Synthetic Antigen Presenting cells reveal the diversity and functional specialisation of extracellular vesicles composing the fourth signal of T cell immunological synapses
Synthetic Antigen Presenting cells reveal the diversity and functional specialisation of extracellular vesicles composing the fourth signal of T cell immunological synapses
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) and RNA-binding proteins (RBPs) associated with SVs and steadily shed EVs. Altogether, we provide evidence for a higher specialisation of SVs, which are enriched not only in effector immune receptors but also in miR and RBPs. Considering the molecular uniqueness and functional complexity of the SV output, which is also accompanied by SMAPs, we propose their classification as signal four.
Dustin Michael L.、Fritzsche Marco、Dong Tao、Dushek Omer、Peacock Ben、Law Alice、Aubert Dimitri、Fischer Roman、Fern¨￠ndez-Messina Lola、Valvo Salvatore、Kvalvaag Audun、Kurz Elke、Peng Yanchun、S¨￠nchez-Madrid Francisco、Jainarayanan Ashwin、Attar Moustafa、Sezgin Erdinc、Hester Svenja、Maj Michal、C¨|spedes Pablo F.、Saliba David G.、Colin-York Huw、Engledow Simon、Siller-Farf¨￠n Jes¨2s A.
Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford||MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of OxfordMRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford||Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of OxfordSir William Dunn School of Pathology, The University of OxfordNanoFCMNanoFCMNanoFCMTarget Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, The University of OxfordImmunology Service, Hospital de la Princesa, Instituto Investigaci¨?n Sanitaria Princesa, Universidad Aut¨?noma de Madrid||Intercellular communication in the inflammatory response. Vascular Physiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC)Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordMRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of Oxford||Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), University of OxfordImmunology Service, Hospital de la Princesa, Instituto Investigaci¨?n Sanitaria Princesa, Universidad Aut¨?noma de Madrid||Intercellular communication in the inflammatory response. Vascular Physiology Area, Centro Nacional de Investigaciones Cardiovasculares (CNIC)Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford||Oxford Genomics Centre, Wellcome Centre for Human Genetics, The University of OxfordScience for Life Laboratory, Department of Women?ˉs and Children?ˉs Health, Karolinska InstitutetTarget Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, The University of OxfordSir William Dunn School of Pathology, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford||MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, The University of OxfordOxford Genomics Centre, Wellcome Centre for Human Genetics, The University of OxfordSir William Dunn School of Pathology, The University of Oxford
细胞生物学分子生物学基础医学
T cellsextracellular vesiclesregulatory T cellscytotoxic T cellschimeric antigen receptor-expressing T cells (CART)synaptic ectosomessynaptic vesiclesCD40LmiRNACD38CD39CD73CD80CD86PD-L1PD-L2HIV gp120ADAM10BST2CD81
Dustin Michael L.,Fritzsche Marco,Dong Tao,Dushek Omer,Peacock Ben,Law Alice,Aubert Dimitri,Fischer Roman,Fern¨￠ndez-Messina Lola,Valvo Salvatore,Kvalvaag Audun,Kurz Elke,Peng Yanchun,S¨￠nchez-Madrid Francisco,Jainarayanan Ashwin,Attar Moustafa,Sezgin Erdinc,Hester Svenja,Maj Michal,C¨|spedes Pablo F.,Saliba David G.,Colin-York Huw,Engledow Simon,Siller-Farf¨￠n Jes¨2s A..Synthetic Antigen Presenting cells reveal the diversity and functional specialisation of extracellular vesicles composing the fourth signal of T cell immunological synapses[EB/OL].(2025-03-28)[2025-07-02].https://www.biorxiv.org/content/10.1101/2021.05.29.445691.点此复制
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