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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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Unresponsiveness induced by DPG is the consequence of  the alteration of TCR proximal signals. Vγ9/Vδ2 clone BCI 49 (106 cells/ ml) was incubated overnight in IL-2–free medium with 1 mM DPG  and washed extensively. Proliferative responses to medium, 100 μM IPP,  1 μg/ml PHA, 500 ng/ml Ca2+ Ionophore A23187 (Iono) 50 ng/ml PMA,  or the indicated combinations were measured.
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Figure 5: Unresponsiveness induced by DPG is the consequence of the alteration of TCR proximal signals. Vγ9/Vδ2 clone BCI 49 (106 cells/ ml) was incubated overnight in IL-2–free medium with 1 mM DPG and washed extensively. Proliferative responses to medium, 100 μM IPP, 1 μg/ml PHA, 500 ng/ml Ca2+ Ionophore A23187 (Iono) 50 ng/ml PMA, or the indicated combinations were measured.

Mentions: To determine which signal transduction pathways might be affected, we applied various procedures described to prevent anergy induction or restore responsiveness. While cyclosporin A completely prevents anergy with αβ T cells (13, 14), it has only a partial effect on γδ T cells (data not shown). This suggests that both the late signals blocked by cyclosporin A, as well as other signals, participate in establishing unresponsiveness. IPP-unresponsive cells could be stimulated by PHA or a combination of PMA and Ca2+ ionophore (Fig. 5). Importantly, reactivity to IPP could be restored by PMA, which was not stimulatory by itself. Thus, IPP can apparently still trigger unresponsive cells with a signal that is mimicked by Ca2+ ionophore. In addition, the ability of PMA to overcome unresponsiveness indicates that the blockade of signaling in unresponsive cells most likely occurs between the TCR and P21ras. Blockade of proximal signaling has been recently shown in two αβ T cell anergy models (15, 16).


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)

Unresponsiveness induced by DPG is the consequence of  the alteration of TCR proximal signals. Vγ9/Vδ2 clone BCI 49 (106 cells/ ml) was incubated overnight in IL-2–free medium with 1 mM DPG  and washed extensively. Proliferative responses to medium, 100 μM IPP,  1 μg/ml PHA, 500 ng/ml Ca2+ Ionophore A23187 (Iono) 50 ng/ml PMA,  or the indicated combinations were measured.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Unresponsiveness induced by DPG is the consequence of the alteration of TCR proximal signals. Vγ9/Vδ2 clone BCI 49 (106 cells/ ml) was incubated overnight in IL-2–free medium with 1 mM DPG and washed extensively. Proliferative responses to medium, 100 μM IPP, 1 μg/ml PHA, 500 ng/ml Ca2+ Ionophore A23187 (Iono) 50 ng/ml PMA, or the indicated combinations were measured.
Mentions: To determine which signal transduction pathways might be affected, we applied various procedures described to prevent anergy induction or restore responsiveness. While cyclosporin A completely prevents anergy with αβ T cells (13, 14), it has only a partial effect on γδ T cells (data not shown). This suggests that both the late signals blocked by cyclosporin A, as well as other signals, participate in establishing unresponsiveness. IPP-unresponsive cells could be stimulated by PHA or a combination of PMA and Ca2+ ionophore (Fig. 5). Importantly, reactivity to IPP could be restored by PMA, which was not stimulatory by itself. Thus, IPP can apparently still trigger unresponsive cells with a signal that is mimicked by Ca2+ ionophore. In addition, the ability of PMA to overcome unresponsiveness indicates that the blockade of signaling in unresponsive cells most likely occurs between the TCR and P21ras. Blockade of proximal signaling has been recently shown in two αβ T cell anergy models (15, 16).

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