Publications by authors named "Corinne Cordier"

18 Publications

  • Page 1 of 1

Hepatitis B virus X protein promotes DNA damage propagation through disruption of liver polyploidization and enhances hepatocellular carcinoma initiation.

Oncogene 2019 04 11;38(14):2645-2657. Epub 2018 Dec 11.

Inserm U1135 CIMI-Paris, Team «Persistent Viral Infections», Paris, France.

Hepatitis B virus X protein (HBx) contributes to Hepatitis B virus (HBV)-related liver cancer. However, its impact on hepatocyte proliferation and genomic stability remains elusive. We studied the role of HBx expression on the progression of cell cycle and liver polyploidization during proliferation and liver carcinogenesis. Full-length HBx transgenic mice (FL-HBx) were developed to investigate liver ploidy as well as hepatocyte proliferation, along normal liver maturation and during cancer initiation (chemical carcinogen treatment). Investigation of postnatal liver development in FL-HBx showed an aberrant G1/S and G2/M transitions, triggered (1) a delay of the formation of hepatocytes binucleation, (2) the early synthesis of polyploidy nuclei (≥4n) and (3) DNA damage appearance. Moreover, HBV infection during hepatocytes proliferation in a humanized liver mouse model led, to modifications in polyploidy of hepatocytes. In initiation of hepatocellular carcinoma, FL-HBx protein decreased ChK1 phosphorylation, Mre11 and Rad51 expression, upregulated IL-6 expression and impaired apoptosis. This was related to DNA damage accumulation in FL-HBx mice. At day 75 after initiation of hepatocellular carcinoma, FL-HBx mice revealed significant cell cycle changes related to the increased amount of 4n nuclei and of markers of cancer progenitor cells. Finally, PLK1 upregulation and p38/ERK activation in FL-HBx mice were implicated in aberrant polyploidization favoring DNA damage propagation and hepatocyte transformation. In conclusion, our data indicate that FL-HBx protein increases DNA damage through the hijack of hepatocyte polyploidization. That leads to enhancement of hepatocellular carcinoma initiation in an inflammatory context.
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http://dx.doi.org/10.1038/s41388-018-0607-3DOI Listing
April 2019

Periosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin.

Nat Commun 2018 02 22;9(1):773. Epub 2018 Feb 22.

INSERM UMR1163, Imagine Institute, Paris Descartes University, 75015, Paris, France.

Bone regeneration relies on the activation of skeletal stem cells (SSCs) that still remain poorly characterized. Here, we show that periosteum contains SSCs with high bone regenerative potential compared to bone marrow stromal cells/skeletal stem cells (BMSCs) in mice. Although periosteal cells (PCs) and BMSCs are derived from a common embryonic mesenchymal lineage, postnatally PCs exhibit greater clonogenicity, growth and differentiation capacity than BMSCs. During bone repair, PCs can efficiently contribute to cartilage and bone, and integrate long-term after transplantation. Molecular profiling uncovers genes encoding Periostin and other extracellular matrix molecules associated with the enhanced response to injury of PCs. Periostin gene deletion impairs PC functions and fracture consolidation. Periostin-deficient periosteum cannot reconstitute a pool of PCs after injury demonstrating the presence of SSCs within periosteum and the requirement of Periostin in maintaining this pool. Overall our results highlight the importance of analyzing periosteum and PCs to understand bone phenotypes.
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http://dx.doi.org/10.1038/s41467-018-03124-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823889PMC
February 2018

A unique CD8(+) T lymphocyte signature in pediatric type 1 diabetes.

J Autoimmun 2016 09 16;73:54-63. Epub 2016 Jun 16.

Institut National de la Sante et de la Recherche Médicale, Unité 1151, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, 75015 Paris, France; Centre National de la Recherche Scientifique, UMR8253, 75015 Paris, France. Electronic address:

