Genetic and immunochemical evidence for CD4-dependent association of p56lck with the alpha beta T-cell receptor (TCR): regulation of TCR-induced activation.

Diez-Orejas, Rosalı́a; Ballester, Sara; Feito, María José; Ojeda, Gloria; Criado, Gabriel; Ronda, M.; Portolés, Pilar; Rojo, José María

doi:10.1002/j.1460-2075.1994.tb06238.x

Cited by 27 publications

(26 citation statements)

References 73 publications

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“…In the P28 human T cell clone, both increases of p56Irk catalytic activity and autophosphorylation were observed after UCHTl triggering [18, 191. Our results suggested that the presence of CD4-p56lCk complexes at the plasma membrane, and thus CD4-p56lCk/CD3-TcR interactions, were critical for CD3 signaling [51]. First, only CD4-modulating agents were able to desensitize the CD3 pathway, preventing the CD3-induced tyrosine phosphorylation of cellular proteins.…”

Section: Discussionmentioning

confidence: 88%

HIV‐1 glycoprotein gp120 disrupts CD4‐p56^lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

et al. 1995

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Using the CD4+ human T cell clone P28, we demonstrated that the HIV-1 glycoprotein gp120 inhibited CD3-induced inositol trisphosphate production, calcium influx and T cell proliferation. Additionally, gp120 was shown to dissociate the tyrosine kinase p56lck from CD4 in CEM cells, with a concommittant inhibition of CD4-linked kinase activity. We have addressed the question whether disruption of CD4/p56lck or CD4/CD3-T cell receptor interactions, or both, could account for the inhibitory effect of gp120 in P28 cells. By comparing the effects of various anti-CD4 monoclonal antibodies (mAb) with those of gp120, we show that gp120 and IOT4a modulate CD4 expression, and decrease CD4-associated p56lck and CD4-linked kinase activity at the plasma membrane. In contrast, OKT4A and OKT4 anti-CD4 mAb have no inhibitory effect. Interestingly, gp120 also inhibits CD3-induced Lck activation and cellular tyrosine phosphorylation, particularly of phosphoinositide-specific phospholipase C-gamma-1. Kinetic experiments reveal that the inhibitory effect of gp120 on CD3-induced tyrosine phosphorylation appears as early as 30 min, but culminate when CD4-p56lck complexes disappear from the cell surface after 4 h. These results suggest that a negative signal is triggered by gp120 that results, after a few hours, in down-modulation of CD4-p56lck complexes and the impairment of CD3 signaling. Supporting this hypothesis, gp120 inhibits CD3-linked kinase activity as shown by the inhibition of the phosphorylation of CD3 chains, leading to the inhibition of subsequent signal transduction.

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Section: Discussionmentioning

confidence: 88%

HIV‐1 glycoprotein gp120 disrupts CD4‐p56^lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

et al. 1995

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“…4) as well as weaker responses to antigen or to solid-phase anti-TCR antibodies (Figs 3, 6, Ref. 24, and data not shown); and (3) with the fact that, in D10.G4.1, the clonotypic antibodies (i.e. 3D3) which induce co-localization of CD4 and the TCR are 20-100-fold more efficient at activating the cells [32,33] and at inducing CD3z phosphorylation [49] than those which do not.…”

Section: Discussionmentioning

confidence: 95%

“…44). This co-receptor function is favoured during antigen recognition by the binding of TCR and co-receptor molecules to the same MHC molecule [45,46], yet it has also been observed in activation systems in the absence of MHC-expressing APC [32,33,47] and might require structural changes in the TCR complex [24,32]. In contrast, CD4-mediated co-stimulation or inhibition can be observed in some systems in cells expressing CD4 constructs lacking the intracytoplasmic tail, which do not associate Lck [39].…”

Section: Discussionmentioning

confidence: 99%

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CD4 Dependence of Activation Threshold and TCR Signalling in Mouse T Lymphocytes

