A Herbelin

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (92)428.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Although it is generally acknowledged that cytokines regulate normal hematopoiesis in an autocrine/paracrine fashion, their possible role in chronic myeloid leukemia (CML) and resistance to imatinib mesylate (IM) treatment remain poorly investigated. Here, we report that CD34(+) progenitors from CML patients at diagnosis are selectively targeted by the cytokine/alarmin IL-33. Indeed, CML CD34(+) progenitors upregulate their cell surface expression of the IL-33-specific receptor chain ST2, proliferate and produce cytokines in response to IL-33, conversely to CD34(+) cells from healthy individuals. Moreover, ST2 overexpression is normalized following IM therapy, while IL-33 counteracts in vitro IM-induced growth arrest in CML CD34(+) progenitors via re-activation of the STAT5 pathway, thus supporting the notion that IL-33 may impede the anti-proliferative effects of IM on CD34(+) progenitors in CML. Clinically, the levels of circulating soluble ST2, commonly considered a functional signature of IL-33 signaling in vivo, correlate with disease burden. Indeed, these elevated peripheral concentrations associated with a high Sokal score predictive of therapeutic outcome are normalized in patients in molecular remission. Finally, we evidenced a facilitating effect of IL-33 on in vivo maintenance of CD34(+) progenitors from CML patients by using xenotransplant experiments in immunodeficient NOG mice, and we showed that engraftment of mouse BCR-ABL-transfected bone marrow progenitors was less efficient in IL-33-deficient mice compared to wild-type recipients. Taken together, our results provide evidence that IL-33/ST2 signaling may represent a novel cytokine-mediated mechanism contributing to CML progenitor growth and support a role for this pathway in CML maintenance and IM resistance.
    Cancer Research 03/2014; · 9.28 Impact Factor
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    ABSTRACT: Interleukin (IL)-33 is a new member of the IL-1 family that exerts pleiotropic activities in innate and adaptive immunity. With its receptor ST2, they have newly emerged as key molecules strongly involved in several inflammatory and autoimmune disorders. Recent evidence suggests that the IL-33/ST2 axis is strongly involved in the pathophysiology of rheumatoid arthritis (RA). However in RA models, the role of IL-33 and its receptor is still controversial. We aimed at deciphering IL-33 mode of action after administration in an experimental model of RA, namely collagen-induced arthritis (CIA). CIA was induced by immunisation of C57Bl/6 mice with type 2 collagen. IL-33 was ip administrated in CIA mice and cells were analysed by flow cytometry on day 28 after CIA induction. We show a previously unshown dramatic inhibition of mouse collagen-induced arthritis (CIA) development after repeated administration of IL-33. This therapeutic effect was related to an enhanced type-2 immune response, including the expansion of eosinophils, Th2 cells, innate type 2 lymphoid cells (ILC2, defined as CD25(+) c-Kit(+) Lin(-) Sca-1(+)ST2L(+)) and an increase in Th2 cytokines levels in the serum of treated mice. Moreover, our work brings out the interplay between Treg and IL-33. Since IL-33 acts directly on Treg via ST2L, we showed that IL-33 treatment of CIA majors Treg frequency and increases the suppressive capacities of those cells. IL-33 also induces the emergence of a CD39(+/high) Treg population in a ST2L dependant manner. In the light of our present study, IL-33 can exert powerful anti-inflammatory properties in CIA, integrating the establishment of a type-2 immune response, the expansion and the activation of Treg. Our study reveals an undescribed mechanism by which IL-33 inhibits arthritis development, thus updating and strengthening the crucial role of IL-33 in RA.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A28. · 8.11 Impact Factor
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    ABSTRACT: The endogenous molecules high mobility group box 1 (HMGB1) and interleukin-33 (IL-33) have been identified as alarmins, capable of mediating danger signals during tissue damage. Here, we address their possible role as innate-immune mediators in ischemia-reperfusion injury (IRI) following human kidney transplantation. We analysed serum and urinary HMGB1 and IL-33 levels, all determined by enzyme-linked immunosorbent assay, in a cohort of 26 deceased renal transplant recipients. Urinary HMGB1 and IL-33 levels were significantly increased as soon as 30 min after reperfusion, as compared to those before treatment. Moreover, both serum and urinary IL-33 (but not HMGB1) increase was positively correlated with cold ischemia time, from 30 min to 3 days post-transplantation. In vitro, human umbilical vein endothelial cells subjected to hypoxia conditions released both HMGB-1 and IL-33, while only the latter was further increased upon subsequent re-oxygenation. Finally, we postulate that leukocytes from renal recipient patients are targeted by both HMGB1 and IL-33, as suggested by increased transcription of their respective receptors (TLR2/4 and ST2L) shortly after transplantation. Consistent with this view, we found that iNKT cells, an innate-like T cell subset involved in IRI and targeted by IL-33 but not by HMGB1 was activated 1 hour post-transplantation. Altogether, these results are in keeping with a potential role of IL-33 as an innate-immune mediator during kidney IRI in humans.
