title: The CD3 conformational change in the γδ T cell receptor is not triggered by antigens but can be enforced to enhance tumor killing.
abstract: Activation of the T cell receptor (TCR) by antigen is the key step in adaptive immunity. In the αβTCR, antigen induces a conformational change at the CD3 subunits (CD3 CC) that is absolutely required for αβTCR activation. Here, we demonstrate that the CD3 CC is not induced by antigen stimulation of the mouse G8 or the human Vγ9Vδ2 γδTCR. We find that there is a fundamental difference between the activation mechanisms of the αβTCR and γδTCR that map to the constant regions of the TCRαβ/γδ heterodimers. Enforced induction of CD3 CC with a less commonly used monoclonal anti-CD3 promoted proximal γδTCR signaling but inhibited cytokine secretion. Utilizing this knowledge, we could dramatically improve in vitro tumor cell lysis by activated human γδ T cells. Thus, manipulation of the CD3 CC might be exploited to improve clinical γδ T cell-based immunotherapies.
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany.
authors.forename: Elaine P
authors.initials: EP
authors.lastname: Dopfer
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany.
authors.forename: Frederike A
authors.initials: FA
authors.lastname: Hartl
authors.affiliation: Institute of Immunology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany.
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany; Robarts Research Institute, Department of Anatomy and Cell Biology, Robarts Research Institute, Western University, London, ON N6A 5B7, Canada.
authors.forename: Gabrielle M
authors.initials: GM
authors.lastname: Siegers
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, 79104 Freiburg, Germany.
authors.forename: O Sascha
authors.initials: OS
authors.lastname: Yousefi
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kock
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, 79104 Freiburg, Germany.
authors.forename: Gina J
authors.initials: GJ
authors.lastname: Fiala
authors.affiliation: Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcillán
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, IL 60637, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Sandstrom
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid, 28049 Madrid, Spain.
authors.forename: Balbino
authors.initials: B
authors.lastname: Alarcón
authors.affiliation: Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Regueiro
authors.affiliation: Institute of Immunology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, IL 60637, USA.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Adams
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany.
authors.forename: Susana
authors.initials: S
authors.lastname: Minguet
authors.affiliation: Institute of Immunology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
authors.affiliation: Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: Department of Molecular Immunology, Faculty of Biology, BIOSS Centre for Biological Signaling Studies and Centre of Chronic Immunodeficiency (CCI), University of Freiburg, Schänzlestrasse 18, 79108 Freiburg, Germany; Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79104 Freiburg, Germany. Electronic address: wolfgang.schamel@biologie.uni-freiburg.de.
authors.forename: Wolfgang W A
authors.initials: WWA
authors.lastname: Schamel
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000737:chemistry* / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011487:Protein Conformation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000737:chemistry* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D017252:CD3 Complex; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D016692:Receptors, Antigen, T-Cell, gamma-delta