Cytokines and Lymphoid Development - INSERM U 668  


  HEADProf. Di SANTO James / disanto@pasteur.fr
  MEMBERSDr ALVES Nuno / BORDACK Allison / CORCUFF Erwan / Dr DECALUWE Hélène / ELKABETS Moshe / Dr GUY-GRAND Delphine / Dr HASAN Milena / Dr HUNTINGTON Nicholas
LESJEAN-POTTIER Sarah / PHAM Cécile / RIBEIRO Vera / RICHARD-LE GOFF Odile / Dr SATOH Naoko / Dr STRICK-MARCHAND Hélène / Dr VOSSHENRICH Christian


  Annual Report

Our research aims to better define the essential roles of cytokines and their receptors in lymphoid homeostasis and during immune responses. We have developed an alymphoid mouse model 1) to study the genetic program which controls NK cell differentiation and 2) for xenotransplantation of human tissues. Collectively, these projects should enrich our understanding of normal immune development and immune responses, and may help design rational new therapies for pathological conditions such as immunodeficiency and autoimmunity.

Signals for lymphocyte differentiation and homeostasis : We have identified downstream transcriptional targets of common g chain cytokines (gc) in naïve and activated CD4+ T cells and have uncovered a novel role for IL-15 in the differentiation of Th1-polarized CD4 T cells. These data suggest that gc cytokines control a late checkpoint in the T cell differentiation process. We are currently constructing reporter mice that will ‘read out’ expression of gc cytokines known to be involved in T cell homeostasis.

Transcription factors in lymphocyte specification : We have identified two novel roles for the transcription factor GATA-3 in early lymphocyte development. First, GATA-3 plays an essential role in T cell specification by acting in concert with Notch signal to suppress B cell differentiation in the thymus. As such, GATA-3 seals T cell commitment of early lymphoid precursors. Second, GATA-3 identifies a thymic pathway of natural killer (NK) cell development. Thymic NK cells have particular phenotypic and functional characteristics and appear similar to one subset of human NK cells. This suggests an evolutionary conserved ‘division of labor’ for NK cell function in immunity. Lastly, we showed that recently described ‘interferon-producing killer dendritic cells’ are activated NK cells that express dendritic cells markers.

Alymphoid mice to study infectious processes : We have previously studied the role for lymphocyte subsets in the immune response to L monocytogenes and S flexneri. We found that immune cells can condition the inflammatory response to pathogenic micro-organisms. This « immune component » could potentially extend to protection against pathogens that are normally controlled by non-lymphoid hematopoietic cells. We are infecting Rag2/gc mice with different pathogens (enteric E coli, Aspergillus and C Albicans) in order to develop new models for testing antimicrobials.

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 conditioning protocols (stimulation of tissue regeneration or irradiation) maximize human cell engraftment. We are developing a human immune system / liver chimeric model in Rag2/gc mice to study HCV infection (‘Grand Challenges for Global Health’ grant).

Keywords: Lymphopoiesis, cytokines, transcription factors, xenotransplantation, immunodeficiency



  Publications

Le Barillec, K., Gamelas, J., Corcuff, E., Thuizat, A., Sansonetti, P.J., Phalipon, A. and Di Santo, J.P. (2005) Roles for T and NK cells in the innate immune response to Shigella flexneri. Journal of Immunology 175:1735-40. PMID: 16034114

Di Santo, J.P. (2006) Natural Killer Cell Developmental Pathways : A Question of Balance. Annual Review of Immunology 24:257-86. PMID: 16551250

Vosshenrich, C.A.J., García-Ojeda, M.E., Samson-Villeger, S.I., Pasquelleto, 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. (2006) A thymic pathway of murine natural killer cell development characterized by Gata3 and interleukin-7 receptor expression. Nature Immunology 7:1217-1224. PMID: 17013389

Masse, G.X., Corcuff, E., Strick-Marchand, H., Guy-Grand, D., Tafuri-Bladt, A., Albert, M.L., Lantz, O. and Di Santo, J.P. (2007) gc cytokines condition the progressive differentiation of CD4+ T cells. Proceedings of the National Academy of Sciences (USA) 104:15442-15447. PMID: 17855567

Vosshenrich, C.A.J., Lesjean-Pottier, S., Hasan, M., Richard-Le Goff, O., Corcuff, O., Mandelboim, O. and Di Santo, J.P. (2007) CD11cloB220+ Interferon-producing killer dendritic cells are activated NK cells. Journal of Experimental Medicine 240:2569-2578. PMID: 17923507





Activity Reports 2007 - Institut Pasteur
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