    PLoS ONE 01/2014; 9(2):e88742. · 3.53 Impact Factor
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    ABSTRACT: Invariant natural killer T (iNKT) cells expressing a CD1d-restricted invariant αβTCR have key regulatory roles in autoimmunity, pathogen immunity, and tumor surveillance, but their function in the control of allergic skin diseases remains poorly documented. Using a model of contact hypersensitivity (CHS) to the hapten DNFB, we show here that iNKT cell deficiency results in enhanced skin inflammation due to augmented hapten-specific IFN-γ-producing CD8(+) effectors in skin draining lymph nodes (dLNs) and their massive recruitment into the allergen-exposed skin. Adoptive transfer and antibody depletion experiments as well as in vitro studies revealed that iNKT cells (1) reduce the severity of CHS, even in presensitized mice, (2) require hapten presentation by CD1d(+) dendritic cells (DCs) to dampen skin inflammation, and (3) produce IL-4 and IL-13 after CD1d-dependent in vitro stimulation by hapten-loaded DCs only in the presence of IFN-γ released from activated CD8(+) effector T cells. In corollary, mice double deficient in IL-4 and IL-13 exhibit an exacerbated CHS. Finally, iNKT-suppressive function is independent of Foxp3(+) regulatory T cells (Tregs). These data highlight that, besides Foxp3(+) Tregs, iNKT cells are potent downregulators of CD8(+) T cell-mediated CHS, and underscore that both cell types are important for the regulation of allergic skin inflammation.Journal of Investigative Dermatology advance online publication, 29 November 2012; doi:10.1038/jid.2012.404.
    Journal of Investigative Dermatology 11/2012; · 6.19 Impact Factor
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    ABSTRACT: The pig is a relevant preclinical model for numerous pathologies used to validate therapeutic strategies for translation to human. Although invariant natural killer T (iNKT) lymphocytes are a component of innate immunity implicated in many pathological processes, little is known on their characterization in swine. By addressing this issue using mouse α-galactosylceramide-loaded CD1d tetramers (α-GC-CD1dTT), which are commonly used to track iNKT cells, we were able to unequivocally identify CD3(+)α-GC-CD1dTT(+) cells in porcine peripheral blood, hereafter referred to as swine iNKT cells. These lymphocytes are enriched in CD4(-)CD8(+) and CD4(-)CD8(-) cells, harbor an activated-memory phenotype (SLA-DR(+)CD45RA(-)), express the intracellular promyelocytic-leukemia-zinc-finger (PLZF) transcription factor and are significantly enriched in IFN-γ-producing cells after in vitro activation in comparison with conventional T cells. Importantly, in presence of IL-2 and IL-15, the iNKT cell ligand α-GC induces selective expansion of CD3(+)α-GC-CD1dTT(+) cells, confirming the reactivity of swine iNKT cells against α-GC. When associated with α-GC, IL-33, an alarmin of IL-1 family recently described to target iNKT cells, leads to a greater expansion of CD3(+)α-GC-CD1dTT(+) cells than IL-2 and IL-15. Altogether, our results provide the first phenotypic and functional description of swine iNKT cells allowing to further study the critical role of iNKT cells in porcine models of organ injury.
    Veterinary Immunology and Immunopathology 07/2012; 149(3-4):272-9. · 1.88 Impact Factor
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    ABSTRACT: Chronic myeloid leukemia (CML) is a clonal hematopoietic stem-cell malignancy characterized by the presence of the chimeric BCR-ABL oncoprotein with deregulated tyrosine-kinase (TK) activity. Although conventional T cells are acknowledged as important players in the control of CML, a possible modification of invariant NKT (iNKT) cells, known for their antitumoral activity, has not been established as yet. Here, we showed that the expression of perforin, CD95L, and promyelocytic leukemia zinc finger, a transcription factor required for maintenance of iNKT cell functions, was reduced or suppressed in CML patients at diagnosis, as compared with healthy individuals. The proliferation rate of blood iNKT cells in response to their cognate ligand was likewise diminished. These functional deficiencies were corrected in patients having achieved complete cytogenetic remission following TK inhibitor or IFN-α therapy. iNKT cells from CML patients in the chronic phase did not display increased TK activity, which argued against a direct autonomous action of BCR-ABL. Instead, we found that their anergic status originated from both intrinsic and APC-dependent dysfunctions. Our data demonstrate that chronic phase CML is associated with functional deficiencies of iNKT cells that are restored upon remission. These results suggest a possible contribution to disease control by TK inhibitor therapies.
