Publications by authors named "Nicolas Serafini"

24 Publications

  • Page 1 of 1

Group 3 innate lymphoid cells mediate host defense against attaching and effacing pathogens.

Curr Opin Microbiol 2021 Jul 15;63:83-91. Epub 2021 Jul 15.

Innate Immunity Unit, Institut Pasteur, Inserm U1223, Paris, France. Electronic address:

Group 3 innate lymphoid cells (ILC3) are innate effector cells that have essential roles in lymphoid organogenesis and maintenance of tissue homeostasis under steady-state and pathogenic conditions. ILC3 also promote immune defense, notably during bacterial breach of epithelial barriers, including those caused by attaching and effacing (A/E) pathogens for which Citrobacter rodentium infection in mice is a relevant pre-clinical model. Through their ability to sustain interactions with tissue-resident immune cells, epithelial cells, neurons or stromal cells, ILC3 constitute a key orchestrator that maintains the intestinal barrier. In this review, we will examine the function of murine ILC3 in host defense against C. rodentium infection and provide a discussion of recent advances that help elucidate the specific roles of these novel innate immune effector cells at mucosal surfaces.
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http://dx.doi.org/10.1016/j.mib.2021.06.005DOI Listing
July 2021

Host genetic control of natural killer cell diversity revealed in the Collaborative Cross.

Proc Natl Acad Sci U S A 2021 Mar;118(10)

Innate Immunity Unit, Immunology Department, Institut Pasteur, 75724 Paris, France;

Natural killer (NK) cells are innate effectors armed with cytotoxic and cytokine-secreting capacities whose spontaneous antitumor activity is key to numerous immunotherapeutic strategies. However, current mouse models fail to mirror the extensive immune system variation that exists in the human population which may impact on NK cell-based therapies. We performed a comprehensive profiling of NK cells in the Collaborative Cross (CC), a collection of novel recombinant inbred mouse strains whose genetic diversity matches that of humans, thereby providing a unique and highly diverse small animal model for the study of immune variation. We demonstrate that NK cells from CC strains displayed a breadth of phenotypic and functional variation reminiscent of that reported for humans with regards to cell numbers, key marker expression, and functional capacities. We took advantage of the vast genetic diversity of the CC and identified nine genomic loci through quantitative trait locus mapping driving these phenotypic variations. SNP haplotype patterns and variant effect analyses identified candidate genes associated with lung NK cell numbers, frequencies of CD94 NK cells, and expression levels of NKp46. Thus, we demonstrate that the CC represents an outstanding resource to study NK cell diversity and its regulation by host genetics.
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http://dx.doi.org/10.1073/pnas.2018834118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958182PMC
March 2021

Microbiota stimulation generates LCMV-specific memory CD8 T cells in SPF mice and determines their TCR repertoire during LCMV infection.

Mol Immunol 2020 08 17;124:125-141. Epub 2020 Jun 17.

Population Biology Unit, CNRS URA 196, Institut Pasteur, Paris 75015, France; INSERM, U1151, CNRS, UMR8253, Institut Necker Enfants Malades, Université Paris Descartes, Paris 75015, France. Electronic address:

Both mouse and human harbour memory phenotype CD8 T cells specific for antigens in hosts that have not been previously exposed to these antigens. The origin and the nature of the stimuli responsible for generation of CD44 CD8 T cells in specific pathogen-free (SPF) mice remain controversial. It is known that microbiota plays a crucial role in the prevention and resolution of systemic infections by influencing myelopoiesis, regulating dendritic cells, inflammasome activation and promoting the production of type I and II interferons. By contrast, here we suggest that microbiota has a direct effect on generation of memory phenotype CD44GP33CD8 T cells. In SPF mice, it generates a novel GP33CD44CD8 T cell sub-population associating the properties of innate and genuine memory cells. These cells are highly enriched in the bone marrow, proliferate rapidly and express immediate effector functions. They dominate the response to LCMV and express particular TCRβ chains. The sequence of these selected TCRβ chains overlaps with that of GP33CD8 T cells directly selected by microbiota in the gut epithelium of SPF mice, demonstrating a common selection mechanism in gut and peripheral CD8 T cell pool. Therefore microbiota has a direct role in priming T cell immunity in SPF mice and in the selection of TCRβ repertoires during systemic infection. We identify a mechanism that primes T cell immunity in SPF mice and may have a major role in colonization resistance and protection from infection.
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http://dx.doi.org/10.1016/j.molimm.2020.05.012DOI Listing
August 2020

An Id2-Reporter Mouse Redefines Innate Lymphoid Cell Precursor Potentials.

