2. Academic Validation
  3. T-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles

T-cell trans-synaptic vesicles are distinct and carry greater effector content than constitutive extracellular vesicles

  • Nat Commun. 2022 Jun 16;13(1):3460. doi: 10.1038/s41467-022-31160-3.
Pablo F Céspedes # 1,  Ashwin Jainarayanan # 2,  Lola Fernández-Messina 3 4,  Salvatore Valvo 2,  David G Saliba 2,  Elke Kurz 2,  Audun Kvalvaag 2,  Lina Chen 2,  Charity Ganskow 2,  Huw Colin-York 2 5,  Marco Fritzsche 2 5,  Yanchun Peng 5 6,  Tao Dong 5 6,  Errin Johnson 7,  Jesús A Siller-Farfán 7,  Omer Dushek 7,  Erdinc Sezgin 8,  Ben Peacock 9,  Alice Law 9,  Dimitri Aubert 9,  Simon Engledow 10,  Moustafa Attar 2 10,  Svenja Hester 11,  Roman Fischer 11,  Francisco Sánchez-Madrid 3 4,  Michael L Dustin 12
Affiliations

Affiliations

  • 1 Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK. pablo.cespedes@kennedy.ox.ac.uk.
  • 2 Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK.
  • 3 Immunology Service, Hospital de la Princesa, Instituto Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
  • 4 Intercellular communication in the inflammatory response. Vascular Physiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • 5 MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford, Oxford, UK.
  • 6 Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
  • 7 Sir William Dunn School of Pathology, The University of Oxford, Oxford, UK.
  • 8 Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  • 9 NanoFCM, MediCity, Nottingham, UK.
  • 10 Oxford Genomics Centre, Wellcome Centre for Human Genetics, The University of Oxford, Oxford, UK.
  • 11 Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, The University of Oxford, Oxford, UK.
  • 12 Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Oxford, UK. michael.dustin@kennedy.ox.ac.uk.
  • # Contributed equally.
PMID: 35710644 DOI: 10.1038/s41467-022-31160-3
Abstract

The immunological synapse is a molecular hub that facilitates the delivery of three activation signals, namely antigen, costimulation/corepression and cytokines, from antigen-presenting cells (APC) to T cells. T cells release a fourth class of signaling entities, trans-synaptic vesicles (tSV), to mediate bidirectional communication. Here we present bead-supported lipid bilayers (BSLB) as versatile synthetic APCs to capture, characterize and advance the understanding of tSV biogenesis. Specifically, the integration of juxtacrine signals, such as CD40 and antigen, results in the adaptive tailoring and release of tSV, which differ in size, yields and immune receptor cargo compared with steadily released extracellular vesicles (EVs). Focusing on CD40L+ tSV as model effectors, we show that PD-L1 trans-presentation together with TSG101, ADAM10 and CD81 are key in determining CD40L vesicular release. Lastly, we find greater RNA-binding protein and MicroRNA content in tSV compared with EVs, supporting the specialized role of tSV as intercellular messengers.

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