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Functional inactivation in the whole population of human V gamma 9/V delta 2 T lymphocytes induced by a nonpeptidic antagonist.

Bürk MR, Carena I, Donda A, Mariani F, Mori L, De Libero G - J. Exp. Med. (1997)

Bottom Line: We report that one of these ligands, 2,3-diphosphoglyceric acid (DPG), which induces expansion of V gamma 9/V delta T cells ex vivo, antagonizes the same cell population after repetitive activation.These findings show that TCR antagonism is a general phenomenon of T cells.However, in contrast to the clonal specificity of altered peptides antagonizing alpha beta T cells, all the tested V gamma 9/V delta 2 polyclonal cell lines and clones become unresponsive, a fact that may be relevant for the regulation of their response in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Research, University Hospital, Basel, Switzerland.

ABSTRACT
Nonpeptidic compounds stimulate human T cells bearing the TCR-gamma delta in the absence of major histocompatibility complex restriction. We report that one of these ligands, 2,3-diphosphoglyceric acid (DPG), which induces expansion of V gamma 9/V delta T cells ex vivo, antagonizes the same cell population after repetitive activation. Stimulation with DPG results in partial early protein tyrosine phosphorylation and a prolonged, but reversible, state of unresponsiveness to agonist ligands in V gamma 9/V delta 2, but not in other T cells. These findings show that TCR antagonism is a general phenomenon of T cells. However, in contrast to the clonal specificity of altered peptides antagonizing alpha beta T cells, all the tested V gamma 9/V delta 2 polyclonal cell lines and clones become unresponsive, a fact that may be relevant for the regulation of their response in vivo.

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DPG reduces the efficacy, but not the potency, of IPP. Proliferation (A) and TNF release (B) of the γδ T cell line PG96 coincubated  with different concentrations of IPP and DPG (1 mM, ▪; 500 μM, •;  250 μM, ▴; 125 μM, ♦), or medium (○). Comparable dose-response  curves were obtained in four independent experiments.
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Figure 2: DPG reduces the efficacy, but not the potency, of IPP. Proliferation (A) and TNF release (B) of the γδ T cell line PG96 coincubated with different concentrations of IPP and DPG (1 mM, ▪; 500 μM, •; 250 μM, ▴; 125 μM, ♦), or medium (○). Comparable dose-response curves were obtained in four independent experiments.

Mentions: Throughout this study we have sued Vγ9/Vδ2 T cells which proliferate to IPP, but no longer to DPG. Both DPG and IPP induce downmodulation of the TCR γδ on these cells (Fig. 1), confirming that activation by DPG and IPP involves TCR stimulation (8). DPG induces TCR downmodulation without cell proliferation, we investigated whether it might behave as a partial agonist or as an antagonist (9, 10). DPG induces neither release of IFNγ and TNF, nor transcription of IL-1, IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α genes in Vγ9/Vδ2 cells (assessed by reverse transcriptase-PCR, data not shown), nor killing of target cells by cytotoxic Vγ9/Vδ2 clones (data not shown), which are all effects detected after stimulation with IPP. Therefore, it is unlikely that DPG is a partial agonist. In another series of experiments, γδ T cells were cultured in the presence of both ligands simultaneously (Fig. 2). Although DPG no longer displays its agonistic properties on cultured γδ T cells, it nevertheless has a clear dosedependent effect whereby it inhibits IPP-induced activation in a noncompetitive manner. DPG lowers the efficacy (maximal response) of IPP, but does not alter the potency of IPP (dose for 50% of maximal effect). These results indicate that DPG does not displace IPP from its binding site, but that it may act as a TCR antagonist.


Functional inactivation in the whole population of human V gamma 9/V delta 2 T lymphocytes induced by a nonpeptidic antagonist.

Bürk MR, Carena I, Donda A, Mariani F, Mori L, De Libero G - J. Exp. Med. (1997)

DPG reduces the efficacy, but not the potency, of IPP. Proliferation (A) and TNF release (B) of the γδ T cell line PG96 coincubated  with different concentrations of IPP and DPG (1 mM, ▪; 500 μM, •;  250 μM, ▴; 125 μM, ♦), or medium (○). Comparable dose-response  curves were obtained in four independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196105&req=5

Figure 2: DPG reduces the efficacy, but not the potency, of IPP. Proliferation (A) and TNF release (B) of the γδ T cell line PG96 coincubated with different concentrations of IPP and DPG (1 mM, ▪; 500 μM, •; 250 μM, ▴; 125 μM, ♦), or medium (○). Comparable dose-response curves were obtained in four independent experiments.
Mentions: Throughout this study we have sued Vγ9/Vδ2 T cells which proliferate to IPP, but no longer to DPG. Both DPG and IPP induce downmodulation of the TCR γδ on these cells (Fig. 1), confirming that activation by DPG and IPP involves TCR stimulation (8). DPG induces TCR downmodulation without cell proliferation, we investigated whether it might behave as a partial agonist or as an antagonist (9, 10). DPG induces neither release of IFNγ and TNF, nor transcription of IL-1, IL-2, IL-3, IL-4, IL-5, GM-CSF, IFN-γ, and TNF-α genes in Vγ9/Vδ2 cells (assessed by reverse transcriptase-PCR, data not shown), nor killing of target cells by cytotoxic Vγ9/Vδ2 clones (data not shown), which are all effects detected after stimulation with IPP. Therefore, it is unlikely that DPG is a partial agonist. In another series of experiments, γδ T cells were cultured in the presence of both ligands simultaneously (Fig. 2). Although DPG no longer displays its agonistic properties on cultured γδ T cells, it nevertheless has a clear dosedependent effect whereby it inhibits IPP-induced activation in a noncompetitive manner. DPG lowers the efficacy (maximal response) of IPP, but does not alter the potency of IPP (dose for 50% of maximal effect). These results indicate that DPG does not displace IPP from its binding site, but that it may act as a TCR antagonist.

Bottom Line: We report that one of these ligands, 2,3-diphosphoglyceric acid (DPG), which induces expansion of V gamma 9/V delta T cells ex vivo, antagonizes the same cell population after repetitive activation.These findings show that TCR antagonism is a general phenomenon of T cells.However, in contrast to the clonal specificity of altered peptides antagonizing alpha beta T cells, all the tested V gamma 9/V delta 2 polyclonal cell lines and clones become unresponsive, a fact that may be relevant for the regulation of their response in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Research, University Hospital, Basel, Switzerland.

ABSTRACT
Nonpeptidic compounds stimulate human T cells bearing the TCR-gamma delta in the absence of major histocompatibility complex restriction. We report that one of these ligands, 2,3-diphosphoglyceric acid (DPG), which induces expansion of V gamma 9/V delta T cells ex vivo, antagonizes the same cell population after repetitive activation. Stimulation with DPG results in partial early protein tyrosine phosphorylation and a prolonged, but reversible, state of unresponsiveness to agonist ligands in V gamma 9/V delta 2, but not in other T cells. These findings show that TCR antagonism is a general phenomenon of T cells. However, in contrast to the clonal specificity of altered peptides antagonizing alpha beta T cells, all the tested V gamma 9/V delta 2 polyclonal cell lines and clones become unresponsive, a fact that may be relevant for the regulation of their response in vivo.

Show MeSH
Related in: MedlinePlus