Immunity 2019 04 26;50(4):1054-1068.e3. Epub 2019 Mar 26.

Innate Immunity Unit, Institut Pasteur, Paris 75724, France; Inserm U1223, Institut Pasteur, Paris 75724, France. Electronic address:

Innate lymphoid cell (ILC) development proposes that ILC precursors (ILCPs) segregate along natural killer (NK) cell versus helper cell (ILC1, ILC2, ILC3) pathways, the latter depending on expression of Id2, Zbtb16, and Gata3. We have developed an Id2-reporter strain expressing red fluorescent protein (RFP) in the context of normal Id2 expression to re-examine ILCP phenotype and function. We show that bone-marrow ILCPs were heterogeneous and harbored extensive NK-cell potential in vivo and in vitro. By multiplexing Id2 with Zbtb16 and Bcl11b strains, we made a single-cell dissection of the ILCP compartment. In contrast with the current model, we have demonstrated that Id2Zbtb16 ILCPs included multi-potent ILCPs that retained NK-cell potential. Late-stage ILC2P and ILC3P compartments could be defined by differential Zbtb16 and Bcl11b expression. We suggest a revised model for ILC differentiation that redefines the cell-fate potential of helper-ILC-restricted Zbtb16 ILCPs.
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http://dx.doi.org/10.1016/j.immuni.2019.02.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477155PMC
April 2019

The Citrobacter rodentium type III secretion system effector EspO affects mucosal damage repair and antimicrobial responses.

PLoS Pathog 2018 10 26;14(10):e1007406. Epub 2018 Oct 26.

MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London, United Kingdom.

Infection with Citrobacter rodentium triggers robust tissue damage repair responses, manifested by secretion of IL-22, in the absence of which mice succumbed to the infection. Of the main hallmarks of C. rodentium infection are colonic crypt hyperplasia (CCH) and dysbiosis. In order to colonize the host and compete with the gut microbiota, C. rodentium employs a type III secretion system (T3SS) that injects effectors into colonic intestinal epithelial cells (IECs). Once injected, the effectors subvert processes involved in innate immune responses, cellular metabolism and oxygenation of the mucosa. Importantly, the identity of the effector/s triggering the tissue repair response is/are unknown. Here we report that the effector EspO ,an orthologue of OspE found in Shigella spp, affects proliferation of IECs 8 and 14 days post C. rodentium infection as well as secretion of IL-22 from colonic explants. While we observed no differences in the recruitment of group 3 innate lymphoid cells (ILC3s) and T cells, which are the main sources of IL-22 at the early and late stages of C. rodentium infection respectively, infection with ΔespO was characterized by diminished recruitment of sub-mucosal neutrophils, which coincided with lower abundance of Mmp9 and chemokines (e.g. S100a8/9) in IECs. Moreover, mice infected with ΔespO triggered significantly lesser nutritional immunity (e.g. calprotectin, Lcn2) and expression of antimicrobial peptides (Reg3β, Reg3γ) compared to mice infected with WT C. rodentium. This overlapped with a decrease in STAT3 phosphorylation in IECs. Importantly, while the reduced CCH and abundance of antimicrobial proteins during ΔespO infection did not affect C. rodentium colonization or the composition of commensal Proteobacteria, they had a subtle consequence on Firmicutes subpopulations. EspO is the first bacterial virulence factor that affects neutrophil recruitment and secretion of IL-22, as well as expression of antimicrobial and nutritional immunity proteins in IECs.
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http://dx.doi.org/10.1371/journal.ppat.1007406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221368PMC
October 2018

Peyer's patch myeloid cells infection by signals through gp38 stromal cells and locks intestinal villus invasion.

