Cytokines and Lymphoid Development - INSERM U 668  


  HEADProf. Di SANTO James / james.di-santo@pasteur.fr
  MEMBERSDr ALVES Nuno / Dr BRAUNER Hanna / CORCUFF Erwan / DARCHE Sylvie / Dr DECALUWE Hélène / GOMES-RIBEIRO Vera / Dr HUNTINGTON Nicholas / LECESTRE Claire / LESJEAN-POTTIER Sarah / Dr MENTION Jean-Jacques / NUNES FIGUEIREDO Sophie / Dr OLIVIER Aurélie / PHAM Cécile / Dr REKIKI Abdessalem / Dr SATOH Naoko / Dr STRICK-MARCHAND Hélène / VOILLOT Anaïs / Dr VOSSHENRICH Christian / WOLTERINK Roel


  Annual Report

Our research aims to define the molecular signals that drive lymphocyte development and control lymphocyte homeostasis, in order to know how these signals can potentially impact and regulate immune responses. A main area of interest involves deciphering the genetic program of NK cell differentiation in both mice and man. A second group develops humanized mice to model human disease. Our projects aim to advance our understanding of immune development and immune responses that may lead to the design of new therapies for pathological conditions.

Signals for lymphocyte differentiation and homeostasis : Transcriptional targets of common g chain cytokines (gc) in naïve and activated CD4+ and CD8+ T cells have been identified that promote Th1-differentiation. These data suggest that gc cytokines control a late checkpoint in the differentiation of CD4+ but not CD8+ T cells. IL-7-GFP reporter mice that identify the thymic IL-7 ‘niche’ have been characterized and we have evidence that a stromal cell:thymocyte crosstalk regulates IL-7 transcription throughout life.

Factors that condition NK cell diversity : Thymic and intestinal NK cells have been characterized that have unusual phenotypic and functional characteristics and depend on specific transcription factors (GATA-3 and RORgt, respectively). We have identified the cytokines that drive development of these different innate lymphoid cell subsets. These results indicate that NK cell phenotypes are not homogeneous, but differ dependent on the tissue and state of activation. Our hypothesis is that diverse subsets of NK cells perform unique (non-stereotyped) roles in immunity.

Alymphoid mice to study infectious processes : We recently found that immune cells can condition the inflammatory response to enteric pathogens (Citrobacter rodentium). Finally, we showed that lymphocytes regulate tissue regeneration within the liver in response to non-infectious stress. The capacity of lymphocytes to condition the inflammatory response therefore operates under non-infectious conditions and during normal ‘physiological’ conditions.

Human xenografts in mice : Immunodeficient Rag2/gc mice are useful hosts for human xenografts (including myoblasts, hepatocytes, and hematopoietic stem cells). We are testing several different genetic modifications to improve the human immune system (HIS) mouse model and a chimeric HIS / liver model to study HCV infection (‘Grand Challenges for Global Health’ grant). We found that IL-15 controls NK cell development in HIS mice. A new model that allows robust human dendritic cell development in the absence of murine DC has been established. These improved HIS models, as well as HIS/Liver double chimeric systems are being tested for their capacity to ‘read out’ human immune responses following vaccination and / or infection by hepatotropic pathogens.

Keywords: Innate immunity, cytokines, transcription factors, xenotransplantation, mouse models



  Publications

Strick-Marchand, H., Masse, G.X. Weiss, M.C. and Di Santo, J.P. (2008) Lymphocytes support oval cell-dependent liver regeneration. Journal of Immunology 181:2764-2771. PMID: 18684967

Satoh-Takayama, N., Vosshenrich, C.A.J., Lesjean-Pottier, S.., Sawa, S., Lochner, M., Rattis, F., Mention, J.-J., Thiam, K., Cerf-Bensussan, N., Mandelboim, O., Eberl, G. and Di Santo, J.P. (2008) Microbial flora drives IL-22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29:958-970. PMID: 19084435

Huntington, N.D., Legrand, N., Alves, N.L., Jaron, B., Weijer, K., Plet, A., Corcuff, E., Mortier, E., Jacques, Y., Spits, H. and Di Santo, J.P. (2009) IL-15 trans-presentation promotes human NK cell development and terminal differentiation in vivo. Journal of Experimental Medicine (in press). PMID: 19103877

Alves, N.L., Richard-Le Goff, O., Huntington, N.D., Sousa, A.P., Ribeiro, V., Bordack, A., Langa Vives, F., Peduto, L., Chidgey, A., Cumano, A., Boyd, R., Eberl, G. and Di Santo, J.P. (2009) Characterization of the thymic IL-7 niche in vivo. Proceedings of the National Academy of Sciences (USA) 106:1512-1517.

Satoh-Takayama, N., Dumontier, L., Lesjean-Pottier, S., Ribeiro, V.S.G., Mandelboim, O., Renauld, J.-C., Vosshenrich, C.A.J., and Di Santo, J.P. (2009) The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium. Journal of Immunology 183:6579-6587.



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Activity Reports 2009 - Institut Pasteur
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