Format

Send to

Choose Destination
Immunity. 2014 Apr 17;40(4):490-500. doi: 10.1016/j.immuni.2014.03.003. Epub 2014 Apr 3.

The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells.

Author information

1
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
2
INSERM, Unité Mixte de Recherche 892, Centre de Recherche en Cancérologie Nantes Angers, 44000 Nantes, France; University of Nantes, 44000 Nantes, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, 44000 Nantes, France.
3
Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA.
4
INSERM, Unité Mixte de Recherche 892, Centre de Recherche en Cancérologie Nantes Angers, 44000 Nantes, France; University of Nantes, 44000 Nantes, France; Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche 6299, 44000 Nantes, France. Electronic address: emmanuel.scotet@univ-nantes.fr.
5
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. Electronic address: ejadams@uchicago.edu.

Abstract

In humans, Vγ9Vδ2 T cells detect tumor cells and microbial infections, including Mycobacterium tuberculosis, through recognition of small pyrophosphate containing organic molecules known as phosphoantigens (pAgs). Key to pAg-mediated activation of Vγ9Vδ2 T cells is the butyrophilin 3A1 (BTN3A1) protein that contains an intracellular B30.2 domain critical to pAg reactivity. Here, we have demonstrated through structural, biophysical, and functional approaches that the intracellular B30.2 domain of BTN3A1 directly binds pAg through a positively charged surface pocket. Charge reversal of pocket residues abrogates binding and Vγ9Vδ2 T cell activation. We have also identified a gain-of-function mutation within this pocket that, when introduced into the B30.2 domain of the nonstimulatory BTN3A3 isoform, transfers pAg binding ability and Vγ9Vδ2 T cell activation. These studies demonstrate that internal sensing of changes in pAg metabolite concentrations by BTN3A1 molecules is a critical step in Vγ9Vδ2 T cell detection of infection and tumorigenesis.

PMID:
24703779
PMCID:
PMC4028361
DOI:
10.1016/j.immuni.2014.03.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center