The CD3 Conformational Change in the γδ T Cell Receptor Is Not Triggered by Antigens but Can Be Enforced to Enhance Tumor Killing
Elaine P. Dopfer,
Frederike A. Hartl,
Hans-Heinrich Oberg,
Gabrielle M. Siegers,
O. Sascha Yousefi,
Sylvia Kock,
Gina J. Fiala,
Beatriz Garcillán,
Andrew Sandstrom,
Balbino Alarcón,
Jose R. Regueiro,
Dieter Kabelitz,
Erin J. Adams,
Susana Minguet,
Daniela Wesch,
Paul Fisch,
Wolfgang W.A. Schamel
Affiliations
Elaine P. Dopfer
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
Frederike A. Hartl
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
Hans-Heinrich Oberg
Institute of Immunology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany
Gabrielle M. Siegers
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
O. Sascha Yousefi
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
Sylvia Kock
Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany
Gina J. Fiala
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
Beatriz Garcillán
Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain
Andrew Sandstrom
Department of Biochemistry and Molecular Biology, University of Chicago, IL 60637, USA
Balbino Alarcón
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autonoma de Madrid, 28049 Madrid, Spain
Jose R. Regueiro
Faculty of Medicine, Universidad Complutense, 28040 Madrid, Spain
Dieter Kabelitz
Institute of Immunology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany
Erin J. Adams
Department of Biochemistry and Molecular Biology, University of Chicago, IL 60637, USA
Susana Minguet
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
Daniela Wesch
Institute of Immunology, Christian-Albrechts University of Kiel, 24105 Kiel, Germany
Paul Fisch
Institute of Pathology, University Medical Center Freiburg, 79106 Freiburg, Germany
Wolfgang W.A. Schamel
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
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.
