BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain

Salim, Mahboob; Knowles, Timothy J; Baker, Alfie T.; Davey, Martin S.; Jeeves, Mark; Sridhar, Pooja; Wilkie, John; Willcox, Carrie R.; Kadri, Hachemi; Taher, Taher E.; Vantourout, Pierre; Hayday, Adrian; Mehellou, Youcef; Mohammed, Fiyaz; Willcox, Benjamin E.

Abstract

Human Vγ9/Vδ2 T-cells detect tumour cells and microbial infections by recognising small phosphorylated prenyl metabolites termed phosphoantigens (P-Ag). The type-1 transmembrane protein Butyrophilin 3A1 (BTN3A1) is critical to the P-Ag-mediated activation of Vγ9/Vδ2 T-cells, however, the molecular mechanisms involved in BTN3A1-mediated metabolite sensing are unclear, including how P-Ag are discriminated from non-antigenic small molecules. Here, we utilised NMR and X-ray crystallography to probe P-Ag sensing by BTN3A1. Whereas the BTN3A1 Immunoglobulin Variable domain failed to bind P-Ag, the intracellular B30.2 domain bound a range of negativelycharged small molecules, including P-Ag, in a positively-charged surface pocket. However, NMR chemical shift perturbations indicated BTN3A1 discriminated P-Ag from non-antigenic small molecules by their ability to induce a specific conformational change in the B30.2 domain that propagated from the P-Ag binding site to distal parts of the domain. These results suggest BTN3A1 selectively detects P-Ag intracellularly via a conformational antigenic sensor in its B30.2 domain, and have implications for rational design of antigens for Vγ9/Vδ2 -based T-cell immunotherapies.

Citation

Salim, M., Knowles, T. J., Baker, A. T., Davey, M. S., Jeeves, M., Sridhar, P., …Willcox, B. E. (2017). BTN3A1 Discriminates γδ T Cell Phosphoantigens from Nonantigenic Small Molecules via a Conformational Sensor in Its B30.2 Domain. ACS Chemical Biology, 12(10), 2631-2643. https://doi.org/10.1021/acschembio.7b00694

• Journal Article Type: Article
• Acceptance Date: Sep 1, 2017
• Online Publication Date: Sep 14, 2017
• Publication Date: Sep 1, 2017
• Deposit Date: Mar 26, 2019
• Publicly Available Date: Apr 15, 2019
• Journal: ACS Chemical Biology
• Print ISSN: 1554-8929
• Electronic ISSN: 1554-8937
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 10
• Pages: 2631-2643
• DOI: https://doi.org/10.1021/acschembio.7b00694
• Related Public URLs: http://orca.cf.ac.uk/104312/