J Exp Med 2018 11 24;215(11):2936-2954. Epub 2018 Oct 24.

Institut Pasteur, Biology of Infection Unit, Paris, France

The foodborne pathogen () crosses the intestinal villus epithelium via goblet cells (GCs) upon the interaction of surface protein InlA with its receptor E-cadherin. Here, we show that infection accelerates intestinal villus epithelium renewal while decreasing the number of GCs expressing luminally accessible E-cadherin, thereby locking portal of entry. This novel innate immune response to an enteropathogen is triggered by the infection of Peyer's patch CX3CR1 cells and the ensuing production of IL-23. It requires STAT3 phosphorylation in epithelial cells in response to IL-22 and IL-11 expressed by lamina propria gp38 stromal cells. -induced IFN-γ signaling and STAT1 phosphorylation in epithelial cells is also critical for -associated intestinal epithelium response. GC depletion also leads to a decrease in colon mucus barrier thickness, thereby increasing host susceptibility to colitis. This study unveils a novel innate immune response to an enteropathogen, which implicates gp38 stromal cells and locks intestinal villus invasion, but favors colitis.
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http://dx.doi.org/10.1084/jem.20181210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219733PMC
November 2018

A human immune system mouse model with robust lymph node development.

Nat Methods 2018 08 31;15(8):623-630. Epub 2018 Jul 31.

Innate Immunity Unit, Institut Pasteur, Paris, France.

Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2Il2rgSirpa (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (T) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN T cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.
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http://dx.doi.org/10.1038/s41592-018-0071-6DOI Listing
August 2018

Innate Lymphoid Cell Development: A T Cell Perspective.

Immunity 2018 06;48(6):1091-1103

Innate Immunity Unit, Institut Pasteur, Paris 75015, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1223, Paris 75015, France. Electronic address:

Innate lymphoid cells (ILCs) and natural killer (NK) cells have garnered considerable interest due to their unique functional properties in immune defense and tissue homeostasis. Our current understanding of how these cells develop has been greatly facilitated by knowledge of T cell biology. Models of T cell differentiation provided the basis for a conceptual classification of these innate effectors and inspired a scheme of their activation and regulation. In this review, we discuss NK cell and ILC development from a "T cell standpoint" in an attempt to extend the analogy between adaptive T cells and their innate ILC and NK cell counterparts.
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http://dx.doi.org/10.1016/j.immuni.2018.05.010DOI Listing
June 2018

Intrathymic Deletion of IL-7 Reveals a Contribution of the Bone Marrow to Thymic Rebound Induced by Androgen Blockade.

J Immunol 2018 02 10;200(4):1389-1398. Epub 2018 Jan 10.

Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal;

Despite the well-documented effect of castration in thymic regeneration, the singular contribution of the bone marrow (BM) versus the thymus to this process remains unclear. The chief role of IL-7 in pre- and intrathymic stages of T lymphopoiesis led us to investigate the impact of disrupting this cytokine during thymic rebound induced by androgen blockade. We found that castration promoted thymopoiesis in young and aged wild-type mice. In contrast, only young germline IL-7-deficient ( ) mice consistently augmented thymopoiesis after castration. The increase in T cell production was accompanied by the expansion of the sparse medullary thymic epithelial cell and the peripheral T cell compartment in young mice. In contrast to young and wild-type mice, the poor thymic response of aged mice after castration was associated with a defect in the expansion of BM hematopoietic progenitors. These findings suggest that BM-derived T cell precursors contribute to thymic rebound driven by androgen blockade. To assess the role of IL-7 within the thymus, we generated mice with conditional deletion of IL-7 ( conditional knockout [cKO]) in thymic epithelial cells. As expected, cKO mice presented a profound defect in T cell development while maintaining an intact BM hematopoietic compartment across life. Unlike mice, castration promoted the expansion of BM precursors and enhanced thymic activity in cKO mice independently of age. Our findings suggest that the mobilization of BM precursors acts as a prime catalyst of castration-driven thymopoiesis.
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http://dx.doi.org/10.4049/jimmunol.1701112DOI Listing
February 2018

A functional DC cross talk promotes human ILC homeostasis in humanized mice.

