Vγ9Vδ2 TCR‐activation by phosphorylated antigens requires butyrophilin 3 A1 <scp>(</scp><i>BTN3A1</i><scp>)</scp> and additional genes on human chromosome 6

Riaño, Felipe; Karunakaran, Mohindar Murugesh; Starick, Lisa; Li, Jianqiang; Scholz, Claus‐Jürgen; Kunzmann, Volker; Olive, Daniel; Amslinger, Sabine; Herrmann, Thomas

doi:10.1002/eji.201444712

Cited by 73 publications

(83 citation statements)

References 20 publications

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“…On the other hand, if the traditional two-signal aggregation/conformational change mechanisms are true [27], then both proteins would require an extracellular ligand on the opposing cell. This model of TCR binding with BTN3A1 co-stimulation is supported by studies that show additional factors on chromosome 6 influence phosphoantigen detection [40]. However, existing data does not appear to exclude a kinetic segregation model as described in other T cell types [41].…”

Section: Discussionmentioning

confidence: 90%

HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors

Kilcollins

Hsiao

et al. 2016

The Journal of Immunology

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Vγ9Vδ2 T effectors lyse cells in response to phosphorus-containing small molecules, providing primates a unique route to remove infected or malignant cells. Yet, the triggering mechanisms remain ill-defined. We examined lysis mediated by human Vγ9Vδ2 T effectors in response to the naturally-occurring (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) or a synthetic cell-permeable prodrug, bis (pivaloyloxymethyl) (E)-4-hydroxy-3-methyl-but-2-enyl phosphonate (POM2-C-HMBP). CD27+/CD45RA− Th1-like effector cells killed K562 target cells though a mechanism that could be enhanced by either compound or TCR antibody and blocked by Src inhibition or BTN3A1 disruption. Pre-treatment at 4°C decreased HMBPP-induced lysis but did not reduce lysis induced by POM2-C-HMBP. Together, our results show that internalization of HMBPP into target cells is required for BTN3A1-dependent lysis by Vγ9Vδ2 T effectors. The enhanced activity of the prodrug analog is due to its ability to bypass the pathways required for entry of HMBPP. These findings support an inside-out model of T cell triggering driven by small-molecule induction of BTN3A1.

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Section: Discussionmentioning

confidence: 90%

HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors

Kilcollins

Hsiao

et al. 2016

The Journal of Immunology

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“…In addition, this observation underlies that different ways are involved in anti-BTN3A 20.1 mAb and N-BP-mediated activation. Indeed, whereas N-BP-mediated activation of Vg9Vd2 T cells requires the expression of the three BTN3A isoforms 19 and putative additional partners, 30 anti-BTN3A 20.1 mAb can trigger each one of the three BTN3A isoforms. 20 BTN3A2 was the most expressed isoform in primary AML blasts.…”

Section: Discussionmentioning

confidence: 99%

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

et al. 2016

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Given their recognized ability to kill acute myeloid leukemia (AML) blasts both in vitro and in vivo, Vg9Vd2 T cells are of growing interest in the design of new strategies of immunotherapy. We show that the Butyrophilin3A (BTN3A, CD277) subfamily is a critical determinant of Vg9Vd2 TCR-mediated recognition of human primary AML blasts ex vivo. Moreover, anti-BTN3A 20.1 agonist monoclonal antibodies (mAbs) can trigger BTN3A on AML blasts leading to further enhanced Vg9Vd2 T cell-mediated killing, but this mAb had no enhancing effect upon NK cell-mediated killing. We show that monocytic differentiation of primary AML blasts accounts for their AminoBisphosphonate (N-BP)-mediated sensitization to Vg9Vd2 T cells. In addition, anti-BTN3A 20.1 mAbs could specifically sensitize resistant blasts to Vg9Vd2 T cells lysis and overcome the poor effect of N-BP treatment on those blasts. We confirmed the enhancement of Vg9Vd2 T cells activity by anti-BTN3A 20.1 mAb using a human AML xenotransplantation mouse model. We showed that anti-BTN3A 20.1 mAb combined with Vg9Vd2 T cells immunotherapy could increase animal survival and decrease the leukemic burden in blood and bone marrow. These findings could be of great interest in the design of new immunotherapeutic strategies for treating AML.

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“…Although mutation of this residue could alter the conformation of the B30.2 domain, it is also possible that this residue interacts with another intracellular protein. Support for the involvement of a second protein comes from the fact that expression of BTN3A1 in murine or Chinese hamster cells is not sufficient to allow them to support HMBPP stimulation of Vγ2Vδ2 T cells whereas transfer of chromosome 6, which encodes other proteins in addition to BTN3A1, does (23, 28). …”

Section: Discussionmentioning

confidence: 99%

“…Basic residues are commonly found in binding sites for phosphates because their positively charged amino groups can form hydrogen bonds to the negatively charged phosphate moieties. Based on the presence of this basic pocket in the BTN3A1 B30.2 domain, the evidence that this domain is required for BTN3A1 function (21), and the lack of high-affinity binding of a prenyl pyrophosphate photoaffinity compound to the extracellular domains of BTN3A1 or BTN3A2, we proposed that prenyl pyrophosphates bind to the basic pocket on the intracellular B30.2 domain of BTN3A1, perhaps in association with a second protein (28). Recent determination of the structure of the BTN3A1 B30.2 domain and in vitro binding studies by the Adams laboratory (25) and other investigators (26, 27) support this model.…”

Section: Introductionmentioning

confidence: 99%

Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells

Wang

Morita

2015

The Journal of Immunology

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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.

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Vγ9Vδ2 TCR‐activation by phosphorylated antigens requires butyrophilin 3 A1 (BTN3A1) and additional genes on human chromosome 6

Abstract: Pyrophosphorylated metabolites of isoprenoid-biosynthesis (phosphoantigens,PAgs

Cited by 73 publications

References 20 publications

HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors

HMBPP Analog Prodrugs Bypass Energy-Dependent Uptake To Promote Efficient BTN3A1-Mediated Malignant Cell Lysis by Vγ9Vδ2 T Lymphocyte Effectors

BTN3A molecules considerably improve Vγ9Vδ2T cells-based immunotherapy in acute myeloid leukemia

Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells

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