butyrophilin subfamily 3 member A1

Immunopharmacology Ligand target has curated data in GtoImmuPdb

Target id: 2948

Nomenclature: butyrophilin subfamily 3 member A1

Family: Butyrophilin and butyrophilin-like proteins

Gene and Protein Information
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
BT3.1 \| BTN3.1 \| CD277

Previous and Unofficial Names

BT3.1 | BTN3.1 | CD277

Database Links
Alphafold	O00481 (Hs)
CATH/Gene3D	2.60.40.10
ChEMBL Target	CHEMBL4105758 (Hs)
Ensembl Gene	ENSG00000026950 (Hs)
Entrez Gene	11119 (Hs)
Human Protein Atlas	ENSG00000026950 (Hs)
KEGG Gene	hsa:11119 (Hs)
OMIM	613593 (Hs)
Pharos	O00481 (Hs)
RefSeq Nucleotide	NM_007048 (Hs)
RefSeq Protein	NP_008979 (Hs)
UniProtKB	O00481 (Hs)
Wikipedia	BTN3A1 (Hs)

Other Binding Ligands

Key to terms and symbols

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Ligand											Sp.	Action	Value	Parameter	Reference
POM2-C-HMBP											Hs	Binding	-	-	1
⤷	[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.

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

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

References

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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 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2948.

butyrophilin subfamily 3 member A1

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References

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