Immunité innée dans les maladies infectieuses et autoimmunes
Projects and grants
1) Study of NK cell differentiation and activation (PI: T. Walzer, funded by ERC)
NK cells express a wide range of transcription factors that control their genetic program. We recently found that Zeb2, a transcription factor previously involved in epithelial-to-mesenchymal transition, was highly expressed in NK cells and regulated terminal NK cell maturation by sustaining the action of T-bet. Current research aims at understanding the respective roles of T-box vs Zeb family members in NK cell differentiation using dedicated transgenic mouse models.
2) Molecular control of NK cell reactivity (PI: A. Marçais, Funding: ANR-JCJC, InCA PLBIO)
NK cell reactivity (ie their ability to express effector functions) is highly regulated at various levels to ensure appropriate responses to viral or tumour challenges. We recently showed that mTOR is an essential checkpoint controlling NK cell activation. Indeed, this kinase integrates a number of environmental signals regulating NK cell reactivity (pro- and anti-inflammatory cytokines, activating and inhibitory receptors…). Mechanistically, mTOR controls NK cell activation by controlling two cardinal signalling events following activating receptor stimulation: the activation of the LFA-1 integrin and the calcium flux. However, the signalling pathways involved remain unknown. Our next aim is to uncover the molecular determinants of this response.
In parallel, we also study mTOR regulation in NK cells during cancer progression and the induction of NK cell exhaustion using a variety of human samples and murine models. We aim at deciphering the molecular determinants of NK cell exhaustion and at exploring strategies to restore NK cell reactivity.
3 ) Role of S1PR5 in NK cell trafficking (PI: T. Walzer, Industrial partners)
NK cells develop in the bone marrow. We previously showed that their release into the circulation was dependent both on the engagement of the chemotactic receptor S1PR5 by sphingosine-1-phosphate and on CXCR4 desensitization by SDF-1. Our current work aims at understanding the role of S1PR5 in various pathological situations, and to understand the role of S1PR5 in human NK cell migration.
4) NK cell exhaustion in chronically-infected patients (PI: U. Hasan, Grants: ANRS, LNCC)
NK cells play an essential role to eradicate Hepatitis B virus (HBV) via attacking the infected cell by cytotoxicity and releasing large amounts of IFN-γ. Nevertheless, HBV has developed mechanisms to negatively deregulate NK cell function. NK cells also display decreased production of antiviral cytokines in HCV and HIV infected individuals. These patients possess NK cells with an altered ‘CD56neg and/or exhaustive’ phenotype. Although there are increasing data implying that these subsets do exist, a full characterization of the panel of NK cell receptors and function has not been concisely attributed. Furthermore, the biological and cellular modifications that alters NK cell function by HBV remains to be studied and is central to our research program.Our three main aims include:
-Using mass cytometry to phenotype the different NK cell subpopulations with functional defects due to HBV chronicity in patients.
-Determine the phosphorylation status and biological events that drive NK cell deregulation.
-Use a CRISPR/cas9 library to identify new genes that are involved in NK cell dysfunction
5) New monogenic forms of SLE (PI: A. Belot, Grants: ANR)
In order to investigate Human tolerance mechanisms, we aim at identifying new forms of monogenic autoimmunity. Systemic Lupus Erythematous (SLE) is the prototypic autoimmune disease resulting from a breakdown of tolerance to self-antigens and production of autoantibodies. SLE is assumed to occur due to a complex interplay of environmental and genetic factors. Recently, rare causes of monogenic SLE have been described, providing unique insight into fundamental mechanisms of immune tolerance. Using Whole Exome Sequencing, we recently identified Protein Kinase C-δ as a new mendelian cause of SLE secondary to PRKCD mutation, enhancing the major role of B cell tolerance in lupus pathogenesis. We recently performed redirected sequencing of about 200 genes in a cohort of more than a hundred patients with pediatric onset lupus. We perform bioinformatic analyses and sanger sequencing to identify new causes of monogenic SLE. We will also generate mouse models for selected mutations, in order to understand the mechanism.