|Director : ACUTO Oreste (email@example.com)|
We study the molecular mechanisms of T cell activation. The molecular information carried by activated antigen presenting cells (APC) loaded with antigen and/or by cytokines (or chemokines) is relayed to the T cell through a complex device formed by membrane receptors and a vast array of cellular components that decode positive (activators) and negative (negative) signals. Intracellular signaling is organized by diverse effectors, such tyrosine and serine/threonine kinases, phosphateses, protein adapters, small GTPases, methyltransferases, lipids and lipid-modifying enzymes and et small molecules. The outcome of these highly complex processes determines whether T cells become effectors of the immune response or memory cells, or tolerized. Our research is focused on understanding the role and regulation of some key signaling components on the signaling machinery. Moreover, we search for new signaling pathways by the use of mass spectrometry applied to intracellular protein complexes and explore new findings indicating that CD28 induces activation of a signaling pathway regulating protein arginine methylation in T cells.
During the last few years, our group has been interested in discovering and defining functionally additional signaling pathways that control initiation, propagation, regulation and storage of signals that activate genetic programs in T cells during the response to antigen.
We have recently identified two signaling pathways that convey " negative " signals at different times after TCR triggering. The first one (studied by Frédérique Michel), implicates the adapters Dok-1 et Dok-2 forming together with the lipid phosphatase SHIP-1 a complex binding to LAT (linker for activation of T cells), the central adapter required for TCR signal propagation. This complex is observed very rapidly (seconds) after TCR triggering and its phosphorylation depends on LAT. Its appearance causes a decrease of activation (e.g., IL-2 production) by partially affecting activation of the kinases Akt and ZAP-70. This mechanism negative-feed back control of the TCR signal may serve to counter-balance homeostatic " tonic " of too high intensity or " for tailoring " incoming activation signals.
A second negative signaling pathway, analyzed by Vincenzo Di Bartolo, appearing much later (10-15 min) after TCR triggering is activated by the serine/threonine kinase HPK-1. We found that HPK-1 phosphorylates SLP-76 on serine at 10-15 minutes after activation and allows binding of 14-3-3 proteins, leading to a sensible down-regulation of the activation signal. This mechanism likely allows a desensitization of the " signalosome ", similar to that previously described for the adapter IRS-1 of the Insulin receptor. Biochemical, fluorescence microscopy and mutation knock-in experiments are underway to understand the specific role of this mechanism on the activation signal and its impact on in vivo T cell responses.
S-Adenosyl-L-Methionine (SAM)-dependent Protein aRginine MethylTransferases (PRMTs) regulates many biological processes, including signal transduction and gene expression. T cell proliferation and differentiation have been shown to depend on cellular protein arginine methylations but the temporal and specific role of PRMTs in T cell activation is unknown. We have recently described that the co-stimulatory receptor CD28 stimulates Protein aRginine MTAse activity arginine methylation of several proteins, including Vav1, a key effector of CD28 signaling. Methylated Vav1 is found in the nucleus. Our findings have uncovered a novel role of CD28 in activating a pathway likely to be critical for T cell activation. Our current research in this area (animated by Brandon T. Schurter) is aimed at understanding the role of Vav methylation and at establishing its physiological role in T cell differentiation.
Keywords: T cells, activation signals, SLP-76, Dok-1/Dok-2, PRMTs
|Publications 2005 of the unit on Pasteur's references database|
|Office staff||Researchers||Scientific trainees||Other personnel|
|HOUSSIN Wendy, firstname.lastname@example.org||ACUTO Oreste, IP, email@example.com
DI BARTOLO Vincenzo, IP, firstname.lastname@example.org
MICHEL Frédérique, IP, email@example.com
SCHURTER Brandon, firstname.lastname@example.org
|DONG Shen, PhD student
DI FRANCESCO Laura, PhD student
|BLOM-POTAR Marie-Christine, engineer
CORRE Béatrice, technician
MONTAGNE Benjamin, technician
HOUSSIN Wendy, secretary