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. 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.

Innate Lymphoid 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). These represent innate versions of Th1 and Th22 subsets, respectively. Other groups have identified innate Th2 and Th17 subsets. Together these form a related family of innate lymphoid cells (ILC). We have identified the cytokines that drive development of some of these different ILC subsets.  ILC diversity provides early immune protection against infection and may be involved in normal and pathological tissue remodeling.

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

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 206:25-34. 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., Lesjean-Pottier, S., Vieira, P., Sawa, S., Eberl, G., Vosshenrich, C.A. and Di Santo, J.P. (2010) IL-7 and IL-15 independently program the differentiation of intestinal CD3^-NKp46⁺ cell subsets from Id2-dependent precursors. Journal of Experimental Medicine 207:273-280.

Decaluwe, H., Taillardet, M., Corcuff, E., Munitic, I., Law, H.K.W., Rocha, B., Rivière, Y. and Di Santo, J.P. (2010) gc deficiency precludes CD8⁺ T cell memory despite formation of potent T cell effectors. Proceedings of the National Academy of Sciences (USA) 107:9311-9316.

Ribeiro, V.S.G., Hasan, M., Wilson, A., Boucontet, L., Pereira, P., Lesjean-Pottier, S., Satoh-Takayama, N., Di Santo, J.P. and Vosshenrich, C.A.J. (2010) Cutting Edge: Thymic NK cells develop independently from T cell precursors. Journal of Immunology 185:4993-4997.