James P. Di Santo
French Institute of Health and Medical Research
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Publication
Featured researches published by James P. Di Santo.
Nature Reviews Immunology | 2013
Hergen Spits; David Artis; Marco Colonna; Andreas Diefenbach; James P. Di Santo; Gérard Eberl; Shigeo Koyasu; Richard M. Locksley; Andrew N. J. McKenzie; Reina E. Mebius; Fiona Powrie; Eric Vivier
Innate lymphoid cells (ILCs) are a family of developmentally related cells that are involved in immunity and in tissue development and remodelling. Recent research has identified several distinct members of this family. Confusingly, many different names have been used to characterize these newly identified ILC subsets. Here, we propose that ILCs should be categorized into three groups based on the cytokines that they can produce and the transcription factors that regulate their development and function.
Immunity | 2008
Naoko Satoh-Takayama; Christian A. J. Vosshenrich; Sarah Lesjean-Pottier; Shinichiro Sawa; Matthias Lochner; Frédérique Rattis; Jean-Jacques Mention; Kader Thiam; Nadine Cerf-Bensussan; Ofer Mandelboim; Gérard Eberl; James P. Di Santo
Natural killer (NK) cells are innate lymphocytes with spontaneous antitumor activity, and they produce interferon-gamma (IFN-gamma) that primes immune responses. Whereas T helper cell subsets differentiate from naive T cells via specific transcription factors, evidence for NK cell diversification is limited. In this report, we characterized intestinal lymphocytes expressing the NK cell natural cytotoxicity receptor NKp46. Gut NKp46+ cells were distinguished from classical NK cells by limited IFN-gamma production and absence of perforin, whereas several subsets expressed the nuclear hormone receptor retinoic acid receptor-related orphan receptor t (RORgammat) and interleukin-22 (IL-22). Intestinal NKp46+IL-22+ cells were generated via a local process that was conditioned by commensal bacteria and required RORgammat. Mice lacking IL-22-producing NKp46+ cells showed heightened susceptibility to the pathogen Citrobacter rodentium, consistent with a role for intestinal NKp46+ cells in immune protection. RORgammat-driven diversification of intestinal NKp46+ cells thereby specifies an innate cellular defense mechanism that operates at mucosal surfaces.
Nature Immunology | 2011
Hergen Spits; James P. Di Santo
Research has identified what can be considered a family of innate lymphoid cells (ILCs) that includes not only natural killer (NK) cells and lymphoid tissue–inducer (LTi) cells but also cells that produce interleukin 5 (IL-5), IL-13, IL-17 and/or IL-22. These ILC subsets are developmentally related, requiring expression of the transcriptional repressor Id2 and cytokine signals through the common γ-chain of the IL-2 receptor. The functional differentiation of ILC subsets is orchestrated by distinct transcription factors. Analogous to helper T cell subsets, these evolutionarily conserved yet distinct ILCs seem to have important roles in protective immunity, and their dysregulation can promote immune pathology.
Nature | 2011
Kosuke Yusa; S. Tamir Rashid; Helene Strick-Marchand; Ignacio Varela; Pei Qi Liu; David Paschon; Elena Miranda; Adriana Ordóñez; Nicholas Hannan; Foad Rouhani; Sylvie Darche; Graeme J. M. Alexander; Stefan J. Marciniak; Noemi Fusaki; Mamoru Hasegawa; Michael C. Holmes; James P. Di Santo; David A. Lomas; Allan Bradley; Ludovic Vallier
Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α1-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α1-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.
Immunology Today | 2000
Martin Turner; Edina Schweighoffer; Francesco Colucci; James P. Di Santo; Victor L. J. Tybulewicz
The tyrosine kinase SYK plays critical roles in signalling through immune receptors. Gene-targeting studies have identified the cell types that require SYK for development and function, and the receptors that use SYK as well as their downstream signalling effectors. There is also evidence of a role for SYK in non-immune cells and in the maintenance of vascular integrity.
Journal of Experimental Medicine | 2008
Matthias Lochner; Lucie Peduto; Marie Cherrier; Shinichiro Sawa; Francina Langa; Rosa Varona; Dieter Riethmacher; Mustapha Si-Tahar; James P. Di Santo; Gérard Eberl
The nuclear hormone receptor retinoic acid receptor–related orphan receptor γt (RORγt) is required for the generation of T helper 17 cells expressing the proinflammatory cytokine interleukin (IL)-17. In vivo, however, less than half of RORγt+ T cells express IL-17. We report here that RORγt+ Tαβ cells include Foxp3+ cells that coexist with IL-17–producing RORγt+ Tαβ cells in all tissues examined. The Foxp3+ RORγt+ Tαβ express IL-10 and CCL20, and function as regulatory T cells. Furthermore, the ratio of Foxp3+ to IL-17–producing RORγt+ Tαβ cells remains remarkably constant in mice enduring infection and inflammation. This equilibrium is tuned in favor of IL-10 production by Foxp3 and CCL20, and in favor of IL-17 production by IL-6 and IL-23. In the lung and skin, the largest population of RORγt+ T cells express the γδ T cell receptor and produce the highest levels of IL-17 independently of IL-6. Thus, potentially antagonistic proinflammatory IL-17–producing and regulatory Foxp3+ RORγt+ T cells coexist and are tightly controlled, suggesting that a perturbed equilibrium in RORγt+ T cells might lead to decreased immunoreactivity or, in contrast, to pathological inflammation.