Human type 1 diabetes results from a destructive auto-reactive immune response in which CD8(+) T lymphocytes play a critical role. Given the intense ongoing efforts to develop immune intervention to prevent and/or cure the disease, biomarkers suitable for prediction of disease risk and progress, as well as for monitoring of immunotherapy are required. We undertook separate multi-parameter analyses of single naïve and activated/memory CD8(+) T lymphocytes from pediatric and adult patients, with the objective of identifying cellular profiles associated with onset of type 1 diabetes. We observe global perturbations in gene and protein expression and in the abundance of T cell populations characterizing pediatric but not adult patients, relative to age-matched healthy individuals. Pediatric diabetes is associated with a unique population of CD8(+) T lymphocytes co-expressing effector (perforin, granzyme B) and regulatory (transforming growth factor β, interleukin-10 receptor) molecules. This population persists after metabolic normalization and is especially abundant in children with high titers of auto-antibodies to glutamic acid decarboxylase and with elevated HbA1c values. These findings highlight striking differences between pediatric and adult type 1 diabetes, indicate prolonged large-scale perturbations in the CD8(+) T cell compartment in the former, and suggest that CD8(+)CD45RA(-) T cells co-expressing effector and regulatory factors are of interest as biomarkers in pediatric type 1 diabetes.
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http://dx.doi.org/10.1016/j.jaut.2016.06.003DOI Listing
September 2016

Serotonin Modulates Developmental Microglia via 5-HT2B Receptors: Potential Implication during Synaptic Refinement of Retinogeniculate Projections.

ACS Chem Neurosci 2015 Jul 17;6(7):1219-30. Epub 2015 Apr 17.

†INSERM UMR-S 839, F75005, Paris, France.

Maturation of functional neuronal circuits during central nervous system development relies on sophisticated mechanisms. First, axonal and dendritic growth should reach appropriate targets for correct synapse elaboration. Second, pruning and neuronal death are required to eliminate redundant or inappropriate neuronal connections. Serotonin, in addition to its role as a neurotransmitter, actively participates in postnatal establishment and refinement of brain wiring in mammals. Brain resident macrophages, that is, microglia, also play an important role in developmentally regulated neuronal death as well as in synaptic maturation and elimination. Here, we tested the hypothesis of cross-regulation between microglia and serotonin during postnatal brain development in a mouse model of synaptic refinement. We found expression of the serotonin 5-HT2B receptor on postnatal microglia, suggesting that serotonin could participate in temporal and spatial synchronization of microglial functions. Using two-photon microscopy, acute brain slices, and local delivery of serotonin, we observed that microglial processes moved rapidly toward the source of serotonin in Htr2B(+/+) mice, but not in Htr2B(-/-) mice lacking the 5-HT2B receptor. We then investigated whether some developmental steps known to be controlled by serotonin could potentially result from microglia sensitivity to serotonin. Using an in vivo model of synaptic refinement during early brain development, we investigated the maturation of the retinal projections to the thalamus and observed that Htr2B(-/-) mice present anatomical alterations of the ipsilateral projecting area of retinal axons into the thalamus. In addition, activation markers were upregulated in microglia from Htr2B(-/-) compared to control neonates, in the absence of apparent morphological modifications. These results support the hypothesis that serotonin interacts with microglial cells and these interactions participate in brain maturation.
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http://dx.doi.org/10.1021/cn5003489DOI Listing
July 2015

Human fucci pancreatic Beta cell lines: new tools to study Beta cell cycle and terminal differentiation.

PLoS One 2014 26;9(9):e108202. Epub 2014 Sep 26.

INSERM U845, Research Center Growth and Signaling, Université Paris Descartes, Faculté de Médecine Cochin, Paris, France.

Regulation of cell cycle in beta cells is poorly understood, especially in humans. We exploited here the recently described human pancreatic beta cell line EndoC-βH2 to set up experimental systems for cell cycle studies. We derived 2 populations from EndoC-βH2 cells that stably harbor the 2 genes encoding the Fucci fluorescent indicators of cell cycle, either from two vectors, or from a unique bicistronic vector. In proliferating non-synchronized cells, the 2 Fucci indicators revealed cells in the expected phases of cell cycle, with orange and green cells being in G1 and S/G2/M cells, respectively, and allowed the sorting of cells in different substeps of G1. The Fucci indicators also faithfully red out alterations in human beta cell proliferative activity since a mitogen-rich medium decreased the proportion of orange cells and inflated the green population, while reciprocal changes were observed when cells were induced to cease proliferation and increased expression of some beta cell genes. In the last situation, acquisition of a more differentiated beta cell phenotype correlates with an increased intensity in orange fluorescence. Hence Fucci beta cell lines provide new tools to address important questions regarding human beta cell cycle and differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108202PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178124PMC
June 2015

Prolactin-induced prostate tumorigenesis links sustained Stat5 signaling with the amplification of basal/stem cells and emergence of putative luminal progenitors.

Am J Pathol 2014 Nov 3;184(11):3105-19. Epub 2014 Sep 3.

