|Cytokine Signalling - CNRS URA 1961|
|HEAD||Dr PELLEGRINI Sandra / firstname.lastname@example.org|
|MEMBERS||Dr BROGARD Béatrice / CORRE Béatrice / DONG Shen / GAKOVIC Milica / HUGOT Bérengère / Dr LIBRI Valentina / MORAGA GONZALEZ Ignacio / Dr MICHEL Frédérique / Dr RAGIMBEAU Josiane
Type I IFN contribute to immediate defense against pathogens, development of adaptive immunity and protective antitumor responses. Several IFN subtypes participate vigorously in the cytokine network that regulates differentiation, function and homeostasis of a variety of cell lineages. IFN are also pathogenic factors in several systemic and organ-specific autoimmune diseases.
An important aspect of our research centers on the molecular mechanisms of type I IFN action, with particular attention to the receptor and the Jak tyrosine kinases.
I- Our recent studies have established new concepts regarding the role of Jaks and receptor traffic. We found that the catalytic activity of Tyk2 is required for ligand-induced serine phosphorylation, ubiquitination and lysosomal proteolysis of the IFNAR1 receptor chain. We also found that the IFNAR2 receptor chain follows a different intracellular route depending on which IFN subtype is bound. We are exploring the possibility that endocytic traffic shapes subtype-specific signaling and contribute to activation of non-Stat signaling molecules.
II- Jakmip1 (Jak and microtubule interacting protein) was identified in a screen for Tyk2 interactors. Jakmip1 associates to microtubules in both neuronal cells and lymphocytes. We have studied Jakmip1 in distinct subsets of human primary lymphocytes. Jakmip1 is not expressed in naïve cells, is induced upon T cell receptor (TCR) stimulation and is maximally expressed in T cell subsets with high effector potential. Lentiviral-mediated silencing of Jakmip1 in primary CD8 T cells suggest that Jakmip1 negatively regulate the killing potential of CTL.
III- Negative regulation of T cell activation. New insights in T cell activation and its biological outcome have been uncovered through the study of inhibitory proteins that modulate TCR and cytokine signaling. We showed that TCR stimulation induces the assembly of a multimolecular complex including the inhibitory adaptor proteins Dok-1 and Dok-2, the lipid phosphatase SHIP-1 and the small adaptor Grb-2. This complex interacts with LAT, the central organizer and propagator of TCR signal, and dampens TCR-induced IL-2 production. We have proposed that Dok-1 and Dok-2 act in a negative feedback loop to attenuate early TCR signal. Our current interests are to understand how LAT integrates positive and negative signals emanating from the TCR and to investigate whether type I IFN, known to exert an anti-proliferative function, influence TCR-induced T cell activation.
Throughout these studies we hope to gain new insights into the molecular mechanisms of IFN action, understand how individual IFN subtypes act differentially and unravel the nature of the cooperative crosstalk between IFN and stimulation of the TCR.
Keywords: signaling, structure function, innate response, inflammation, lupus
Steindler, C., Z. Li , M. Algarté, A. Alcover, V. Libri, J. Ragimbeau, and S. Pellegrini. 2004. Jamip1 (Marlin-1) defines a family of proteins interacting with Jaks and microtubules. J. Biol. Chem., 279 : 43168-43177.PMID: 15277531
Dondi, E. , G. Roue, V. J. Yuste, S. A. Susin, and S. Pellegrini. 2004. A dual role of IFNαin the balance between proliferation and death of human CD4+T lymphocytes during primary response.J. Immunol., 173 : 3740-3747. PMID: 15356120
Marijanovic, M., J. Ragimbeau, K. G. S. Kumar, S.Y. Fuchs, and S. Pellegrini. 2006. Tyk2 activity promotes the ligand-induced IFNAR1 proteolysis.Biochem. J., 397 : 31-38. PMID: 16551269
Dong S, B. Corre, E. Foulon, E. Dufour, A. Veillette, O. Acuto, and F. Michel. 2006. T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J. Exp. Med. 203 : 2509-2518. PMID: 17043143
Marijanovic, Z., J. Ragimbeau, J. Van der Heyden, G. Uzé, and S. Pellegrini. 2007. Comparable potency of IFNα and IFNβon immediate Jak/Stat activation but differential down-regulation of IFNAR2. Biochem. J., 407 : 141-151. PMID: 17627610
Activity Reports 2007 - Institut Pasteur
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