Publication Date:
2014-02-04
Description:
The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen-presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus-like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949170/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949170/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choudhuri, Kaushik -- Llodra, Jaime -- Roth, Eric W -- Tsai, Jones -- Gordo, Susana -- Wucherpfennig, Kai W -- Kam, Lance C -- Stokes, David L -- Dustin, Michael L -- 100262/Wellcome Trust/United Kingdom -- AI043542/AI/NIAID NIH HHS/ -- AI045757/AI/NIAID NIH HHS/ -- AI055037/AI/NIAID NIH HHS/ -- AI088377/AI/NIAID NIH HHS/ -- AI093884/AI/NIAID NIH HHS/ -- EY016586/EY/NEI NIH HHS/ -- K99 AI093884/AI/NIAID NIH HHS/ -- K99AI093884/AI/NIAID NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R01 AI043542/AI/NIAID NIH HHS/ -- R01 AI088377/AI/NIAID NIH HHS/ -- R21 AI055037/AI/NIAID NIH HHS/ -- R37 AI043542/AI/NIAID NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Mar 6;507(7490):118-23. doi: 10.1038/nature12951. Epub 2014 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, New York 10016, USA [2]. ; 1] Program in Structural Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, New York 10016, USA [2]. ; Northwestern University Atomic and Nanoscale Characterization Experimental Center, Northwestern University, 2220 Campus Drive, Evanston, Illinois 60208, USA. ; Department of Biomedical Engineering, Columbia University, 500 W 120th Street, New York, New York 10027, USA. ; 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Program in Immunology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; 1] Program in Structural Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, 540 First Avenue, New York, New York 10016, USA [2] New York Structural Biology Center, 89 Convent Avenue, New York, New York 10027, USA. ; 1] Department of Pathology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA [2] Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, The University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7FY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24487619" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigen-Presenting Cells/cytology/immunology/metabolism
;
B-Lymphocytes/cytology/immunology/metabolism
;
CD4-Positive T-Lymphocytes/immunology/metabolism/*secretion/virology
;
*Cell Polarity
;
DNA-Binding Proteins/metabolism
;
Endosomal Sorting Complexes Required for Transport/metabolism
;
Female
;
HIV/metabolism
;
Histocompatibility Antigens Class I/immunology/metabolism
;
Humans
;
Immunological Synapses/metabolism/*secretion/ultrastructure
;
Intercellular Adhesion Molecule-1/metabolism
;
Lymphocyte Activation
;
Male
;
Mice
;
Protein Binding
;
Protein Transport
;
Receptors, Antigen, T-Cell/immunology/*metabolism/ultrastructure
;
Secretory Vesicles/*metabolism/secretion
;
Signal Transduction
;
Transcription Factors/metabolism
;
Vesicular Transport Proteins/metabolism
;
Virus Release
;
gag Gene Products, Human Immunodeficiency Virus/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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