Necker Institute for Sick Children, Inserm U1151 - CNRS UMR 8253, Hormone Pathophysiology Team PRL/GH, University Paris Descartes, Sorbonne Paris Cité, Faculty of Medicine, Paris, France. Electronic address:

Current androgen ablation therapies for prostate cancer are initially successful, but the frequent development of castration resistance urges the generation of alternative therapies and represents an important health concern. Prolactin/signal transducer and activator of transcription 5 (STAT5) signaling is emerging as a putative target for alternative treatment for prostate cancer. However, mechanistic data for its role in development or progression of prostate tumors are scarce. In vivo mouse studies found that local prolactin induced the amplification of prostate epithelial basal/stem cells. Because these cells are proposed cells of origin for prostate cancer and disease recurrence, we looked further into this amplification. Our results indicated that sustained Stat5 activation was associated with the occurrence of abnormal basal/stem cell clusters in prostate epithelium of prostate-specific prolactin-transgenic mice. Analysis of epithelial areas containing these clusters found high proliferation, Stat5 activation, and expression of stem cell antigen 1. Furthermore, enhanced prolactin signaling also led to amplification of a luminal cell population that was positive for stem cell antigen 1. These cells may originate from amplified basal/stem cells and might represent important progenitors for tumor development in prostate epithelium. These data provide a deeper understanding of the initial stages of prostate tumorigenesis induced by prolactin to help determine whether this hormone or its downstream messengers could be useful targets for prostate cancer treatment in the future.
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http://dx.doi.org/10.1016/j.ajpath.2014.07.020DOI Listing
November 2014

Massive diversification in aging colonies of Escherichia coli.

J Bacteriol 2014 Sep 30;196(17):3059-73. Epub 2014 Jun 30.

INSERM U1001, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine Paris Descartes, Paris, France

The evolutionary success of bacteria depends greatly on their capacity to continually generate phenotypic diversity. Structured environments are particularly favorable for diversification because of attenuated clonal interference, which renders selective sweeps nearly impossible and enhances opportunities for adaptive radiation. We examined at the microscale level the emergence and the spatial and temporal dynamics of phenotypic diversity and their underlying causes in Escherichia coli colonies. An important dynamic heterogeneity in the growth, metabolic activity, morphology, gene expression patterns, stress response induction, and death patterns among cells within colonies was observed. Genetic analysis indicated that the phenotypic variation resulted mostly from mutations and that indole production, oxidative stress, and the RpoS-regulated general stress response played an important role in the generation of diversity. We observed the emergence and persistence of phenotypic variants within single colonies that exhibited variable fitness compared to the parental strain. Some variants showed improved capacity to produce biofilms, whereas others were able to use different nutrients or to tolerate antibiotics or oxidative stress. Taken together, our data show that bacterial colonies provide an ecological opportunity for the generation and maintenance of vast phenotypic diversity, which may increase the probability of population survival in unpredictable environments.
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http://dx.doi.org/10.1128/JB.01421-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135658PMC
September 2014

Increased CD127 expression on activated FOXP3+CD4+ regulatory T cells.

Eur J Immunol 2010 Sep;40(9):2528-38

INSERM, U1012, Le Kremlin-Bicêtre, France.

Regulatory T cells (Treg) are commonly identified by CD25 (IL-2R alpha) surface expression and/or intracellular expression of the FOXP3 transcription factor. In addition, Treg are also characterized by low CD127 (IL-7R alpha) expression when compared to conventional T cells and their biology in the periphery is considered essentially independent of IL-7. We further investigated CD127 expression on Treg and we demonstrated differential CD127 expression depending on Treg subsets considered. Notably, we observed high CD127 expression on inducible costimulatory molecule (ICOS)- and CD103-expressing Treg subsets. Since these two markers reflect activation status, we addressed whether Treg activation modulated CD127 expression. We demonstrated that in contrast to conventional T cells, Treg significantly upregulated CD127 expression during in vitro and in vivo activation using adoptive transfer and contact dermatitis models. High CD127 expression on Treg was also predominantly detected ex vivo in some specific sites, notably bone marrow and skin. Importantly, higher CD127 expression on Treg correlated with higher phosphorylation of STAT5 upon IL-7 exposure. High CD127 expression on Treg also provided survival advantage upon in vitro incubation with IL-7. We thus demonstrated that low CD127 expression is not an intrinsic characteristic of Treg and we identified activated Treg as a potential target of endogenous or therapeutic IL-7.
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http://dx.doi.org/10.1002/eji.201040531DOI Listing
September 2010

Reliable detection of dead microbial cells by using fluorescent hydrazides.

