Cytokines and Lymphoid Development - INSERM U668  

  HEADDr Di SANTO James /
  MEMBERSDr DECALUWE Hélène / ENAULT Laurence / Dr GUY-GRAND Delphine / Dr HASAN Milena
Dr HUNTINGTON Nicholas / MASSE Guillemette / Dr STRICK-MARCHAND Hélène / Dr VOSSHENRICH Christian

  Annual Report

Our projects seek to better define the essential roles of gc–dependent cytokines and their receptors in lymphopoiesis, peripheral lymphoid homeostasis and during immune responses. We have developed a unique 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 gc cytokines 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.

Alymphoid mice to study infectious processes : We have previously used alymphoid mice to study the role for different 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 assessing the susceptibility of Rag2/gc mice to several different bacterial pathogens (including enteric infection by pathogenic E coli, pulmonary infection by Aspergillus and mucosal infection by C Albicans), which could lead to the development of novel mouse models for testing and developing new antimicrobials.

Human xenografts in mice : 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. W are developing a human immune system / liver chimeric model in Rag2/gc mice to study HCV infection (‘Grand Challenges for Global Health’ grant).


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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