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  Quantitative analysis of membrane proximal signalling events regulating the activation and proliferation of peripheral T-cells

Wang, X., Kliche, S., Saez-Rodriguez, J., Gilles, E. D., & Schraven, B. (2005). Quantitative analysis of membrane proximal signalling events regulating the activation and proliferation of peripheral T-cells. Poster presented at 36th Annual Meeting of the DGFI German Society of Immunology, Kiel, Germany.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0013-9BB3-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-C0F7-7
Genre: Poster

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 Creators:
Wang, X., Author
Kliche, S., Author
Saez-Rodriguez, J.1, Author              
Gilles, E. D.1, Author              
Schraven, B., Author
Affiliations:
1Systems Biology, Max Planck Institute for Dynamics of Complex Technical Systems, Max Planck Society, ou_1738155              

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 Abstract: Most of our knowledge about T-cell signaling stems from experiments in which antibodies (mAbs) directed at the TCR were used for stimulation. Whether or not mAb-mediated stimulation qualitatively and quantitatively reflects the molecular events that occur after binding of cognate antigen/MHC to the TCR is unknown. To address this question we compared intracellular signaling events in primary mouse OT-I TCR tg splenic T-cells after stimulation with either CD3+CD8 mAbs or with peptide-loaded MHC-I tetramers. We show that CD3/CD8 triggering by mAbs induces very rapid and very strong phosphorylation of ZAP-70 and PLCgamma and, consequently, produces a strong rise in intracellular calcium. In contrast, the same signals are very weak, sometimes even hard to detect, after tetramer stimulation. However, despite inducing strong membrane proximal signaling events, CD3/CD8 mAb stimulation only generates a transient activation of Erk whereas Erk activation is sustained after tetramer stimulation. Similarly, T-cells proliferate only poorly upon CD3/CD8 mAb stimulation but vigorously after application of tetramers (Note that both stimuli induce comparable levels of TCR downregulation and apoptosis). Surprisingly, further biochemical experiments revealed that the transient Erk signal after CD3/CD8 mAb mediated stimulation likely results from a rapid degradation of the ZAP-70 protein tyrosine kinase. In contrast, expression of ZAP-70 remains unaffected after stimulation with tetramers. Collectively, these data suggest, that CD3/CD8 mAb mediated signals (=strong signals) initiate negative feedback loops which could serve to prevent inappropriate T-cell activation. These findings are of importance for system biology approaches aimed at mathematically describing TCR-mediated signaling in peripheral T-lymphocytes. Indeed, it appears as if both the quantitative and the qualitative aspects of mAb-mediated T-cell signaling do not reflect the conditions that occur after binding of cognate peptide MHC-complexes to the TCR (at least in the periphery). Further studies are now aimed at elucidating the contributions of the Grb2/SOS vs. RasPRP signaling pathways for TCR-mediated activation of Erk.

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Language(s): eng - English
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 Publication Status: Not specified
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 Identifiers: eDoc: 239990
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Title: 36th Annual Meeting of the DGFI German Society of Immunology
Place of Event: Kiel, Germany
Start-/End Date: 2005-09-21 - 2005-09-24

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