Appl Environ Microbiol 2010 Mar 28;76(5):1674-8. Epub 2009 Dec 28.

INSERM U571, Faculté de Médecine Paris Descartes, Université René Descartes, 156 rue de Vaugirard, 75730 Paris Cedex 15, France.

We have developed a new method for accurate quantification of dead microbial cells. This technique employs the simultaneous use of fluorescent hydrazides and nucleic acid dyes. Fluorescent hydrazides allow detection of cells that cannot be detected with currently used high-affinity nucleic acid dyes. This is particularly important for nongrowing bacterial populations and for multicellular communities containing physiologically heterogeneous cell populations, such as colonies and biofilms.
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http://dx.doi.org/10.1128/AEM.02125-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2832359PMC
March 2010

Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+ IgD+ CD27+ B cell repertoire in infants.

J Exp Med 2008 Jun 2;205(6):1331-42. Epub 2008 Jun 2.

Institut National de la Santé et de la Recherche Médicale U783, Développement du Système Immunitaire, Université Paris Descartes, Faculté de Médecine, Site Necker Enfants-Malades, Paris 75015, France.

T cell-dependent immune responses develop soon after birth, whereas it takes 2 yr for humans to develop T cell-independent responses. We used this dissociation to analyze the repertoire diversification of IgM(+)IgD(+)CD27(+) B cells (also known as "IgM memory" B cells), comparing these cells with switched B cells in children <2 yr of age, with the aim of determining whether these two subsets are developmentally related. We show that the repertoire of IgM(+)IgD(+)CD27(+) B cells in the spleen and blood displays no sign of antigen-driven activation and expansion on H-CDR3 spectratyping, despite the many antigenic challenges provided by childhood vaccinations. This repertoire differed markedly from those of switched B cells and splenic germinal center B cells, even at the early stage of differentiation associated with mu heavy chain expression. These data provide evidence for the developmental diversification of IgM(+)IgD(+)CD27(+) B cells, at least in very young children, outside of T cell-dependent and -independent immune responses.
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http://dx.doi.org/10.1084/jem.20071555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413031PMC
June 2008

Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites.

J Immunol 2007 Oct;179(8):4969-78

Laboratoire de Biologie et Thérapeutique des Pathologies Immunitaires, Centre National de la Recherche Scientifique-Unité Mixte de Recherche 7087, Université Pierre et Marie Curie-Paris 6, Hôpital Pitié-Salpêtrière, Paris, France.

Natural regulatory T cells (Tregs) are present in high frequencies among tumor-infiltrating lymphocytes and in draining lymph nodes, supposedly facilitating tumor development. To investigate their role in controlling local immune responses, we analyzed intratumoral T cell accumulation and function in the presence or absence of Tregs. Tumors that grew in normal BALB/c mice injected with the 4T1 tumor cell line were highly infiltrated by Tregs, CD4 and CD8 cells, all having unique characteristics. Most infiltrating Tregs expressed low levels of CD25Rs and Foxp3. They did not proliferate even in the presence of IL-2 but maintained a strong suppressor activity. CD4 T cells were profoundly anergic and CD8 T cell proliferation and cytotoxicity were severely impaired. Depletion of Tregs modified the characteristics of tumor infiltrates. Tumors were initially invaded by activated CD4(+)CD25(-) T cells, which produced IL-2 and IFN-gamma. This was followed by the recruitment of highly cytotoxic CD8(+) T cells at tumor sites leading to tumor rejection. The beneficial effect of Treg depletion in tumor regression was abrogated when CD4 helper cells were also depleted. These findings indicate that the massive infiltration of tumors by Tregs prevents the development of a successful helper response. The Tregs in our model prevent Th cell activation and subsequent development of efficient CD8 T cell activity required for the control of tumor growth.
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http://dx.doi.org/10.4049/jimmunol.179.8.4969DOI Listing
October 2007

The thymus exports long-lived fully committed T cell precursors that can colonize primary lymphoid organs.

Nat Immunol 2006 Jan 11;7(1):76-82. Epub 2005 Dec 11.

Institut National de la Santé et de la Recherche Médicale U591, Necker Institute, Medical Faculty René Descartes, Paris, France.

