gamma 9 delta 2T cell diversity and the receptor interface with tumor cells
Vyborova, Anna; Beringer, Dennis X; Fasci, Domenico; Karaiskaki, Froso; van Diest, Eline; Kramer, Lovro; de Haas, Aram; Sanders, Jasper; Janssen, Anke; Straetemans, Trudy; Olive, Daniel; Leusen, Jeanette Hw; Boutin, Lola; Nedellec, Steven; Schwartz, Samantha L; Wester, Michael J; Lidke, Keith A; Scotet, Emmanuel; Lidke, Diane; Heck, Albert Jr; Sebestyen, Zsolt; Kuball, Jurgen
(2020) Journal of Clinical Investigation, volume 130, issue 9, pp. 4637 - 4651
(Article)
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
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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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Keywords: General Medicine
ISSN: 0021-9738
Publisher: The American Society for Clinical Investigation
Note: Funding Information: We thank the staff of the Flow Core Facility and the Multiplex Core Facility at UMC Utrecht and the MicroPICell cellular and tissue imaging core facilities at CRCINA, Nantes, SFR F. Bonamy, and the University of Nantes for their expert assistance. We thank Erin Adams (University of Chicago, Chicago, Illinois, USA) for providing the CD277-KO HEK293T cell line and Halvard Boe-nig (Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt AM Main, Germany) for providing feeder cells. We thank Rachael Grattan, Aubrey Gibson, and David Schodt for help with the sample preparation and super-resolution imaging. Funding for this study was provided by grants ZonMW 43400003 and VIDI-ZonMW 917.11.337, UU 2013-6426, UU 2014-6790, and UU 2015-7601 and Gadeta (to JK), UU 2018-11393 (to ZS and JK), Marie Curie 749010 (to DXB), NIH grants R01GM100114 (to DSL), P50GM085273 (to the New Mexico Spatiotemporal Modeling Center), and P30CA118100 (to the UNM Comprehensive Cancer Center). DF and AJRH acknowledge financial support from the NWO-funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (project 184.034.019). ES and LB are supported by grants from INSERM, CNRS, Université de Nantes, FRM (DEQ20170839118), and Ligue Contre le Cancer AO GO2019 (Côtes d’Armor, Association pour la Recherche contre le Cancer (PJA20191209404). This work was realized in the context of the LabEx IGO program, which is supported by the French National Research Agency Investissements d’Avenir. Funding Information: We thank the staff of the Flow Core Facility and the Multiplex Core Facility at UMC Utrecht and the MicroPICell cellular and tissue imaging core facilities at CRCINA, Nantes, SFR F. Bonamy, and the University of Nantes for their expert assistance. We thank Erin Adams (University of Chicago, Chicago, Illinois, USA) for providing the CD277-KO HEK293T cell line and Halvard Boenig (Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt AM Main, Germany) for providing feeder cells. We thank Rachael Grattan, Aubrey Gibson, and David Schodt for help with the sample preparation and super-resolution imaging. Funding for this study was provided by grants ZonMW 43400003 and VIDI-ZonMW 917.11.337, UU 2013-6426, UU 2014-6790, and UU 2015-7601 and Gadeta (to JK), UU 2018-11393 (to ZS and JK), Marie Curie 749010 (to DXB), NIH grants R01GM100114 (to DSL), P50GM085273 (to the New Mexico Spatiotemporal Modeling Center), and P30CA118100 (to the UNM Comprehensive Cancer Center). DF and AJRH acknowledge financial support from the NWO-funded Netherlands Proteomics Centre through the National Road Map for Large-scale Infrastructures program X-Omics (project 184.034.019). ES and LB are supported by grants from INSERM, CNRS, Universit? de Nantes, FRM (DEQ20170839118), and Ligue Contre le Cancer AO GO2019 (C?tes d'Armor, Association pour la Recherche contre le Cancer (PJA20191209404). This work was realized in the context of the LabEx IGO program, which is supported by the French National Research Agency Investissements d'Avenir. Publisher Copyright: Copyright: © 2020, American Society for Clinical Investigation.
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