Nature Immunology | 2006
Christian A. J. Vosshenrich; Marcos E García-Ojeda; Sandrine I Samson-Villéger; Valérie Pasqualetto; Laurence Enault; Odile Richard-Le Goff; Erwan Corcuff; Delphine Guy-Grand; Benedita Rocha; Ana Cumano; Lars Rogge; Sophie Ezine; James P. Di Santo
Natural killer (NK) cell development is thought to occur in the bone marrow. Here we identify the transcription factor GATA-3 and CD127 (IL-7Rα) as molecular markers of a pathway of mouse NK cell development that originates in the thymus. Thymus-derived CD127+ NK cells repopulated peripheral lymphoid organs, and their homeostasis was strictly dependent on GATA-3 and interleukin 7. The CD127+ NK cells had a distinct phenotype (CD11bloCD16−CD69hiLy49lo) and unusual functional attributes, including reduced cytotoxicity but considerable cytokine production. Those characteristics are reminiscent of human CD56hiCD16− NK cells, which we found expressed CD127 and had more GATA-3 expression than human CD56+CD16+ NK cells. We propose that bone marrow and thymic NK cell pathways generate distinct mouse NK cells with properties similar to those of the two human CD56 NK cell subsets.
Hepatology | 2010
Thomas Touboul; Nicholas Hannan; Sébastien Corbineau; Amélie Martinez; Clémence Martinet; Sophie Branchereau; Sylvie Mainot; Helene Strick-Marchand; Roger A. Pedersen; James P. Di Santo; Anne Weber; Ludovic Vallier
Generation of hepatocytes from human embryonic stem cells (hESCs) could represent an advantageous source of cells for cell therapy approaches as an alternative to orthotopic liver transplantation. However, the generation of differentiated hepatocytes from hESCs remains a major challenge, especially using a method compatible with clinical applications. We report a novel approach to differentiate hESCs into functional hepatic cells using fully defined culture conditions, which recapitulate essential stages of liver development. hESCs were first differentiated into a homogenous population of endoderm cells using a combination of activin, fibroblast growth factor 2, and bone morphogenetic protein 4 together with phosphoinositide 3‐kinase inhibition. The endoderm cells were then induced to differentiate further into hepatic progenitors using fibroblast growth factor 10, retinoic acid, and an inhibitor of activin/nodal receptor. After further maturation, these cells expressed markers of mature hepatocytes, including asialoglycoprotein receptor, tyrosine aminotransferase, α1‐antitrypsin, Cyp7A1, and hepatic transcription factors such as hepatocyte nuclear factors 4α and 6. Furthermore, the cells generated under these conditions exhibited hepatic functions in vitro, including glycogen storage, cytochrome activity, and low‐density lipoprotein uptake. After transduction with a green fluorescent protein–expressing lentivector and transplantation into immunodeficient uPA transgenic mice, differentiated cells engrafted into the liver, grew, and expressed human albumin and α1‐antitrypsin as well as green fluorescent protein for at least 8 weeks. In addition, we showed that hepatic cells could be generated from human‐induced pluripotent cells derived from reprogrammed fibroblasts, demonstrating the efficacy of this approach with pluripotent stem cells of diverse origins. Conclusion: We have developed a robust and efficient method to differentiate pluripotent stem cells into hepatic cells, which exhibit characteristics of human hepatocytes. Our approach should facilitate the development of clinical grade hepatocytes for transplantation and for research on drug discovery. (HEPATOLOGY 2010.)
Nature Immunology | 2011
Shinichiro Sawa; Matthias Lochner; Naoko Satoh-Takayama; Sophie Dulauroy; Marion Bérard; Melanie A. Kleinschek; Daniel J. Cua; James P. Di Santo; Gerard Eberl
Lymphoid cells that express the nuclear hormone receptor RORγt are involved in containment of the large intestinal microbiota and defense against pathogens through the production of interleukin 17 (IL-17) and IL-22. They include adaptive IL-17-producing helper T cells (TH17 cells), as well as innate lymphoid cells (ILCs) such as lymphoid tissue–inducer (LTi) cells and IL-22-producing NKp46+ cells. Here we show that in contrast to TH17 cells, both types of RORγt+ ILCs constitutively produced most of the intestinal IL-22 and that the symbiotic microbiota repressed this function through epithelial expression of IL-25. This function was greater in the absence of adaptive immunity and was fully restored and required after epithelial damage, which demonstrates a central role for RORγt+ ILCs in intestinal homeostasis. Our data identify a finely tuned equilibrium among intestinal symbionts, adaptive immunity and RORγt+ ILCs.
Journal of Experimental Medicine | 2009
Nicholas D. Huntington; Nicolas Legrand; Nuno L. Alves; Barbara Jaron; Kees Weijer; Ariane Plet; Erwan Corcuff; Erwan Mortier; Yannick Jacques; Hergen Spits; James P. Di Santo
The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self–major histocompatability complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2−/−γc−/− mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor α (IL-15Rα) significantly augmented human NK cells. IL-15–IL-15Rα complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16+KIR+ NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56hiCD16−KIR− to CD56loCD16+KIR−, and finally to CD56loCD16+KIR+. These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15–responsive cells during immunotherapy strategies.