Thymic export of cells is believed to be restricted to mature T cells. Here we show that the thymus also exports fully committed T cell precursors that colonize primary lymphoid organs. These precursor cells exited the thymus before T cell receptor rearrangements and colonized lymphoid organs such as the thymus and the gut. Migration of the thymic T cell-committed precursors led to permanent colonization of the gut precursor compartment, improved the capacity of gut precursors to further differentiate into T cells and was sufficient for the generation of 'euthymic like' CD8alphaalpha(+) intraepithelial lymphocytes. These data demonstrate a new function for the thymus in peripheral seeding with T cell precursors that become long lived after thymus export.
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http://dx.doi.org/10.1038/ni1293DOI Listing
January 2006

Peripheral CD8+CD25+ T lymphocytes from MHC class II-deficient mice exhibit regulatory activity.

J Immunol 2005 Jul;175(1):246-53

Institut National de la Santé et de la Recherche Médicale U561, Hôpital Saint Vincent de Paul, Paris, France.

We characterized CD8(+) T cells constitutively expressing CD25 in mice lacking the expression of MHC class II molecules. We showed that these cells are present not only in the periphery but also in the thymus. Like CD4(+)CD25(+) T cells, CD8(+)CD25(+) T cells appear late in the periphery during ontogeny. Peripheral CD8(+)CD25(+) T cells from MHC class II-deficient mice also share phenotypic and functional features with regulatory CD4(+)CD25(+) T cells: in particular, they strongly express glucocorticoid-induced TNFR family-related gene, CTLA-4 and Foxp3, produce IL-10, and inhibit CD25(-) T cell responses to anti-CD3 stimulation through cell contacts with similar efficiency to CD4(+)CD25(+) T cells. However, unlike CD4(+)CD25(+) T cells CD8(+)CD25(+) T cells from MHC class II-deficient mice strongly proliferate and produce IFN-gamma in vitro in response to stimulation in the absence of exogenous IL-2.
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http://dx.doi.org/10.4049/jimmunol.175.1.246DOI Listing
July 2005

Extrathymic hemopoietic progenitors committed to T cell differentiation in the adult mouse.

J Immunol 2005 Feb;174(4):1980-8

Institut National de la Sant é et de la Recherche Médicale Unit é 591, Institut Necker, Faculté de Médecine René Descartes Paris V, Paris, France.

The role of the thymus in T cell commitment of hemopoietic precursor is yet controversial. We previously identified a major T cell progenitor activity in precursor cells isolated from bone marrow-derived spleen colonies. In this study, we characterize the properties of these pre-T cells. We demonstrate that they have unique phenotype and can be generated in a total absence of any thymic influence. Indeed, even when studied at the single-cell level, extrathymic T cell-committed precursors express T cell-specific genes. Moreover, these cells are not committed to a particular T cell differentiation pathway because they can generate both extrathymic CD8alphaalpha+ intraepithelial lymphocytes and thymus-derived conventional thymocytes. We also compared these pre-T cells with fully T cell-committed thymic progenitors. When tested in vitro or by direct intrathymic transfer, these cells have a low clonogenic activity. However, after i.v. transfer, thymus repopulation is efficient and these precursors generate very high numbers of peripheral T cells. These results suggest the existence of extra steps of pre-T cell maturation that improve thymus reconstitution capacity and that can be delivered even after full T cell commitment. Consequently, our studies identify a source of extrathymic progenitors that will be helpful in defining the role of the thymus in the earliest steps of T cell differentiation.
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http://dx.doi.org/10.4049/jimmunol.174.4.1980DOI Listing
February 2005

Enrichment for a CD26hi SIRP- subset in lymph dendritic cells from the upper aero-digestive tract.

J Leukoc Biol 2004 Sep 14;76(3):553-61. Epub 2004 Jun 14.

VIM UR892 INRA, Cedex, France.

Dendritic cells (DC) have been reported to migrate in afferent lymph in the steady state. However, it is unknown whether DC traffic is modulated by the nature of the drained tissue. To analyze the influence of mucosal versus cutaneous microenvironments on the constitutive DC release, we exploited a novel technique of lymph cannulation in sheep, which allowed a comparison of afferent lymph DC migrating from the head mucosae [cervical DC (CerDC)] with DC migrating from skin [prescapular DC (PresDC)]. The migration rate was lower for CerDC than for PresDC. Compared with PresDC, CerDC contained a higher proportion of the CD26hi signal regulatory protein (SIRP)- DC subset. It is interesting that cytoplasmic apoptotic DNA as well as cytokeratin-positive inclusions were primarily detected among CD26hi SIRP- DC, an observation similar to that made in rats, which leads to the suggestion that this subset was involved in self-antigen presentation and tolerance induction. After the inoculation of cholera toxin (CT) onto the oro-nasal mucosae, migration of CD26hi SIRP- and CD26lo SIRP+ DC was accelerated in lymph, indicating that the effect of CT on DC mobilization is not subset-specific. Our results show that a mucosal environment influences DC output and the relative DC subset representation in lymph. This modulation of DC traffic to lymph nodes by mucosal surfaces is likely to affect the bias of the mucosal immune responses.
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http://dx.doi.org/10.1189/jlb.0404223DOI Listing
September 2004

Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire.

