BTN3A1 discriminates γδ T cell phosphoantigens from non-antigenic small molecules via a conformational sensor in its B30.2 domain

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

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)
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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 negatively-charged 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.
Original languageEnglish
Pages (from-to)2631-2643
Number of pages13
JournalACS chemical biology
Volume12
Issue number10
Early online date1 Sep 2017
DOIs
Publication statusPublished - 14 Sep 2017

Keywords

  • Antigens
  • Antigens, CD/genetics
  • Butyrophilins/genetics
  • Cloning, Molecular
  • Coculture Techniques
  • Gene Expression Regulation/physiology
  • HEK293 Cells
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Chemical
  • Mutation
  • Phosphoproteins
  • Protein Conformation
  • Protein Domains
  • Receptors, Antigen, T-Cell, gamma-delta/genetics
  • T-Lymphocytes/metabolism

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