Blood Adv 2017 Apr 6;1(10):601-614. Epub 2017 Apr 6.

Innate Immunity Unit, Institut Pasteur, Paris, France.

Humanized mice harboring human hematopoietic systems offer a valuable small-animal model to assess human immune responses to infection, inflammation, and cancer. Human immune system (HIS) mice develop a broad repertoire of antigen receptor bearing B and T cells that can participate in adaptive immune responses after immunization. In contrast, analysis of innate immune components, including innate lymphoid cells (ILCs) and natural killer (NK) cells, is limited in current HIS mouse models, partly because of the poor development of these rare lymphoid subsets. Here we show that novel dendritic cell (DC)-boosted BALB/c (BRGSF) HIS mice harbor abundant NK cells and tissue-resident ILC subsets in lymphoid and nonlymphoid mucosal sites. We find that human NK cells and ILCs are phenotypically and functionally mature and provide evidence that human DC activation in BRGSF-based HIS mice can "cross talk" to human NK cells and ILCs. This novel HIS mouse model should provide the opportunity to study the immunobiology of human NK cell and ILC subsets in vivo in response to various environmental challenges.
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http://dx.doi.org/10.1182/bloodadvances.2017004358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728352PMC
April 2017

Lactobacillus paracasei feeding improves immune control of influenza infection in mice.

PLoS One 2017 20;12(9):e0184976. Epub 2017 Sep 20.

Bioaster, Paris, France.

Respiratory tract infections such as flu cause severe morbidity and mortality and are among the leading causes of death in children and adults worldwide. Commensal microbiota is critical for orchestrating tissue homeostasis and immunity in the intestine. Probiotics represent an interesting source of immune modulators and several clinical studies have addressed the potential beneficial effects of probiotics against respiratory infections. Therefore, we have investigated the mechanisms of protection conferred by L. paracasei CNCM I-1518 strain in a mouse model of influenza infection. Notably, local myeloid cells accumulation is generated in the lungs after seven days feeding with L. paracasei prior to viral infection. L. paracasei-fed mice showed reduced susceptibility to the influenza infection, associated with less accumulation of inflammatory cells in the lungs, faster viral clearance and general health improvement. Interestingly, Allobaculum was significantly increased in L. paracasei-fed mice 7 days after influenza infection, even if the gut microbiota composition was not altered overall. L. paracasei-purified peptidoglycan partially recapitulated the protective phenotype observed with the entire bacteria. Collectively, our results demonstrate that oral consumption of L. paracasei CNCM I-1518 modulates lung immunity was associated with an improved control of influenza infection. These results further extend the beneficial role for certain lactobacilli to alleviate the burden of respiratory tract infections.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607164PMC
October 2017

Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation.

Cell 2017 03;168(6):1086-1100.e10

Innate Immunity Unit, Institut Pasteur, 75724 Paris, France; Inserm U1223, 75015 Paris, France. Electronic address:

Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES natural killer (NK) cells, interferon gamma-positive (IFN-γ) ILC1s, interleukin (IL)-13 ILC2s, and for IL-22, but not for IL-17A ILC3s. Our results support a model of tissue ILC differentiation ("ILC-poiesis"), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.
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http://dx.doi.org/10.1016/j.cell.2017.02.021DOI Listing
March 2017

The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome.

