Immunobiology of Dendritic Cells - INSERM U818  


  HEADALBERT Matthew / albert@pasteur.fr
  MEMBERSDr AZAR Georges / CHANG Huey Hsuan / DECALF Jérémie / SCHILTE Clémentine
UHL Martin / Dr WALTER Lisa


  Annual Report

Our group’s basic science and clinical research goals are to investigate the cellular and molecular mechanisms underlying the different immunologic outcomes of antigen cross-presentation — cross-priming versus cross-tolerization of cytolytic T lymphocytes (CTLs); and to identify pathologic as well as physiologic examples of this immunologic pathway. Specifically, we aim to identify key points of regulation that are interrupted by intracellular organisms and small molecule inhibitors.

To study the role for CD4+ T cell help in skewing the immunologic outcome of cross-presentation. Using both human and mouse models for cross-presentation of viral and tumor antigens, we hope to identify points of regulation in the decision between CD8+ T cell activation and tolerance. Specifically, we investigate the role for CD40 signaling at the CD4 T cell / DC interface and are defining the pathways responsible for ‘licensing’ DCs to prime a CD8+ T cell response.

To define the antigen processing and presentation pathway(s) for loading MHC I with exogenous antigen. Apoptotic cells are an interesting source of antigen as they are complex entities and possess the machinery required for generating antigenic peptides. We have recently discovered that dying cells may play an active role in the transfer of antigen to DCs for the loading of MHC I / peptide complexes. We now aim to develop assay systems that will allow us to track processed antigen from within the apoptotic cells, and compare it to the defined phagosome-to-cytosol pathway in which the DC generates the antigenic peptide. Relevant knock-out mice will be employed to dissect the respective cross-presentation pathways.

To demonstrate the therapeutic utility of apoptotic cells for the delivery of antigen to dendritic cells. We investigate patients with superficial transitional cell carcinoma of the bladder in order to test our hypothesis that the BCG therapy they receive (resulting in >70% cure rates) acts by initiating the cross-priming of tumor-reactive CD8+ T cells; and establish key surrogate makers for clinically effective tumor immunity. This study is carried out in collaboration with Dr. Nicolas Thiounn at The Necker Hospital. We have also developed a cohort of chronically infected hepatitis C patients (collaboration with Pr. Stanislas Pol, Hospital Necker) and have begun a collaboration with investigators in Egypt on the analysis of acutely infected subjects (Dr. Mostafa Mohamed, Tropical Medicine Research Institute, Cairo Egypt). The goal is to evaluate the role of dendritic cells in HCV pathogenesis and to better define the immune mechanisms accounting for viral clearance.

albert.jpg

Image of dendritic cells engulfing apoptotic cells—the first step for antigen cross-presentation



  Publications

Publications 2006 of the unit on Pasteur's references database




Activity Reports 2006 - Institut Pasteur
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