Cytokine Signalling - CNRS URA1961  


  HEADDr PELLEGRINI Sandra / pellegri@pasteur.fr
  MEMBERSDr BROGARD Béatrice / DONG Shen / GAKOVIC Milica / Dr LIBRI Valentina
MORAGA GONZALEZ Ignacio / Dr MICHEL Frédérique / Dr RAGIMBEAU Josiane


  Annual Report

Type I IFN contribute to immediate defense against pathogens, development of adaptive immunity and protective antitumor responses. Several subtypes exist which participate vigorously in the cytokine network that regulates differentiation, function and homeostasis of a variety of cell lineages. An important aspect of our research centers on the molecular mechanisms of type I IFN action, with particular attention to the role of Jak tyrosine kinases.

I- Tyk2 and receptor traffic. Our recent studies have established new concepts regarding the role of Jak tyrosine kinases in signaling and receptor traffic. We have analyzed Tyk2 function in steps that drive internalization and lysosomal degradation of the IFNAR1 receptor subunit in response to ligand. We found that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for the ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis. We now focus on the regulation of surface IFNAR2.

II- Study of Jakmip1 in CD8 T lymphocytes.

Jakmip1 (Jak and microtubule interacting protein) was identified in a two-hybrid screen as an interactor of Tyk2. Jakmip1 is expressed uniquely in neuronal cells and in lymphocytes and co-localizes with microtubules, affecting their dynamic equilibrium. We focus on cytotoxic T lymphocytes (CTL) whose killing activity strongly relies on the microtubule network. We found that Jakmip1 is not expressed in naïve CD8 T lymphocytes and is induced upon TCR stimulation. Moreover, it is more highly expressed in the CCR7- effector T cell subset. To address Jakmip1 role in CTL, we monitor effector functions by RNAi in primary CD8 cells. Our results suggest Jakmip1 could be part of a negative feedback loop induced upon TCR activation and down modulating the killing potential of CTL.

III. Role of Dok-1 and Dok-2 inhibitory adaptors in TCR signaling. Dok-1 and Dok-2 have been proposed as negative regulators of signaling in different cell types. We are interested in understanding Dok-1/2 function in human T cell activation. We found that TCR stimulation of primary T cells leads to formation of a multimolecular complex including Dok-2, the lipid phosphatase SHIP-1 and the membrane Linker for Activation of T cells (LAT). LAT plays a central role in TCR signaling by anchoring major signaling complexes. Using RNAi, we have shown that LAT and SHIP-1 control TCR-mediated Dok-2 recruitment and that Dok-1 and Dok-2 together impair TCR-induced IL-2 production. Our current model is that Dok-1 and Dok-2 act in a negative feedback loop that attenuates early TCR signal. Our data also point to LAT as integrator of positive and negative signals emanating from the TCR.

pellegrini.jpg

Suite à la stimulation du TCR, le complexe Grb-2/SHIP-1/Dok-1/2 est recruté par LAT et régule négativement le signal précoce issu du TCR.

Upon TCR stimulation, the Grb-2/SHIP-1/Dok-1/2 complex is recruited by LAT and negatively regulates early TCR signal



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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