    European Journal of Immunology 05/2012; 42(7):1870-5. · 4.97 Impact Factor
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    ABSTRACT: The development of inflammatory granulomas around infected Kupffer cells is necessary for hepatic parasite clearance during visceral leishmaniasis. Invariant NKT (iNKT) cells are predominant T cells in the mouse liver and can synthesize large quantities of IL-4 and IFN-γ, two cytokines involved in granuloma formation. This study analyzed the role of iNKT cells in the hepatic immune response during Leishmania donovani infection, using a murine model of wild-type (WT) and iNKT cell-deficient (Jα18⁻/⁻) C57BL/6 mice sacrificed 15, 30 or 60 days post-infection. We recorded hepatic parasite loads, cytokine expression, and analyzed granulomatous response by immunohistochemistry and hepatic immune cell infiltration by flow cytometry. Whereas WT animals rapidly controlled the infection and developed an inflammatory response associated with a massive influx of iNKT cells observed by flow cytometry, Jα18⁻/⁻ mice had significantly higher parasitic loads on all time points. This lack of control of parasite burden was associated with a delay in granuloma maturation (28.1% of large granulomas at day 60 versus 50.7% in WT). Cytokine transcriptome analysis showed that mRNA of 90/101 genes encoding chemokines, cytokines and their receptors, was underexpressed in Jα18⁻/⁻ mice. Detection of IL-4 and TNF-α by ELISA in liver extracts was also significantly lower in Jα18⁻/⁻ mice. Consistent with flow cytometry analysis, cytokinome profile in WT mice showed a bias of expression towards T cell-chemoattractant chemokines on D15, and displayed a switch towards expression of granulocytes and/or monocytes -chemoattractant chemokines on D60. In Jα18⁻/⁻ mice, the significantly lower expression of CXCL5, MIP-2 and CCL2 mRNA was correlated with a defect in myeloperoxidase positive-cell attraction observed by immunohistochemistry and with a lower granulocyte and monocyte infiltration in the liver, as shown by flow cytometry. These data indicate that iNKT cells play a role in early and sustained pro-inflammatory cytokine response warranting efficient organization of hepatic granulomas and parasite clearance.
    PLoS ONE 01/2012; 7(3):e33413. · 3.53 Impact Factor
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    ABSTRACT: Despite increasing knowledge on the mechanisms of invariant natural killer T (iNKT)-cell development in the thymus, the function of recent thymic emigrant (RTE) iNKT cells remains largely unexplored, principally because of a lack of bona fide markers to distinguish RTE from long-lived iNKT cells. Whether the recently described IL-17-producing iNKT cell subset is part of RTE has notably not been addressed. In the present study, we show that neuropilin-1 (Nrp-1), a transmembrane receptor mainly found on T-regulatory (Treg) cells in the murine immune system, is specifically expressed on RTE iNKT cells in naive mice. We used the Nrp-1 marker to discriminate RTE from mature iNKT cells and compare their functions. We show that RTE iNKT cells proliferate more than mature iNKT cells after in vitro activation; that, unlike mature iNKT cells, most RTE iNKT cells fail to rapidly produce IFN-γ and IL-4 after in vivo activation; and, most importantly, that IL-17-producing iNKT cells in lymphoid organs of naive mice are contained within the RTE iNKT cell pool. Our results establish an accurate marker of RTE iNKT cells and reveal that continuous thymic output is required for pro-inflammatory IL-17 secretion, a key function of adult iNKT cells.
    Blood 06/2011; 118(11):2993-3002. · 9.78 Impact Factor
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    ABSTRACT: Invariant natural killer T (iNKT) cells are involved in the intrahepatic immune response and in hepatitis. In particular, iNKT lymphocytes are responsible for hepatocyte death in concanavalin A-induced hepatitis in mice. We examined the role of iNKT cells in acute hepatitis induced by a hepatotoxic agent, carbon tetrachloride (CCl(4) ). WT and iNKT cell-deficient (Jα18(-/-) ) mice were challenged with a single dose of 2.4 g/kg CCl(4) and both hepatic physiopathology and immune responses were studied. Plasma alanine and aspartate amino-transferase levels were significantly higher in Jα18(-/-) mice than in WT mice two days after CCl(4) administration. Chemokine CXCL1/keratinocyte-derived chemokine (KC) and MMP-8 were significantly higher in iNKT cell-deficient mice than in control mice. The more severe liver injury in Jα18(-/-) mice was associated with greater leukocyte infiltrate, which was enriched in neutrophils (CD11b(+) CD11c(-) Gr-1(+) cells), in agreement with CXCL1/KC and MMP-8 levels. Complementary experiments with NK-depleted animals indicate a minor role for NK cells in the liver damage found in iNKT-deficient mice. Thus, unlike for ConA-induced hepatitis, we report that iNKT cells protect the liver against acute hepatitis induced by CCl(4) and limit neutrophil infiltration.
