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Major histocompatibility complex class I molecules modulate activation threshold and early signaling of T cell antigen receptor-gamma/delta stimulated by nonpeptidic ligands.

Carena I, Shamshiev A, Donda A, Colonna M, Libero GD - J. Exp. Med. (1997)

Bottom Line: CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen.CD94 engagement has major effects on TCR signaling cascade.These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

View Article: PubMed Central - PubMed

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

ABSTRACT
Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompatibility complex class I-specific inhibitory receptors expressed by natural killer cells, T cell antigen receptor (TCR)-gamma/delta cells, and a subset of TCR-alpha/beta cells. We studied the functional interaction between TCR-gamma/delta and CD94, this inhibitory receptor being expressed on the majority of gamma/delta T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR-gamma/delta by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 zeta chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

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TNF-α release is  highly influenced by HLA class  I+ APCs when TCR-γ/δ is  stimulated with low doses, but  not high doses, of IPP. Two  CD94+ clones, G2B2 (A and C)  and D1C55 (B and D) were  stimulated with increasing  amounts of IPP in the presence  of normal (□) or Daudi-β2 cells  (○). Anti-CD94 (▵), but not an  isotype-matched irrelevant mAb  (○), partially restores TNF-α release in the presence of Daudi-β2 cells (C and D). Similar  results were obtained in 14 independent experiments using these  two clones and four other  CD94+ γ/δ clones, derived from  different donors. The amount of TNF-α released by a given clone in any  given experiment was different and correlated with its activation state.  Daudi cells do not release detectable TNF-α when incubated with IPP  (not shown). Bars indicate SD.
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Figure 3: TNF-α release is highly influenced by HLA class I+ APCs when TCR-γ/δ is stimulated with low doses, but not high doses, of IPP. Two CD94+ clones, G2B2 (A and C) and D1C55 (B and D) were stimulated with increasing amounts of IPP in the presence of normal (□) or Daudi-β2 cells (○). Anti-CD94 (▵), but not an isotype-matched irrelevant mAb (○), partially restores TNF-α release in the presence of Daudi-β2 cells (C and D). Similar results were obtained in 14 independent experiments using these two clones and four other CD94+ γ/δ clones, derived from different donors. The amount of TNF-α released by a given clone in any given experiment was different and correlated with its activation state. Daudi cells do not release detectable TNF-α when incubated with IPP (not shown). Bars indicate SD.

Mentions: Human γ/δ T cells also react to a variety of nonpeptidic ligands, some of which are phosphorylated metabolites (19–21). We studied whether TCR-γ/δ activation by IPP, a strong agonist ligand (20, 21), could be inhibited by CD94. γ/δ clones were stimulated with different doses of IPP in the presence of Daudi or Daudi-β2 cells as APCs and TNF-α release was measured. The results confirmed that HLA class I+ APCs greatly reduce TCR-γ/δ–mediated cell activation (Fig. 3, A and B). TNF-α release was partially restored by addition of anti-CD94 mAbs, but not by isotype-matched irrelevant mAb (Fig. 3, C and D), thus further supporting the involvement of CD94. More importantly, CD94 engagement shifted the dose–response curve towards higher amounts of ligand. In the presence of Daudi-β2 APCs, 5–20 times higher doses of IPP were required than in the presence of Daudi APCs for an equivalent TNF-α release. This effect was consistently observed with four additional γ/δ clones (data not shown). These findings suggest that CD94 might serve the function of setting a higher cell activation threshold, as shown for other lymphocyte surface molecules (27).


Major histocompatibility complex class I molecules modulate activation threshold and early signaling of T cell antigen receptor-gamma/delta stimulated by nonpeptidic ligands.