Cell 2016 Aug 18;166(5):1231-1246.e13. Epub 2016 Aug 18.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. Here, we combine genome-wide RNA-seq, ChIP-seq, and ATAC-seq to compare the transcriptional and epigenetic identity of small intestinal ILCs, identifying thousands of distinct gene profiles and regulatory elements. Single-cell RNA-seq and flow and mass cytometry analyses reveal compartmentalization of cytokine expression and metabolic activity within the three classical ILC subtypes and highlight transcriptional states beyond the current canonical classification. In addition, using antibiotic intervention and germ-free mice, we characterize the effect of the microbiome on the ILC regulatory landscape and determine the response of ILCs to microbial colonization at the single-cell level. Together, our work characterizes the spectrum of transcriptional identities of small intestinal ILCs and describes how ILCs differentially integrate signals from the microbial microenvironment to generate phenotypic and functional plasticity.
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http://dx.doi.org/10.1016/j.cell.2016.07.043DOI Listing
August 2016

Phenotypic and Functional Plasticity of Murine Intestinal NKp46+ Group 3 Innate Lymphoid Cells.

J Immunol 2016 06 22;196(11):4731-8. Epub 2016 Apr 22.

Unité d'Immunité Innée, Institut Pasteur, 75724 Paris, France; INSERM U1223, 75724 Paris, France;

Group 3 innate lymphoid cells (ILC3) actively participate in mucosal defense and homeostasis through prompt secretion of IL-17A, IL-22, and IFN-γ. Reports identify two ILC3 lineages: a CCR6(+)T-bet(-) subset that appears early in embryonic development and promotes lymphoid organogenesis and a CCR6(-)T-bet(+) subset that emerges after microbial colonization and harbors NKp46(+) ILC3. We demonstrate that NKp46 expression in the ILC3 subset is highly unstable. Cell fate mapping using Ncr1(CreGFP) × Rosa26(RFP) mice revealed the existence of an intestinal RFP(+) ILC3 subset (Ncr1(FM)) lacking NKp46 expression at the transcript and protein levels. Ncr1(FM) ILC3 produced more IL-22 and were distinguishable from NKp46(+) ILC3 by differential CD117, CD49a, DNAX accessory molecule-1, and, surprisingly, CCR6 expression. Ncr1(FM) ILC3 emerged after birth and persisted in adult mice following broad-spectrum antibiotic treatment. These results identify an unexpected phenotypic instability within NKp46(+) ILC3 that suggests a major role for environmental signals in tuning ILC3 functional plasticity.
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http://dx.doi.org/10.4049/jimmunol.1502673DOI Listing
June 2016

Transcriptional regulation of innate lymphoid cell fate.

Nat Rev Immunol 2015 Jul 12;15(7):415-28. Epub 2015 Jun 12.

Innate Immunity Unit, Institut Pasteur, Paris 75015, and the Institut National de la Santé et de la Recherche Médicale (INSERM) U668, Paris 75015, France.

Innate lymphoid cells (ILCs) are a recently described family of lymphoid effector cells that have important roles in immune defence, inflammation and tissue remodelling. It has been proposed that ILCs represent 'innate' homologues of differentiated effector T cells, and they have been categorized into three groups — namely, ILC1s, ILC2s and ILC3s — on the basis of their expression of cytokines and transcription factors that are typically associated with T helper 1 (T(H)1)-, T(H)2- and T(H)17-type immune responses, respectively. Indeed, remarkable similarity is seen between the specific transcription factors required for the development and diversification of different ILC groups and those that drive effector T cell differentiation. The recent identification of dedicated ILC precursors has provided a view of the mechanisms that control this first essential stage of ILC development. Here, we discuss the transcriptional mechanisms that regulate ILC development and diversification into distinct effector subsets with key roles in immunity and tissue homeostasis. We further caution against the current distinction between 'helper' versus 'killer' subsets in the evolving area of ILC nomenclature.
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http://dx.doi.org/10.1038/nri3855DOI Listing
July 2015

Trpm4 gene invalidation leads to cardiac hypertrophy and electrophysiological alterations.

PLoS One 2014 22;9(12):e115256. Epub 2014 Dec 22.

INSERM U1046, Université Montpellier1, Université Montpellier2, Montpellier, France.