    European Journal of Immunology 03/2011; 41(6):1720-32. · 4.97 Impact Factor
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    ABSTRACT: Activation of invariant natural killer T (iNKT) cells by treatment with their α-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-γ production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.
    European Journal of Immunology 02/2011; 41(2):299-305. · 4.97 Impact Factor
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    ABSTRACT: Despite their increasing use in autoimmune, inflammatory, and allergic conditions, the mechanism of action of i.v. Igs (IVIg) is poorly understood. On the basis of the critical role of invariant NKT (iNKT) cells in allergic airway inflammation (AAI) and their constitutive expression of the low-affinity IgG receptor FcγRIIIA, we surmised that IVIg targets iNKT cells to exert their anti-inflammatory effect. We found that IVIg treatment significantly inhibited AAI in OVA-sensitized C57BL/6 mice and downregulated α-galactosylceramide-induced iNKT cell activation and cytokine production. Allergic responses were restored in iNKT cell-deficient mice by transferring iNKT cells from PBS- but not from IVIg-treated mice, suggesting that IVIg acts directly on activated iNKT cells that have a critical role in AAI. The inhibitory effects of IVIg on both iNKT cell activation/function and OVA-driven AAI were lost in FcγRIIIA(-/-) mice. Our data unravel an FcγRIIIA-dependent inhibitory effect of IVIg on activated iNKT cells that confers protection in AAI.
    The Journal of Immunology 02/2011; 186(6):3289-93. · 5.52 Impact Factor
  • Nephrologie & Therapeutique - NEPHROL THER. 01/2011; 7(5):384-384.
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    ABSTRACT: It has been documented that TLR7 stimulation triggers not only antiviral responses, but also alleviates experimental asthma. Considering the implication of invariant NKT (iNKT) cells in both situations, we postulated that they might contribute to the anti-inflammatory effect of TLR7 ligands. We show in this study that spleen cells activated by the TLR7 agonist resiquimod (R848) attenuate allergic inflammation upon adoptive transfer when they are recovered from wild-type, but not from iNKT cell-deficient Jα18(-/-) mice, which proves the specific involvement of this regulatory population. Furthermore, we provide evidence that IFN-γ is critical for the protective effect, which is lost when transferred iNKT cells are sorted from IFN-γ-deficient mice. In support of a direct activation of iNKT cells through TLR7 signaling in vivo, we observed a prompt increase of serum IFN-γ levels, associated with upregulation of CD69 expression on iNKT cells. Moreover, we demonstrate that iNKT cells effectively express TLR7 and respond to R848 in vitro by producing high levels of IFN-γ in the presence of IL-12, consistent with the conclusion that their contribution to the alleviation of allergic inflammation upon treatment with TLR7 ligands is mediated through IFN-γ.
    The Journal of Immunology 01/2011; 186(1):284-90. · 5.52 Impact Factor
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    ABSTRACT: Administration of attenuated pathogenic T cell clones, a procedure known as T cell vaccination, induces CD8+ T cells specific for peptides derived from the Vbeta-chain of the TCR presented by the MHC class Ib molecule, Qa-1 expressed on the vaccine cells. These regulatory CD8+ T cells have the capacity to control the activation of endogenous T cells expressing the same TCR Vbeta-chain as the vaccinating cells. We hypothesized that vaccination with NKT cells could also induce Qa-1-restricted CD8+ T cells that would control NKT cell activation. We tested this hypothesis in a murine model of Con A-induced hepatitis that is induced by NKT cells. Vaccination with NKT cells effectively induced protective Qa-1-restricted CD8+ T cells that prevented hepatitis. Surprisingly, upon vaccination with T cells expressing Vbeta-chains irrelevant to NKT cells, we discovered that the specificity of vaccine-induced Qa-1-restricted CD8+ T cells was not limited to the Vbeta-chain of the vaccinating cells. We further show that these regulatory Qa-1-restricted CD8+ T cells arise spontaneously upon polyclonal activation of T cells in the absence of deliberate T cell vaccination. These experiments provide new insight into a CD8+ T cell compartment that regulates the immediate reactivation of conventional T cells and NKT cells.