Carena I, Shamshiev A, Donda A, Colonna M, Libero GD - J. Exp. Med. (1997)

TNF-α release is  highly influenced by HLA class  I+ APCs when TCR-γ/δ is  stimulated with low doses, but  not high doses, of IPP. Two  CD94+ clones, G2B2 (A and C)  and D1C55 (B and D) were  stimulated with increasing  amounts of IPP in the presence  of normal (□) or Daudi-β2 cells  (○). Anti-CD94 (▵), but not an  isotype-matched irrelevant mAb  (○), partially restores TNF-α release in the presence of Daudi-β2 cells (C and D). Similar  results were obtained in 14 independent experiments using these  two clones and four other  CD94+ γ/δ clones, derived from  different donors. The amount of TNF-α released by a given clone in any  given experiment was different and correlated with its activation state.  Daudi cells do not release detectable TNF-α when incubated with IPP  (not shown). Bars indicate SD.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2199143&req=5

Figure 3: TNF-α release is highly influenced by HLA class I+ APCs when TCR-γ/δ is stimulated with low doses, but not high doses, of IPP. Two CD94+ clones, G2B2 (A and C) and D1C55 (B and D) were stimulated with increasing amounts of IPP in the presence of normal (□) or Daudi-β2 cells (○). Anti-CD94 (▵), but not an isotype-matched irrelevant mAb (○), partially restores TNF-α release in the presence of Daudi-β2 cells (C and D). Similar results were obtained in 14 independent experiments using these two clones and four other CD94+ γ/δ clones, derived from different donors. The amount of TNF-α released by a given clone in any given experiment was different and correlated with its activation state. Daudi cells do not release detectable TNF-α when incubated with IPP (not shown). Bars indicate SD.
Mentions: Human γ/δ T cells also react to a variety of nonpeptidic ligands, some of which are phosphorylated metabolites (19–21). We studied whether TCR-γ/δ activation by IPP, a strong agonist ligand (20, 21), could be inhibited by CD94. γ/δ clones were stimulated with different doses of IPP in the presence of Daudi or Daudi-β2 cells as APCs and TNF-α release was measured. The results confirmed that HLA class I+ APCs greatly reduce TCR-γ/δ–mediated cell activation (Fig. 3, A and B). TNF-α release was partially restored by addition of anti-CD94 mAbs, but not by isotype-matched irrelevant mAb (Fig. 3, C and D), thus further supporting the involvement of CD94. More importantly, CD94 engagement shifted the dose–response curve towards higher amounts of ligand. In the presence of Daudi-β2 APCs, 5–20 times higher doses of IPP were required than in the presence of Daudi APCs for an equivalent TNF-α release. This effect was consistently observed with four additional γ/δ clones (data not shown). These findings suggest that CD94 might serve the function of setting a higher cell activation threshold, as shown for other lymphocyte surface molecules (27).

Bottom Line: CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen.CD94 engagement has major effects on TCR signaling cascade.These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

View Article: PubMed Central - PubMed

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

ABSTRACT
Killer cell inhibitory receptors and CD94-NKG2-A/B heterodimers are major histocompatibility complex class I-specific inhibitory receptors expressed by natural killer cells, T cell antigen receptor (TCR)-gamma/delta cells, and a subset of TCR-alpha/beta cells. We studied the functional interaction between TCR-gamma/delta and CD94, this inhibitory receptor being expressed on the majority of gamma/delta T cells. When engaged by human histocompatibility leukocyte antigen class I molecules, CD94 downmodulates activation of human TCR-gamma/delta by phosphorylated ligands. CD94-mediated inhibition is more effective at low than at high doses of TCR ligand, which may focus T cell responses towards antigen-presenting cells presenting high amounts of antigen. CD94 engagement has major effects on TCR signaling cascade. It facilitates recruitment of SHP-1 phosphatase to TCR-CD3 complex and affects phosphorylation of Lck and ZAP-70 kinase, but not of CD3 zeta chain upon TCR triggering. These events may cause abortion of proximal TCR-mediated signaling and set a higher TCR activation threshold.

Show MeSH