Immunoregulation - CNRS URA 1961  


  HEADLars ROGGE, PhD / lars.rogge@pasteur.fr
  MEMBERSElisabetta BIANCHI, MD / Maryaline COFFRE / Gauthier GARRET / Sylvie MAIELLA / Katarzyna PLACEK / Emmanuel SECHET


  Annual Report

The lab studies the molecular mechanisms that control the differentiation and function of human helper T cell subsets, and analyzes their roles in the pathogenesis of inflammatory diseases.

Differentiation of naïve CD4+ T lymphocytes into functionally distinct T cell subsets is essential for efficient immune responses against different types of pathogens. T helper type 1 (Th1) cells promote cell-mediated immunity and clear intracellular pathogens whereas Th2 responses are essential to combat parasites. The recently identified Th17 subset is required for defenses against extracellular bacteria and fungi. On the other hand, CD4+ T cell subsets play key roles in the pathogenesis of chronic inflammatory/autoimmune diseases, allergies and asthma, indicating that regulation of the Th1, Th2 and Th17 pathways has profound effects on immunity to pathogens and the pathogenesis of various immune-mediated diseases.

Control of human Th1 cell differentiation

We are studying the signaling pathways, epigenetic modifications and genetic networks involved in T helper cell differentiation. In a recent study we have determined how signals originating at the T cell receptor and at cytokine receptors are integrated to shape a Th1-specific gene expression program in primary human CD4+ T cells. We could demonstrate that chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induced expression of the signaling subunit of the IL-12 receptor, IL-12Rβ2, during human Th1 cell differentiation (Letimier et al. EMBO J. 2007).

Further studies revealed that expression of T-bet, the “master” transcription factor of the Th1 lineage, is controlled by a distinct mechanism. We found that remodeling of the human T-bet locus and gene expression are initiated by TCR-induced NFAT recruitment and amplified by IL-12-mediated STAT4 binding to two distinct distal regulatory elements during human Th1 cell differentiation. These data suggest that epigenetic modifications and gene expression at the T-bet locus are controlled at least in part by two distal regulatory elements that serve as platforms to integrate TCR and cytokine signaling during human CD4+ T cell differentiation.

Collectively, our results indicate that two independent signaling pathways act in parallel to control human Th1 cell differentiation.

Th1 versus Th17 cells in inflammatory disease

Ongoing studies focus on the pathways and mechanisms that regulate human Th17 cell development and on the role of distinct T cell subsets in chronic inflammatory diseases. In particular, we study the role of Th1 versus Th17 subsets in the pathogenesis of ankylosing spondylitis and determine how IL23R variants affect IL-23 signaling and CD4+ T cell functions in patients. Projects are pursued in close collaboration with the Center for Human Immunology (CIH), a recently created structure providing access to state-of-the-art equipment to support translational research projects.

Keywords: CD4+ T cell subsets, Th17 cells, Cytokine signaling, Chromatin remodeling, Chronic inflammatory diseases

Imreg.jpg

Two independent signaling pathways control human Th1 cell differentiation. 1. TCR-induced recruitment of the BAF complex initiates IL12RB2 locus remodeling and gene expression, which is enhanced by STAT4. This process is insensitive to the immunosuppressive drug cyclosporine A (CsA). 2. TCR signaling induces chromatin remodeling at the TBX21 (T-bet) locus and gene expression via activation of NFAT (CsA-sensitive).



  Publications

1. Libri V, Schulte D, van Stijn A, Ragimbeau J, Rogge L, Pellegrini S. 2008. Jakmip1 is expressed upon T cell differentiation and has an inhibitory function in cytotoxic T lymphocytes.J Immunol. 2008 Nov 1;181(9):5847-56. PMID: 18941173

2. Letimier FA, Passini N, Gasparian S, Bianchi E, Rogge L. 2007. Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation. EMBO J. Mar 7;26(5):1292-302. PMID: 17304212

3. Jacquelin B, Mayau V, Brysbaert G, Regnault B, Diop OM, Arenzana-Seisdedos F, Rogge L, Coppée JY, Barré-Sinoussi F, Benecke A, Müller-Trutwin MC. 2007. Long oligonucleotide microarrays for African green monkey gene expression profile analysis. FASEB J. Oct;21(12):3262-71. PMID: 17507667

4. Vosshenrich CA, García-Ojeda ME, Samson-Villéger SI, Pasqualetto V, Enault L, Richard-Le Goff O, Corcuff E, Guy-Grand D, Rocha B, Cumano A, Rogge L, Ezine S, Di Santo JP. 2006. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol. Nov;7(11):1217-24.PMID: 17013389

5. Denti S, Fernandez-Sanchez ME, Rogge L, Bianchi E. 2006. The COP9 signalosome regulates Skp2 levels and proliferation of human cells. J Biol Chem. Oct 27;281(43):32188-96. PMID: 16943200





Activity Reports 2009 - Institut Pasteur
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