et al. 1997

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The effect of CD4 expression on the activation threshold of mouse T lymphocytes has been analysed. To do this, the authors studied the response to antigen and other T cell receptor (TCR) ligands in a series of CD4 ¹ mutants obtained from the SR.D10 clone. This non-tumour clone spontaneously arose from the Th2 clone D10.G4.1, and characteristically shows a low threshold for antigen activation as well as reactivity to syngeneic antigen presenting cells (APC). Although SR.D10 CD4¹ mutant cells can be stimulated by antigen, they need higher antigen concentration or more APC than SR.D10 or CD4 transfectants to yield optimal antigen responses. Furthermore, CD4¹ clones are not activated by syngeneic APC or by clonotypic antibodies. These effects do not correlate with changes in the expression of cell surface molecules implicated in antigen recognition, like TCR/CD3, CD2, LFA-1, or CD45, or with lower p56 lck or p59 fyn activity in the mutant cells. Since inhibition experiments using anti-CD4 antibodies have previously shown that activation of the CD4 + T cell clone D10.G4.1 by antigen or alloantigens is largely dependent on CD4, our results indicate that activation by antigen-plus self MHC may become CD4-independent if the activation threshold is lowered enough, e.g. in cells like SR.D10. Expression of CD4 further lowers the activation threshold of the cells, allowing the detection of low-affinity TCR reactivities like those directed at self MHC. Moreover, by using anti-TCR/CD3 antibodies, the authors have confirmed the importance of CD4-associated tyrosine kinase activity in early TCR/CD3 signalling in this Th2 cell line, as (1) upon TCR/CD3 ligation, tyrosine phosphorylation is detected only in those CD3 chains co-precipitating with CD4; and (2) CD4 expression is needed for efficient early tyrosine phosphorylation and detectable p56 lck -TCR co-precipitation.

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“…Given the importance of tyrosine kinases in TcR signaling, and since ZAP-70 association to phosphorylated ARAM in TcWCD3 chains is secondary to TcR activation [21,221 and needs the presence of p56Ick or ~5 9~" [21,25,26], much interest has focused on those tyrosine kinases ~5 9~" and p56ICk, which, according to immunochemical, genetic, and functional data, are associated with the TcR, or play a major role in TcR-mediated activation [25,[27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

CD4‐dependent and ‐independent association of protein tyrosine kinases to the T cell receptor/CD3 complex of CD4⁺ mouse T lymphocytes

1996

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Tyrosine phosphorylation of different substrates is the earliest intracellular signal detected after T cell receptor (TcR) ligation. Several tyrosine kinases have been detected associated to the CD3-TcR complex in stimulated or unstimulated cells, including p56lck, p59fyn and ZAP-70. We have observed, in one mouse T helper CD4 T cell line, that most TcR- or CD3-associated tyrosine kinase activity comes from CD4:p56lck (Diez-Orejas, R., Ballester, S., Feito, M. J., Ronda, M., Ojeda, G., Criado, G., Portolés, P. and Rojo, J. M., EMBO J. 1994. 13: 90). To analyze whether this is a major way of tyrosine kinase association to the TcR in normal CD4+ T cells, we examined the nature and mode of association of tyrosine kinases to the TcR complex in normal spleen CD4+ T lymphocytes. Our results show that, in normal CD4+ T lymphocytes, as in CD4+ T cell lines, there is a stable and readily detectable association between CD4:p56lck and the TcR/CD3 complex, as determined by in vitro kinase activity in immunoprecipitates from cell lysates. However, TcR/CD3 complexes from nature CD4+ lymphocytes have detectable amounts of p56lck associated in a CD4-independent manner, as shown by immunodepletion of the lysates with anti-CD4 antibodies. In addition, TcR/CD3 also bind p59fyn regardless of the presence of CD4. Conversely, we have observed that CD4 co-precipitates small quantities of p56fyn in a TcR/CD3-independent manner. Overall, our data suggest the existence of different possible molecular complexes between TcR/CD3, CD4 and their attending kinases, as well as some quantitative and qualitative differences between CD4+ T cells and CD4+ T cell lines in kinase association to the TcR/CD3 complex.

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Genetic and immunochemical evidence for CD4-dependent association of p56lck with the alpha beta T-cell receptor (TCR): regulation of TCR-induced activation.

Cited by 27 publications

References 73 publications

HIV‐1 glycoprotein gp120 disrupts CD4‐p56^lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

HIV‐1 glycoprotein gp120 disrupts CD4‐p56^lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

CD4 Dependence of Activation Threshold and TCR Signalling in Mouse T Lymphocytes

CD4‐dependent and ‐independent association of protein tyrosine kinases to the T cell receptor/CD3 complex of CD4⁺ mouse T lymphocytes

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Genetic and immunochemical evidence for CD4-dependent association of p56lck with the alpha beta T-cell receptor (TCR): regulation of TCR-induced activation.

Cited by 27 publications

References 73 publications

HIV‐1 glycoprotein gp120 disrupts CD4‐p56lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

HIV‐1 glycoprotein gp120 disrupts CD4‐p56lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

CD4 Dependence of Activation Threshold and TCR Signalling in Mouse T Lymphocytes

CD4‐dependent and ‐independent association of protein tyrosine kinases to the T cell receptor/CD3 complex of CD4+ mouse T lymphocytes

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HIV‐1 glycoprotein gp120 disrupts CD4‐p56^lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

HIV‐1 glycoprotein gp120 disrupts CD4‐p56^lck/CD3‐T cell receptor interactions and inhibits CD3 signaling

CD4‐dependent and ‐independent association of protein tyrosine kinases to the T cell receptor/CD3 complex of CD4⁺ mouse T lymphocytes