Phosphoantigen sensing combines TCR-dependent recognition of the BTN3A IgV domain and germline interaction with BTN2A1.

Autor:	Willcox CR; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK. Electronic address: c.r.willcox@bham.ac.uk., Salim M; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK., Begley CR; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK., Karunakaran MM; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany., Easton EJ; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK., von Klopotek C; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany., Berwick KA; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK., Herrmann T; Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany., Mohammed F; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK., Jeeves M; Henry Wellcome Building for NMR, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK. Electronic address: m.jeeves@bham.ac.uk., Willcox BE; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; Cancer Immunology and Immunotherapy Centre, University of Birmingham, Birmingham, UK. Electronic address: b.willcox@bham.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Apr 25; Vol. 42 (4), pp. 112321. Date of Electronic Publication: 2023 Mar 28.
DOI:	10.1016/j.celrep.2023.112321
Abstrakt:	Vγ9Vδ2 T cells play critical roles in microbial immunity by detecting target cells exposed to pathogen-derived phosphoantigens (P-Ags). Target cell expression of BTN3A1, the "P-Ag sensor," and BTN2A1, a direct ligand for T cell receptor (TCR) Vγ9, is essential for this process; however, the molecular mechanisms involved are unclear. Here, we characterize BTN2A1 interactions with Vγ9Vδ2 TCR and BTN3A1. Nuclear magnetic resonance (NMR), modeling, and mutagenesis establish a BTN2A1-immunoglobulin V (IgV)/BTN3A1-IgV structural model compatible with their cell-surface association in cis. However, TCR and BTN3A1-IgV binding to BTN2A1-IgV is mutually exclusive, owing to binding site proximity and overlap. Moreover, mutagenesis indicates that the BTN2A1-IgV/BTN3A1-IgV interaction is non-essential for recognition but instead identifies a molecular surface on BTN3A1-IgV essential to P-Ag sensing. These results establish a critical role for BTN3A-IgV in P-Ag sensing, in mediating direct or indirect interactions with the γδ-TCR. They support a composite-ligand model whereby intracellular P-Ag detection coordinates weak extracellular germline TCR/BTN2A1 and clonotypically influenced TCR/BTN3A-mediated interactions to initiate Vγ9Vδ2 TCR triggering. Competing Interests: Declaration of interests B.E.W. provides consultancy regarding the development of γδ T cell immunotherapy approaches for Ferring Ventures SA, linked to Ferring Pharmaceuticals. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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