The Juxtamembrane Domain of Butyrophilin BTN3A1 Controls Phosphoantigen-Mediated Activation of Human Vγ9Vδ2 T Cells

Peigné, Cassie-Marie; Léger, Alexandra; Gesnel, Marie-Claude; Konczak, Fabienne; Olive, Daniel; Bonneville, Marc; Breathnach, Richard; Scotet, Emmanuel

doi:10.4049/jimmunol.1601910

Cited by 38 publications

(46 citation statements)

References 23 publications

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“…Finally, another short subregion between the TM and B30.2 domains of BTN3A1 (YNEWKKALFKPA), recently found to be functionally important ( 23 ), is centered on an EWK motif that we also found to be functionally indispensable for Vγ9Vδ2 + cell activation ( Fig. S9 C ).…”

Section: Resultsmentioning

confidence: 55%

Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

Vantourout

Laing

Woodward

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

137

153

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SignificanceAlthough gamma delta (γδ) T cells compose an evolutionarily conserved third lineage of diversified lymphocytes, alongside αβ T cells and B cells, they can seem overtly different across species and tissues. Thus, human blood γδ cells show butyrophilin (BTN)3A1-dependent responses to metabolites (“phosphoantigens”) not seen by rodent γδ cells, whereas some rodent, γδ-rich compartments, notably in the skin, lack obvious human counterparts. Recently, however, mouse and human intraepithelial gut γδ cells were found to be regulated by pairings of BTN-like genes. This study now shows that BTN3A1 also functions as a pairing, with its subcellular trafficking and optimal activity both regulated by BTN3A2. Hence, seemingly diverse γδ cell biologies across species and tissues are underpinned by conserved mechanisms.

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Section: Resultsmentioning

confidence: 55%

Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

Vantourout

Laing

Woodward

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

137

153

View full text Add to dashboard Cite

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“…Our in vitro experiment did not confirm the binding of PPL to BTN3A1; further cellular analysis is needed to assess the possibility of their interactions. Furthermore, both Ser/Thr 296/297 and Thr 304 fall within the box 2 sequence (aa 288-308) of the BTN3A1 juxtamembrane region, which was recently reported to be necessary for full activation by nitrogenous bisphosphonates (44).…”

Section: Discussionmentioning

confidence: 97%

The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region

Nguyen

Puthenveetil

et al. 2017

FASEB j.

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Small isoprenoid diphosphates, such as ()-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), are ligands of the internal domain of BTN3A1. Ligand binding in target cells promotes activation of Vγ9Vδ2 T cells. We demonstrate by small-angle X-ray scattering (SAXS) that HMBPP binding to the internal domain of BTN3A1 induces a conformational change in the position of the B30.2 domain relative to the juxtamembrane (JM) region. To better understand the molecular details of this conformational rearrangement, NMR spectroscopy was used to discover that the JM region interacts with HMBPP, specifically at the diphosphate. The spectral location of the affected amide peaks, partial NMR assignments, and JM mutants (STAA or TA) investigated, confirm that the backbone amide of at least one Thr (Thr), adjacent to conserved Ser, comes close to the HMBPP diphosphate, whereas double mutation of nonconserved residues (Ser/Thr) may perturb the local fold. Cellular mutation of either of the identified Thr residues reduces the activation of Vγ9Vδ2 T cells by HMBPP, zoledronate, and POM-C-HMBP, but not by a partial agonist BTN3 antibody. Taken together, our results show that ligand binding to BTN3A1 induces a conformational change within the intracellular domain that involves the JM region and is required for full activation.-Nguyen, K., Li, J., Puthenveetil, R., Lin, X., Poe, M. M., Hsiao, C.-H. C., Vinogradova, O., Wiemer, A. J. The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region.

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“…Intron lengths were calculated based on location in contigs and putative deletions are shown by dashed lines and “d”. Stop codons are indicated by “s” at the approximate location in the gene (*location of the proposed juxtamembrane motif important for PAg recognition ( 41 ); **location of the putative ATG at nt 1982).…”

Section: Resultsmentioning

confidence: 99%

The Armadillo (Dasypus novemcinctus): A Witness but Not a Functional Example for the Emergence of the Butyrophilin 3/Vγ9Vδ2 System in Placental Mammals

et al. 2018

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1–5% of human blood T cells are Vγ9Vδ2 T cells whose T cell receptor (TCR) contain a TRGV9/TRGJP rearrangement and a TRDV2 comprising Vδ2-chain. They respond to phosphoantigens (PAgs) like isopentenyl pyrophosphate or (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate (HMBPP) in a butyrophilin 3 (BTN3)-dependent manner and may contribute to the control of mycobacterial infections. These cells were thought to be restricted to primates, but we demonstrated by analysis of genomic databases that TRGV9, TRDV2, and BTN3 genes coevolved and emerged together with placental mammals. Furthermore, we identified alpaca (Vicugna pacos) as species with typical Vγ9Vδ2 TCR rearrangements and currently aim to directly identify Vγ9Vδ2 T cells and BTN3. Other candidates to study this coevolution are the bottlenose dolphin (Tursiops truncatus) and the nine-banded armadillo (Dasypus novemcinctus) with genomic sequences encoding open reading frames for TRGV9, TRDV2, and the extracellular part of BTN3. Dolphins have been shown to express Vγ9- and Vδ2-like TCR chains and possess a predicted BTN3-like gene homologous to human BTN3A3. The other candidate, the armadillo, is of medical interest since it serves as a natural reservoir for Mycobacterium leprae. In this study, we analyzed the armadillo genome and found evidence for multiple non-functional BTN3 genes including genomic context which closely resembles the organization of the human, alpaca, and dolphin BTN3A3 loci. However, no BTN3 transcript could be detected in armadillo cDNA. Additionally, attempts to identify a functional TRGV9/TRGJP rearrangement via PCR failed. In contrast, complete TRDV2 gene segments preferentially rearranged with a TRDJ4 homolog were cloned and co-expressed with a human Vγ9-chain in murine hybridoma cells. These cells could be stimulated by immobilized anti-mouse CD3 antibody but not with human RAJI-RT1Bl cells and HMBPP. So far, the lack of expression of TRGV9 rearrangements and BTN3 renders the armadillo an unlikely candidate species for PAg-reactive Vγ9Vδ2 T cells. This is in line with the postulated coevolution of the three genes, where occurrence of Vγ9Vδ2 TCRs coincides with a functional BTN3 molecule.

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The Juxtamembrane Domain of Butyrophilin BTN3A1 Controls Phosphoantigen-Mediated Activation of Human Vγ9Vδ2 T Cells

Cited by 38 publications

References 23 publications

Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology

The butyrophilin 3A1 intracellular domain undergoes a conformational change involving the juxtamembrane region

The Armadillo (Dasypus novemcinctus): A Witness but Not a Functional Example for the Emergence of the Butyrophilin 3/Vγ9Vδ2 System in Placental Mammals

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