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 T cell differentiation process. IL-7-GFP reporter mice that identify the thymic IL-7 ‘niche’ have been characterized (Alves et al , PNAS, in press).

Factors that condition NK cell diversity :
Thymic and intestinal NK cells have been characterized that have unusual phenotypic and functional characteristics and dépend on specific transcription factors (GATA-3 and RORgt, respectively). We also showed that activated NK cells can bear dendritic cell markers .These results iindicate that NK cell phénotypes are not homogeneous, but differ dependent on the tissue and state of activation. Our hypothesis is that diverse subsets of NK cells perform uniques (non-stereotyped) roles in immunity.

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 more 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. Using Rag2/gc mice we have generated new models for testing antimicrobials against different pathogens (enteric E coli, Aspergillus and C Albicans).

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).

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

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) CD11c^loB220⁺ Interferon-producing killer dendritic cells are activated NK cells. Journal of Experimental Medicine 240:2569-2578. PMID: 17923507

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). Epub 2008 Dec 22. PMID: 19103877