Immunoregulation - CNRS URA 1961  


  HEADLars ROGGE, PhD / lars.rogge@pasteur.fr
  MEMBERSElisabetta BIANCHI, MD / Maryaline COFFRE / Shen DONG, PhD / Sylvie MAIELLA / Katarzyna PLACEK / Mathilde ROUMIER / Emmanuel SECHET


  Annual Report

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

Functionally distinct subsets of CD4+ T lymphocytes are essential to orchestrate 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 fight parasites. The recently identified Th17 subset is required for defenses against extracellular bacteria and fungi. On the other hand, Th1 and Th17 cells play critical roles in the pathogenesis of several inflammatory and autoimmune diseases, whereas Th2 cells have been associated with 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.

Epigenetic mechanisms controlling human Th1 cell differentiation

We have performed an integrated analysis of the signaling pathways, epigenetic modifications and genetic networks involved in T helper cell differentiation. We have defined how signals originating at the T cell receptor (TCR) and at cytokine receptors are integrated to shape a Th1-specific gene expression program in primary human CD4+ T cells. We could show 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.

Further studies revealed that expression of T-bet, the "master" transcription factor of the Th1 lineage, is controlled by a different mechanism. We found that remodeling of the human T-bet locus and T-bet 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 by two 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.

In vivo expansion of regulatory T cell populations in IL-2-treated HIV patients

In a more clinically oriented project, we have studied the long-term effects of recombinant, human IL-2 therapy on CD4+ T cell homeostasis and function in HIV patients. In particular, we have studied phenotypic, functional, and molecular characteristics of a subset of CD4+ T cells expressing high-levels of the IL-2 receptor alpha chain (CD25) that appears in the peripheral blood of IL-2-treated HIV patients. We found that the principal effect of long-term IL-2 therapy was the expansion of two distinct CD4+CD25+FOXP3+ T cell populations. IL-2-expanded CD4+CD25+ T cells suppressed proliferation of effector cells in vitro and therefore shared functional characteristics of natural regulatory CD4+CD25hiFOXP3+ T cells (Treg) from healthy donors. To assess the molecular characteristics of IL-2-expanded T cells, we performed a longitudinal analysis of the gene expression profiles of CD4+CD25+ T cells from HIV patients before and after IL-2 treatment. We found that the gene expression signatures before and after IL-2 treatment cycles are closely related and resemble the gene expression profiles generated from sorted CD4+CD25hi Treg from healthy donors. In conclusion, our data demonstrate that IL-2 treatment expands CD4+CD25+ T cell populations that share phenotypic, functional, and molecular characteristics with Treg.

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.

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



  Publications

1. Placek, K., Gasparian, S., Coffre, M., Maiella, S., Sechet, E., Bianchi, E. and Rogge, L. Integration of distinct intracellular signaling pathways at distal regulatory elements directs T-bet expression in human CD4+ T cells.J Immunol 183, 7743-7751 (2009).PMID: 19923468

2. Placek, K., Coffre, M., Maiella, S., Bianchi, E. and Rogge, L. Genetic and epigenetic networks controlling T helper 1 cell differentiation.Immunology 127, 155-162 (2009). PMID: 19476511

3. Libri, V., Schulte, D., van Stijn, A., Ragimbeau, J., Rogge, L. and Pellegrini, S. Jakmip1 is expressed upon T cell differentiation and has an inhibitory function in cytotoxic T lymphocytes.J Immunol 181, 5847-5856 (2008).PMID: 18941173

4. Letimier, F.A., Passini, N., Gasparian, S., Bianchi, E. and Rogge, L. Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rbeta2 expression during human Th1 cell differentiation.EMBO J 26, 1292-1302 (2007). PMID: 17304212

5. Vosshenrich, C.A., Garcia-Ojeda, M.E., Samson-Villeger, S.I., Pasqualetto, V., Enault, L., Richard-Le Goff, O., Corcuff, E., Guy-Grand, D., Rocha, B., Cumano, A., Rogge, L., Ezine, S. and Di Santo, J.P. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127. Nat Immunol 7, 1217-1224 (2006). PMID: 17013389





Activity Reports 2009 - Institut Pasteur
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