Immunobiology of Dendritic Cells - INSERM U818  


  HEADDr ALBERT Matthew / albert@pasteur.fr
  MEMBERSDr Georges AZAR, Post-doc / Aurélie BISIAUX, Engineer / Isabelle BOUVIER, M2 training / Maryse BRANDT, Secretary / Armanda CASROUGE, Engineer / Huey Hsuan CHANG, PhD student / Jérémie DECALF, PhD student
Hélène SAKLANI, Engineer / Clémentine SCHILTE, PhD Student / Stéphanie THOMAS, Projects Assistant / Martin UHL, Medical Fellow / Lisa WALTER, Post-doc


  Annual Report

The goals of the lab are to further characterize the apoptosis-dependent antigen presentation pathway, with a specific focus on points of regulation that control the immunologic outcome of cross-presentation—priming vs. tolerance. We are committed in translational research with the idea of exploring in vivo examples in which apoptotic cells are responsible for delivering antigen to the immune system for purposes of eliciting effective tumor and viral immunity.

To define the molecular mechanism by which CD4+ helper T cells license DCs and permit the cross-priming of CD8+ T cells. Using both mouse and human models for cross-presentation we aim to identify key points of regulation in the decision between CD8+ T cell activation and tolerance. Specifically, we investigated the role for CD40L / CD40 signaling at the CD4 T cell / DC interface and define the signaling pathway responsible for ‘licensing’ DCs to prime a CD8+ T cell response. This work also focused on the role for the immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO). Strikingly, IDO may be responsible for both DC mediated tolerance, as well as tumor mediated tolerance (e.g. breast and cervical cancer). With respect to DC biology, we have discovered that IDO is markedly upregulated in response to maturation signals; we believe that signals from the CD4+ T cell switches IDO to an inactive state, in turn permitting CD8+ T cell cross-priming. Thus, in the absence of tumor-reactive CD4+ T cells, IDO remains activate, and attempts to prime CD8+T cells may instead result in the opposite immunologic effect. By defining a role for IDO we may not only gain insight into fundamental aspects of cross-priming, but we may also identify strategies to inhibit IDO while maintaining the necessary properties of a DC to achieve tumor immunity.

To define the antigen processing and presentation pathway(s) for loading MHC I with exogenous antigen. Apoptotic cells are an interesting and physiologically important source of information for the immune system. We have recently discovered that the dying cells 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 the processed antigen from within the apoptotic cell into the DCs MHC I antigen presentation pathway, and compare this route 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; and to identify surrogate markers for monitoring clinical immunotherapy trials. We have been investigating 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. We currently have two open clinical with collaborating investigators at Necker Hospital. We have more recently started work in hepatitis C. Our first objective in this long-term project was to characterize the role of DCs in HCV pathogenesis. Based on our results and through new collaborative partnerships both in Paris and Cairo we have extended our work to include the study of the adaptive immune response in acute HCV infection as well as an unbiased search for biomarkers that could be used to predict responsiveness to therapy.

Keywords: Antigen, bladder, cross-presentation, dendritic cells, hepatitis, immunotherapy, interferon

Icd.jpg

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



  Publications

Randy S. Longman, Sandra Pelegrini, Charles M. Rice, Robert B. Darnell and Matthew L. Albert. 2007. Dendritic cell maturation alters intracellular signaling networks enabling differential effects of type I IFNs on antigen cross-presentation. Blood 109: 1113-22 (2007).

Decalf J, Fernandes S, Longman R, Ahloulay M, Audat F, Lefrerre F, Rice CM, Pol S, Albert ML. 2007. Plasmacytoid dendritic cells initiate a complex chemokine and cytokine network and are a viable drug target in chronic HCV patients. The Journal of Experimental Medicine. 204(10):2423-37.

Nathalie Blachère, Heather K. Morris, Deborah Braun, Hélène Saklani, James P. Di Santo, Robert B. Darnell and Matthew L. Albert. 2006. Interleukin-2 is required for the activation of memory CD8+ T cells via antigen cross-presentation. J Immunol.176: 7288-300.

Nathalie Blachère, Robert B. Darnell and Matthew L. Albert. 2005. Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation.PLoS Biology. 3:e185. 

Matthew L. Albert. 2004. Death-defying immunity: do apoptotic cells influence antigen processing and presentation. Nature Reviews Immunology, 4: 223-31.



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Activity Reports 2007 - Institut Pasteur
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