Blood 2004 Dec 10;104(12):3647-54. Epub 2004 Jun 10.

Institut National de Santé et de la Recherche Médicale U373, Paris, France.

The human peripheral B-cell compartment displays a large population of immunoglobulin M-positive, immunoglobulin D-positive CD27(+) (IgM(+)IgD(+)CD27(+)) "memory" B cells carrying a mutated immunoglobulin receptor. By means of phenotypic analysis, complementarity-determining region 3 (CDR3) spectratyping during a T-independent response, and gene-expression profiling of the different blood and splenic B-cell subsets, we show here that blood IgM(+)IgD(+)CD27(+) cells correspond to circulating splenic marginal zone B cells. Furthermore, analysis of this peripheral subset in healthy children younger than 2 years shows that these B cells develop and mutate their immunoglobulin receptor during ontogeny, prior to their differentiation into T-independent antigen-responsive cells. It is therefore proposed that these IgM(+)IgD(+)CD27(+) B cells provide the splenic marginal zone with a diversified and protective preimmune repertoire in charge of the responses against encapsulated bacteria.
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http://dx.doi.org/10.1182/blood-2004-01-0346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2590648PMC
December 2004

Suppression of CD4+ T lymphocyte effector functions by CD4+CD25+ cells in vivo.

J Immunol 2004 Mar;172(6):3391-8

Institut National de la Santé et de la Recherche Médicale Unité 561, Hôpital Saint Vincent de Paul, Paris, France.

CD4+CD25+ regulatory T cells have been extensively studied during the last decade, but how these cells exert their regulatory function on pathogenic effector T cells remains to be elucidated. Naive CD4+ T cells transferred into T cell-deficient mice strongly expand and rapidly induce inflammatory bowel disease (IBD). Onset of this inflammatory disorder depends on IFN-gamma production by expanding CD4+ T cells. Coinjection of CD4+CD25+ regulatory T cells protects recipient mice from IBD. In this study, we show that CD4+CD25+ regulatory T cells do not affect the initial activation/proliferation of injected naive T cells as well as their differentiation into Th1 effectors. Moreover, naive T cells injected together with CD4+CD25+ regulatory T cells into lymphopenic hosts are still able to respond to stimuli in vitro when regulatory T cells are removed. In these conditions, they produce as much IFN-gamma as before injection or when injected alone. Finally, when purified, they are able to induce IBD upon reinjection into lymphopenic hosts. Thus, prevention of IBD by CD4+CD25+ regulatory T cells is not due to deletion of pathogenic T cells, induction of a non reactive state (anergy) among pathogenic effector T cells, or preferential induction of Th2 effectors rather than Th1 effectors; rather, it results from suppression of T lymphocyte effector functions, leading to regulated responses to self.
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http://dx.doi.org/10.4049/jimmunol.172.6.3391DOI Listing
March 2004

A unique subpopulation of CD4+ regulatory T cells controls wasting disease, IL-10 secretion and T cell homeostasis.

Eur J Immunol 2003 Sep;33(9):2419-28

INSERM U. 591, Institut Necker, Paris, France.

CD25(+)CD4(+) regulatory T cells have major roles in controlling immune responses, and use heterogeneous regulatory mechanisms. It is possible that these different activities are mediated by different subsets. Here we show that CD103(+)CD25(+)CD4(+) T cells (that control inflammatory bowel disease) are highly enriched in gut-associated lymphoid tissue and have unique functional properties. In vivo, only this subpopulation is able to control wasting disease and peripheral T cell homeostasis. In vitro, only this subpopulation is able to regulate IL-10 secretion, and it might also mediate infectious suppression. These results demonstrate that regulatory T cells can be divided into discrete subpopulations with defined functional properties and regulatory mechanisms.
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http://dx.doi.org/10.1002/eji.200324205DOI Listing
September 2003