Journal article
Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells
The Journal of immunology (1950), Vol.195(10), pp.4583-4594
11/15/2015
DOI: 10.4049/jimmunol.1500314
PMCID: PMC4848273
PMID: 26475929
Abstract
Vγ2Vδ2 T cells play important roles in human immunity to pathogens and in cancer immunotherapy by responding to isoprenoid metabolites, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and isopentenyl pyrophosphate. The Ig superfamily protein butyrophilin (BTN)3A1 was shown to be required for prenyl pyrophosphate stimulation. We proposed that the intracellular B30.2 domain of BTN3A1 binds prenyl pyrophosphates, resulting in a change in the extracellular BTN3A1 dimer that is detected by Vγ2Vδ2 TCRs. Such B30.2 binding was demonstrated recently. However, other investigators reported that the extracellular BTN3A1 IgV domain binds prenyl pyrophosphates, leading to the proposal that the Vγ2Vδ2 TCR recognizes the complex. To distinguish between these mechanisms, we mutagenized residues in the two binding sites and tested the mutant BTN3A1 proteins for their ability to mediate prenyl pyrophosphate stimulation of Vγ2Vδ2 T cells to proliferate and secrete TNF-α. Mutagenesis of residues in the IgV site had no effect on Vγ2Vδ2 T cell proliferation or secretion of TNF-α. In contrast, mutagenesis of residues within the basic pocket and surrounding V regions of the B30.2 domain abrogated prenyl pyrophosphate-induced proliferation. Mutations of residues making hydrogen bonds to the pyrophosphate moiety also abrogated TNF-α secretion, as did mutation of aromatic residues making contact with the alkenyl chain. Some mutations further from the B30.2 binding site also diminished stimulation, suggesting that the B30.2 domain may interact with a second protein. These findings support intracellular sensing of prenyl pyrophosphates by BTN3A1 rather than extracellular presentation.
Details
- Title: Subtitle
- Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells
- Creators
- Hong Wang - Division of Immunology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Veterans Affairs, Iowa City Health Care System, Iowa City, IA 52246; andCraig T Morita - Division of Immunology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242; Department of Veterans Affairs, Iowa City Health Care System, Iowa City, IA 52246; and Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Iowa City, IA 52242 Craig-Morita@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.195(10), pp.4583-4594
- DOI
- 10.4049/jimmunol.1500314
- PMID
- 26475929
- PMCID
- PMC4848273
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- I01 BX000972 / BLRD VA P30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS CA097274 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
- Language
- English
- Date published
- 11/15/2015
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984094322002771
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