Rationale: TRPM4 is a non-selective Ca2+-activated cation channel expressed in the heart, particularly in the atria or conduction tissue. Mutations in the Trpm4 gene were recently associated with several human conduction disorders such as Brugada syndrome. TRPM4 channel has also been implicated at the ventricular level, in inotropism or in arrhythmia genesis due to stresses such as ß-adrenergic stimulation, ischemia-reperfusion, and hypoxia re-oxygenation. However, the physiological role of the TRPM4 channel in the healthy heart remains unclear.

Objectives: We aimed to investigate the role of the TRPM4 channel on whole cardiac function with a Trpm4 gene knock-out mouse (Trpm4-/-) model.

Methods And Results: Morpho-functional analysis revealed left ventricular (LV) eccentric hypertrophy in Trpm4-/- mice, with an increase in both wall thickness and chamber size in the adult mouse (aged 32 weeks) when compared to Trpm4+/+ littermate controls. Immunofluorescence on frozen heart cryosections and qPCR analysis showed no fibrosis or cellular hypertrophy. Instead, cardiomyocytes in Trpm4-/- mice were smaller than Trpm4+/+with a higher density. Immunofluorescent labeling for phospho-histone H3, a mitosis marker, showed that the number of mitotic myocytes was increased 3-fold in the Trpm4-/-neonatal stage, suggesting hyperplasia. Adult Trpm4-/- mice presented multilevel conduction blocks, as attested by PR and QRS lengthening in surface ECGs and confirmed by intracardiac exploration. Trpm4-/-mice also exhibited Luciani-Wenckebach atrioventricular blocks, which were reduced following atropine infusion, suggesting paroxysmal parasympathetic overdrive. In addition, Trpm4-/- mice exhibited shorter action potentials in atrial cells. This shortening was unrelated to modifications of the voltage-gated Ca2+ or K+ currents involved in the repolarizing phase.

Conclusions: TRPM4 has pleiotropic roles in the heart, including the regulation of conduction and cellular electrical activity which impact heart development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115256PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274076PMC
August 2015

The chemokine receptor CXCR6 controls the functional topography of interleukin-22 producing intestinal innate lymphoid cells.

Immunity 2014 Nov 6;41(5):776-88. Epub 2014 Nov 6.

Innate Immunity Unit, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France; Inserm U668, 75724 Paris, France. Electronic address:

Interleukin-22 (IL-22) plays a critical role in mucosal defense, although the molecular mechanisms that ensure IL-22 tissue distribution remain poorly understood. We show that the CXCL16-CXCR6 chemokine-chemokine receptor axis regulated group 3 innate lymphoid cell (ILC3) diversity and function. CXCL16 was constitutively expressed by CX3CR1(+) intestinal dendritic cells (DCs) and coexpressed with IL-23 after Citrobacter rodentium infection. Intestinal ILC3s expressed CXCR6 and its ablation generated a selective loss of the NKp46(+) ILC3 subset, a depletion of intestinal IL-22, and the inability to control C. rodentium infection. CD4(+) ILC3s were unaffected by CXCR6 deficiency and remained clustered within lymphoid follicles. In contrast, the lamina propria of Cxcr6(-/-) mice was devoid of ILC3s. The loss of ILC3-dependent IL-22 epithelial stimulation reduced antimicrobial peptide expression that explained the sensitivity of Cxcr6(-/-) mice to C. rodentium. Our results delineate a critical CXCL16-CXCR6 crosstalk that coordinates the intestinal topography of IL-22 secretion required for mucosal defense.
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http://dx.doi.org/10.1016/j.immuni.2014.10.007DOI Listing
November 2014

GATA-3 function in innate and adaptive immunity.

