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butyrophilin subfamily 3 member A1

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Target id: 2948

Nomenclature: butyrophilin subfamily 3 member A1

Family: Butyrophilin and butyrophilin-like proteins

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 513 6p22.2 BTN3A1 butyrophilin subfamily 3 member A1
Gene and Protein Information Comments
Several transcript variants and protein isoforms are predicted from the human gene. We provide details for the longest form (variant 1, isoform a) here.
Previous and Unofficial Names Click here for help
BT3.1 | BTN3.1 | CD277
Database Links Click here for help
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
POM2-C-HMBP Small molecule or natural product Immunopharmacology Ligand Hs Binding - - 1
Immunopharmacology Comments
Vγ2Vδ2 (a.k.a. Vγ9Vδ2) T cells bridge the gap between innate and adaptive immunity and play roles in microbial immunity and tumour immunity [2]. Evidence supports a role for BTN3A1 in mediating activation of Vγ2Vδ2 T cells by detecting both self and non-self isoprenoid metabolites [4]. Vγ2Vδ2 T cells activated by this mechanism proliferate and can traffic to peripheral sites where they secrete Th1 cytokines, such as IFN-β and TNF-α, inflammatory chemokines, and growth factors while killing infected cells, and can use their TCR and NK receptors to recognize and kill a variety of tumour cells, in a tissue origin, MHC expression, or MHC haplotype independent manner [2]. Aminobisphosphonates (e.g. zoledronic acid, or zoledronate) and alkylamines expand Vγ2Vδ2 T cells via inhibition of farnesyl diphosphate synthase (one of the steps of the lanosterol biosynthesis pathway), which results in the accumulation of the upstream isopentenyl pyrophosphate (IPP) metabolite that stimulates the Vγ2Vδ2 T cells.

Druggability: A synthetic, cell-permeable prodrug analogue of the Vγ2Vδ2 T cell activator (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), POM2-C-HMBP, acts intracellularly to mediate BTN3A1-dependent lysis of malignant cells by Vγ2Vδ2 effector T cells. Zoledronate has been shown to enhance BTN3A1 expression by epithelial cells and tumour-associated fibroblasts in colorectal cancer (CRC), and to activate Vγ2Vδ2-mediated killing of ex-vivo CRC cells [5]. See also [3] which describes BTN3A1-binding agonistic nucleotidic phosphoantigens.

This protein contains an immunoglobulin (Ig)-like domain that resembles the antibody variable domain, that has been coined the 'V-set domain'. The genes for all human V-set domain containing proteins are listed in HGNC gene group 590.
Immuno Process Associations
Immuno Process:  T cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Immuno Process:  B cell (activation)
Physiological Functions Click here for help
The γδ T cell subset expressing the T cell receptor Vγ2Vδ2, are activated by isoprenoid metabolites, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP- a foreign microbial antigen) and isopentenyl pyrophosphate (IPP- a self-metabolite). Activation appears to be mediated by binding to an intracellular domain of the BTN3A1 protein. Using this mechanism, BTN3A1 functions as a sensor for intracellular isoprenoid metabolism to signal changes to Vγ2Vδ2 T cells.
Species:  Human
Tissue:  γδ T cells
References:  4


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1. Kilcollins AM, Li J, Hsiao CH, Wiemer AJ. (2016) HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors. J Immunol, 197 (2): 419-28. [PMID:27271567]

2. Morita CT, Jin C, Sarikonda G, Wang H. (2007) Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev, 215: 59-76. [PMID:17291279]

3. Moulin M, Alguacil J, Gu S, Mehtougui A, Adams EJ, Peyrottes S, Champagne E. (2017) Vγ9Vδ2 T cell activation by strongly agonistic nucleotidic phosphoantigens. Cell Mol Life Sci, 74 (23): 4353-4367. [PMID:28669030]

4. Wang H, Morita CT. (2015) Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells. J Immunol, 195 (10): 4583-94. [PMID:26475929]

5. Zocchi MR, Costa D, Venè R, Tosetti F, Ferrari N, Minghelli S, Benelli R, Scabini S, Romairone E, Catellani S et al.. (2017) Zoledronate can induce colorectal cancer microenvironment expressing BTN3A1 to stimulate effector γδ T cells with antitumor activity. Oncoimmunology, 6 (3): e1278099. [PMID:28405500]

How to cite this page

Butyrophilin and butyrophilin-like proteins: butyrophilin subfamily 3 member A1. Last modified on 07/08/2019. Accessed on 20/05/2024. IUPHAR/BPS Guide to PHARMACOLOGY,