Anna Vyborova, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Dennis X. Beringer, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Domenico Fasci, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Froso Karaiskaki, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Eline van Diest, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Lovro Kramer, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Aram de Haas, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Jasper Sanders, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Anke Janssen, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Trudy Straetemans, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Daniel Olive, Centre de Recherche en Cancérologie Marseille, INSERM, Institut Paoli-Calmettes, Marseille, France
Jeanette Leusen, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Lola Boutin, Université de Nantes, INSERM, CNRS, CRCINA, LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France
Steven Nedellec, Structure Fédérative de Recherche en Santé François Bonamy (SFR-Santé), INSERM, CNRS, CHU Nantes, Nantes, France
Samantha L. Schwartz, Department of Pathology. Comprehensive Cancer CenterUniversity of New Mexico (UNM), Albuquerque, New Mexico, USA.
Michael J. Wester, Department of Physics and Astronomy, University of New Mexico (UNM), Albuquerque, New Mexico, USA
Keith A. Lidke, Department of Physics and Astronomy, University of New Mexico (UNM), Albuquerque, New Mexico, USA.
Emmanuel Scotet, Université de Nantes, INSERM, CNRS, CRCINA, LabEx IGO "Immunotherapy, Graft, Oncology," Nantes, France.
Diane S. Lidke, Department of Pathology Comprehensive Cancer Center,University of New Mexico (UNM), Albuquerque, New Mexico, USA.
Albert Jr Heck, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, NetherlandsNetherlands Proteomics Centre, Utrecht, Netherlands
Zsolt Sebestyen, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands
Jürgen Kuball, Center for Translational Immunology, University Medical Center (UMC) Utrecht, Utrecht University, Utrecht, Netherlands Department of Hematology, UMC Utrecht, Utrecht University, Utrecht, Netherlands

Document Type

Article

Publication Date

9-1-2020

Abstract

γ9δ2T cells play a major role in cancer immune surveillance, yet the clinical translation of their in vitro promise remains challenging. To address limitations of previous clinical attempts using expanded γ9δ2T cells, we explored the clonal diversity of γ9δ2T cell repertoires and characterized their target. We demonstrated that only a fraction of expanded γ9δ2T cells was active against cancer cells and that activity of the parental clone, or functional avidity of selected γ9δ2 T cell receptors (γ9δ2TCRs), was not associated with clonal frequency. Furthermore, we analyzed the target-receptor interface and provided a 2-receptor, 3-ligand model. We found that activation was initiated by binding of the γ9δ2TCR to BTN2A1 through the regions between CDR2 and CDR3 of the TCR γ chain and modulated by the affinity of the CDR3 region of the TCRδ chain, which was phosphoantigen independent (pAg independent) and did not depend on CD277. CD277 was secondary, serving as a mandatory coactivating ligand. We found that binding of CD277 to its putative ligand did not depend on the presence of γ9δ2TCR, did depend on usage of the intracellular CD277, created pAg-dependent proximity to BTN2A1, enhanced cell-cell conjugate formation, and stabilized the immunological synapse (IS). This process critically depended on the affinity of the γ9δ2TCR and required membrane flexibility of the γ9δ2TCR and CD277, facilitating their polarization and high-density recruitment during IS formation.

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