Immunity 2014 Aug;41(2):191-206

Department of Pulmonary Medicine, Erasmus MC, 3000 CA Rotterdam, the Netherlands. Electronic address:

The zinc-finger transcription factor GATA-3 has received much attention as a master regulator of T helper 2 (Th2) cell differentiation, during which it controls interleukin-4 (IL-4), IL-5, and IL-13 expression. More recently, GATA-3 was shown to contribute to type 2 immunity through regulation of group 2 innate lymphoid cell (ILC2) development and function. Furthermore, during thymopoiesis, GATA-3 represses B cell potential in early T cell precursors, activates TCR signaling in pre-T cells, and promotes the CD4(+) T cell lineage after positive selection. GATA-3 also functions outside the thymus in hematopoietic stem cells, regulatory T cells, CD8(+) T cells, thymic natural killer cells, and ILC precursors. Here we discuss the varied functions of GATA-3 in innate and adaptive immune cells, with emphasis on its activity in T cells and ILCs, and examine the mechanistic basis for the dose-dependent, developmental-stage- and cell-lineage-specific activity of this transcription factor.
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http://dx.doi.org/10.1016/j.immuni.2014.06.006DOI Listing
August 2014

Innate lymphoid cells: of precursors and products….

Curr Biol 2014 Jun;24(12):R573-R576

Innate Immunity Unit, Institut Pasteur, Paris, France; INSERM U668, Paris, France. Electronic address:

Recent reports have identified committed innate lymphoid cell (ILC) precursors and tissue-resident ILC subsets that have unique functional attributes. Taken together, these studies provide a framework for understanding how distinct ILCs are generated during hematopoiesis and further suggest additional parallels between models of ILC and T helper cell differentiation.
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http://dx.doi.org/10.1016/j.cub.2014.05.010DOI Listing
June 2014

Gata3 drives development of RORγt+ group 3 innate lymphoid cells.

J Exp Med 2014 Feb 13;211(2):199-208. Epub 2014 Jan 13.

Innate Immunity Unit, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris, France.

Group 3 innate lymphoid cells (ILC3) include IL-22-producing NKp46(+) cells and IL-17A/IL-22-producing CD4(+) lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt(+) ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt(+) ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.
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http://dx.doi.org/10.1084/jem.20131038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920560PMC
February 2014

Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL-13+ type 2 innate lymphoid cells.

Proc Natl Acad Sci U S A 2013 Jun 3;110(25):10240-5. Epub 2013 Jun 3.

Immunology Department, Innate Immunity Unit, Institut Pasteur, 75724 Paris, France.

Group 2 innate lymphoid cells (ILC2s; also called nuocytes, innate helper cells, or natural helper cells) provide protective immunity during helminth infection and play an important role in influenza-induced and allergic airway hyperreactivity. Whereas the transcription factor GATA binding protein 3 (Gata3) is important for the production of IL-5 and -13 by ILC2s in response to IL-33 or -25 stimulation, it is not known whether Gata3 is required for ILC2 development from hematopoietic stem cells. Here, we show that chimeric mice generated with Gata3-deficient fetal liver hematopoietic stem cells fail to develop systemically dispersed ILC2s. In these chimeric mice, in vivo administration of IL-33 or -25 fails to expand ILC2 numbers or to induce characteristic ILC2-dependent IL-5 or -13 production. Moreover, cell-intrinsic Gata3 expression is required for ILC2 development in vitro and in vivo. Using mutant and transgenic mice in which Gata3 gene copy number is altered, we show that ILC2 generation from common lymphoid progenitors, as well as ILC2 homeostasis and cytokine production, is regulated by Gata3 expression levels in a dose-dependent fashion. Collectively, these results identify Gata3 as a critical early regulator of ILC2 development, thereby extending the paradigm of Gata3-dependent control of type 2 immunity to include both innate and adaptive lymphocytes.
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http://dx.doi.org/10.1073/pnas.1217158110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690884PMC
June 2013

The TRPM4 channel controls monocyte and macrophage, but not neutrophil, function for survival in sepsis.

J Immunol 2012 Oct 29;189(7):3689-99. Epub 2012 Aug 29.

INSERM U699, Paris F-75018, France.

