Immunoregulation - CNRS URA 1961  


  HEADDr ROGGE Lars / lrogge@pasteur.fr
  MEMBERSDr BIANCHI Elisabetta / Dr FERNANDEZ SANCHEZ Maria Elena / COFFRE Maryaline / MAIELLA Sylvia / PLACEK Katarzyna / XHAARD AliÈnor / SECHET Emmanuel / AYTAC Marie-Dominique


  Annual Report

Our lab studies the molecular mechanisms that control the differentiation and function of human helper T cell subsets and analyzes their role in infectious and 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, uncontrolled T helper cell responses play critical roles in the pathogenesis of various immunopathologies, such as allergies, asthma, chronic inflammatory and autoimmune 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. In contrast to IL-12Rβ2, T-bet expression and remodeling of the T-bet locus require NFAT activation. These results indicate that two independent signaling pathways act in parallel to control human Th1 cell differentiation.

Ongoing studies focus on the pathways and mechanisms that regulate human Th17 cell development, the relative contribution of Th1 versus Th17 subsets in human autoimmune pathology, and the characterization of a novel transcription factor specifically expressed by human regulatory T cells.

A systems biology approach to study human CD4+ T lymphocyte subsets

The construction of robust molecular fingerprints for physiologic and pathologic cellular phenotypes is of great value for the understanding of cellular pathophysiology and has direct applications in the biomedical domain. In collaboration with A. Benecke (IHES, Bures-sur-Yvette) we have devised a novel strategy combining gene expression profiling and global signaling pathway analysis by aid of a geometric correction to generate unique transcriptome signatures. Our integrated global pathway analysis has revealed new important features of human regulatory T cells.

Keywords: CD4+ T cell subsets, Th17 cells, Cytokine signaling, Chromatin remodeling, Immunology, Autoimmune diseases, 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. 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

2. 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

3. 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

4. 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

5. De Benedetti F, Pignatti P, Biffi M, Bono E, Wahid S, Ingegnoli F, Chang SY, Alexander H, Massa M, Pistorio A, Martini A, Pitzalis C, Sinigaglia F, Rogge L. 2003. Increased expression of alpha(1,3)-fucosyltransferase-VII and P-selectin binding of synovial fluid T cells in juvenile idiopathic arthritis. J Rheumatol. Jul;30(7):1611-5. PMID: 12858466





Activity Reports 2007 - Institut Pasteur
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