Immunobiology of Dendritic Cells - INSERM U818  


  HEADDr ALBERT Matthew, MD, PhD / matthew.albert@pasteur.fr
  MEMBERSCécile ALANIO, M2 / Charlotte AURIAU, Animal Technician / Claire BIOT, PhD student / Aurélie BISIAUX, Engineer / Isabelle BOUVIER, PhD student / Marie-Laure GOUPIL, Secretary / Dr Matthew BUCKWALTER, postdoc / Armanda CASROUGE, Engineer / Dr Alessandra GIODINI, postdoc / Dr. Anton KRAXNER (left September 2009) / Dr Melissa LAIRD, Postdoc / Hélène SAKLANI, Engineer / Clémentine SCHILTE, PhD Student / Stéphanie THOMAS, Projects manager / Nader YATIM, M1


  Annual Report

The ALBERT Lab focuses on the characterization of the cellular and molecular mechanisms underlying the cross-priming of tumor and viral-specific cytolytic T lymphocytes (CTLs). To achieve this goal and maintain a strong link to physiologic and pathologic problems, the laboratory is organised using a bedside-to-bench approach to biomedical research. These efforts require close collaborations and interactions between clinical scientists and basic scientists. And the interactions, in turn, stimulate new avenues for advances in clinical and basic investigations.

Defining the regulation of antigen cross-presentation

The exogenous (or indirect) pathway for MHC I antigen presentation has been a major focus of the lab to define a physiologically relevant mechanism for the activation of T cells specific for tissue-restricted antigens (e.g. tumor and self proteins). This pathway is called cross-priming due to the crossing of the classically defined restriction of MHC I to protein antigens that are synthesized by the presenting cell. Dendritic cells (DCs) engulf apoptotic cells and process the internalized material for the generation of MHC I / peptide complexes. We expect that with a better understanding of this pathway, it will be possible to design methods for boosting CTL responses in which apoptotic cells are used as a source of antigen for purposes of immunotherapy.

The lab has offered new insights on four points of regulation.

- The mechanism of cell death influences the efficiency of cross-priming.

- Dying cells play an active role in processing antigen for presentation by DCs.

- Dendritic cell maturation alters intracellular signaling networks.

- The molecular mechanism by which CD4+ helper T cells license DCs to cross-priming CD8+ T cells.

demonstrating the therapeutic utility of and physiologic relevance for apoptotic cells in delivering antigen to dendritic cells

We have focused our interest on two disease pathogenesis : bladder cancer and hepatitis C.

BCG-mediated tumor immunity in patients with transitional cell carcinoma of the bladder. The lab has extended its interest in examples of effective tumor immunity in hopes of using such positive control patients for the development and validation of assays useful in the monitoring of clinical trials. Specifically, the lab has been investigating patients with superficial transitional cell carcinoma of the bladder in order to test hypothesis that the BCG therapy they receive acts by initiating the cross-priming of tumor-reactive CD8+ T cells. Over the last four years, we have run two observational studies (sponsored by Institut Pasteur) with collaborating investigators at Necker Hospital. The lab established a first generation MAP of the inflammatory response to intravesical BCG therapy. We have identified a new class of biomarkers that may serve as useful predictors of response to therapy. A follow-up multi-centric study has just opened with the aim of validating these initial studies.

Hepatitis C virus pathogenesis and dendritic cell biology. Hepatitis C infection for several key reasons: it is a major public health concern with ~175 million infected world-wide. 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 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.

Collaborative work immune

pathogenesis of infectious disease

This collaborative work has exposed the lab to questions pertaining to infectious organisms related to those studied by the lab and has permitted us to develop our expertise in immune monitoring.

Chikungunya virus infection is controlled by type I IFN produced by non-hematopoetic cells. The principle project concerns the role of type I IFN in chikungunya disease pathogenesis. This work has provided an additional viral model for use to dissect the role of type I IFNs in immune regulation and anti-viral responses. Specifically, we have worked with Drs. Olivier Schwartz and Marc Lecuit to define the tropism of CHIKV infection and to develop an in vivo mouse model. Using these model systems, we have demonstrated a critical role for type I IFNs in the control of CHIKV replication and disease. In addition, we have identified RIG-I as the host sensor responsible for producing IFNα/b in CHIKV infected cells. Current efforts are aimed at characterizing the disease pathogenesis in neonates and identifying the interferon stimulated gene that exerts direct antiviral activity by restricting CHIKV replication.

Keywords: Immunobiology, Dendritic cells, Cross-presentation, Autophagy, Inflammation, Biomarker, Bladder cancer, Interaction, Host pathogen, hepatitis, immunotherapy, interferon



  Publications

Clémentine Schilte*, Thérèse Couderc*, Fabrice Chretien, Marion Sourisseau, Florence Guivel-Benhassine, Alain Michault, Fernando Arenzana-Seisdedos, Marco Colonna, Olivier Schwartz, Marc Lecuit and Matthew L. Albert. Chikungunya virus infection is controlled by type I IFN produced by non-hematopoetic cells. The Journal of Experimental Medicine (2010). 207: 429 - 442.

Martin Uhl*, Oliver Kepp*, Hélène Jusforgues-Saklani, Jose-Miguel Vicencio, Guido Kroemer and Matthew L. Albert. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming. Cell Death & Differentiation (2009). 16(7):991-1005. (2009).

Aurélie Bisiaux, Nicolas Thiounn, Marc-Olivier Timsit, Ahmed Eladaoui, Huey-Hsuan Chang, James Mapes, Agnès Mogenet, Jean-Louis Bresson, Dominique Prié, Stéphane Béchet, Camille Baron, Christine Sadorge, Stéphanie Thomas, Elaine B. Albert, Peter S. Albert and Matthew L. Albert. 2009. Mapping the Early Events and Tissue Conditioning following Intravesical BCG Therapy in Patients with Carcinoma of the Bladder. The Journal of Urology (2009). 181(4):1571-80. (2009).

Hélène Jusforgues-Saklani, Martin Uhl, Nathalie Blachère, Fabrice Lemaître, Olivier Lantz, Philippe Bousso, Deborah Braun and Matthew L. Albert. 2008. Antigen persistence is required for efficient cross-priming of minor histocompatibility antigen specific CD8+ T cells. Journal of Immunology 181(5):3067-76.

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.



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Activity Reports 2009 - Institut Pasteur
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