin, Ben Peacock, Alice Law, Dimitri Aubert, Simon Engledow, Moustafa Attar, Svenja Hester, Roman Fischer, Francisco Sánchez-Madrid, Michael L. Dustin
bioRxiv 2021.05.29.445691; doi: https://doi.org/10.1101/2021.05.29.445691

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