A favorable outcome following acute bacterial infection depends on the ability of phagocytic cells to be recruited and properly activated within injured tissues. Calcium (Ca(2+)) is a ubiquitous second messenger implicated in the functions of many cells, but the mechanisms involved in the regulation of Ca(2+) mobilization in hematopoietic cells are largely unknown. The monovalent cation channel transient receptor potential melastatin (TRPM) 4 is involved in the control of Ca(2+) signaling in some hematopoietic cell types, but the role of this channel in phagocytes and its relevance in the control of inflammation remain unexplored. In this study, we report that the ablation of the Trpm4 gene dramatically increased mouse mortality in a model of sepsis induced by cecal ligation and puncture. The lack of the TRPM4 channel affected macrophage population within bacteria-infected peritoneal cavities and increased the systemic level of Ly6C(+) monocytes and proinflammatory cytokine production. Impaired Ca(2+) mobilization in Trpm4(-/-) macrophages downregulated the AKT signaling pathway and the subsequent phagocytic activity, resulting in bacterial overgrowth and translocation to the bloodstream. In contrast, no alteration in the distribution, function, or Ca(2+) mobilization of Trpm4(-/-) neutrophils was observed, indicating that the mechanism controlling Ca(2+) signaling differs among phagocytes. Our results thus show that the tight control of Ca(2+) influx by the TRPM4 channel is critical for the proper functioning of monocytes/macrophages and the efficiency of the subsequent response to infection.
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http://dx.doi.org/10.4049/jimmunol.1102969DOI Listing
October 2012

The calcium-activated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells.

Nat Immunol 2008 Oct 31;9(10):1148-56. Epub 2008 Aug 31.

Institut National de la Santé et de la Recherche Médicale U699, Paris, France.

Dendritic cell (DC) maturation and migration are events critical for the initiation of immune responses. After encountering pathogens, DCs upregulate the expression of costimulatory molecules and subsequently migrate to secondary lymphoid organs. Calcium (Ca(2+)) entry governs the functions of many hematopoietic cell types, but the role of Ca(2+) entry in DC biology remains unclear. Here we report that the Ca(2+)-activated nonselective cation channel TRPM4 was expressed in and controlled the Ca(2+) homeostasis of mouse DCs. The absence of TRPM4, which elicited Ca(2+) overload, did not influence DC maturation but did considerably impair chemokine-dependent DC migration. Our results establish TRPM4-regulated Ca(2+) homeostasis as crucial for DC mobility but not maturation and emphasize that DC maturation and migration are independently regulated.
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http://dx.doi.org/10.1038/ni.1648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956271PMC
October 2008

SLC41A1 is a novel mammalian Mg2+ carrier.

J Biol Chem 2008 Jun 25;283(23):16235-47. Epub 2008 Mar 25.

Institute of Veterinary-Physiology, FU Berlin, Oertzenweg 19b, D-14163 Berlin, Germany.

The molecular biology of mammalian magnesium transporters and their interrelations in cellular magnesium homeostasis are largely unknown. Recently, the mouse SLC41A1 protein was suggested to be a candidate magnesium transporter with channel-like properties when overexpressed in Xenopus laevis oocytes. Here, we demonstrate that human SLC41A1 overexpressed in HEK293 cells forms protein complexes and locates to the plasma membrane without, however, giving rise to any detectable magnesium currents during whole cell patch clamp experiments. Nevertheless, in a strain of Salmonella enterica exhibiting disruption of all three distinct magnesium transport systems (CorA, MgtA, and MgtB), overexpression of human SLC41A1 functionally substitutes these transporters and restores the growth of the mutant bacteria at magnesium concentrations otherwise non-permissive for growth. Thus, we have identified human SLC41A1 as being a bona fide magnesium transporter. Most importantly, overexpressed SLC41A1 provide HEK293 cells with an increased magnesium efflux capacity. With outwardly directed Mg(2+) gradients, a SLC41A1-dependent reduction of the free intracellular magnesium concentration accompanied by a significant net decrease of the total cellular magnesium concentration could be observed in such cells. SLC41A1 activity is temperature-sensitive but not sensitive to the only known magnesium channel blocker, cobalt(III) hexaammine. Taken together, these data functionally identify SLC41A1 as a mammalian carrier mediating magnesium efflux.
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http://dx.doi.org/10.1074/jbc.M707276200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2414286PMC
June 2008
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