    The Journal of Immunology 06/2010; 184(12):6585-91. · 5.52 Impact Factor
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    ABSTRACT: Invariant NKT (iNKT) cells are a distinctive subtype of CD1d-restricted T cells involved in regulating autoimmunity and capable of producing various T helper type 1 (Th1), Th2 and Th17 cytokines. Activation of iNKT cells by their exogenous ligand alpha-galactosylceramide (alpha-GalCer) exerts therapeutic effects in autoimmune diseases such as rheumatoid arthritis (RA). However, the pathophysiological role of iNKT cells in RA, in the absence of exogenous stimulation, is incompletely understood. We investigated the potential pathophysiological effects of iNKT cells in mice with collagen-induced arthritis (CIA), a model of RA. We found that iNKT cells underwent activation only in the early phases of the disease (6 days post-induction). In the liver, but not the spleen or lymph nodes, this early activation led to the release of interleukins -4, -17A and -10 and of interferon-gamma; and an increased CD69 expression. Importantly, clinical and histological signs of arthritis were improved by the functional blockade of iNKT cells by a monoclonal antibody to CD1d at the early phase of the disease. This improvement was associated on day 6 post-induction with decreased expression of co-stimulatory molecules (CD80, CD86, CD40) on splenic dendritic cells and macrophages, whereas regulatory T-cell suppressive effects and proportions were not modified. Taken in concert, these findings suggest that iNKT cells are activated early in the course of CIA and contribute to the pathogenesis of arthritis. Therefore, iNKT-cell activation may be a valid treatment target in RA.
    Immunology 06/2010; 130(2):296-306. · 3.71 Impact Factor
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    ABSTRACT: IL-33, a new member of the IL-1 family, has been described as an important inducer of Th2 cytokines and mediator of inflammatory responses. In this study, we demonstrate that murine basophils sorted directly from the bone marrow, without prior exposure to IL-3 or Fc(epsilon)R cross-linking, respond to IL-33 alone by producing substantial amounts of histamine, IL-4, and IL-6. These cells express ST2 constitutively and generate a cytokine profile that differs from their IL-3-induced counterpart by a preferential production of IL-6. In vivo, IL-33 promotes basophil expansion in the bone marrow (BM) through an indirect mechanism of action depending on signaling through the beta(c) chain shared by receptors for IL-3, GM-CSF, and IL-5. IL-3 can still signal through its specific beta(IL-3) chain in these mutant mice, which implies that it is not the unique growth-promoting mediator in this setup, but requires IL-5 and/or GMCSF. Our results support a major role of the latter growth factor, which is readily generated by total BM cells as well as sorted basophils in response to IL-33 along with low amounts of IL-3. Furthermore, GM-CSF amplifies IL-3-induced differentiation of basophils from BM cells, whereas IL-5 that is also generated in vivo, affects neither their functions nor their growth in vitro or in vivo. In conclusion, our data provide the first evidence that IL-33 not only activates unprimed basophils directly, but also promotes their expansion in vivo through induction of GM-CSF and IL-3.
    The Journal of Immunology 09/2009; 183(6):3591-7. · 5.52 Impact Factor
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    ABSTRACT: IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-gamma rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-gamma production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.
    European Journal of Immunology 04/2009; 39(4):1046-55. · 4.97 Impact Factor
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    ABSTRACT: T cells differentiate into functionally distinct effector subsets in response to pathogen encounter. Cells of the innate immune system direct this process; CD1d-restricted invariant natural killer T (iNKT) cells, for example, can either promote or inhibit Th(1) and Th(2) responses. Recently, a new subset of CD4(+) T helper cells, called Th(17), was identified that is implicated in mucosal immunity and autoimmune disorders. To investigate the influence of iNKT cells on the differentiation of naïve T cells we used an adoptive transfer model of traceable antigen-specific CD4(+) T cells. Transferred naïve CD25(-)CD62L(+) CD4(+) T cells were primed by antigen immunization of the recipient mice, permitting their expansion and Th(17) differentiation. This study establishes that in vivo activation of iNKT cells during T-cell priming impedes the commitment of naïve T cells to the Th(17) lineage. In vivo cytokine neutralization experiments revealed a role for IL-4, IL-10, and IFN-gamma in the iNKT-cell-mediated regulation of T-cell lineage development. Moreover, by comparing IL-17 production by antigen-experienced T cells from unmanipulated wild-type mice and iNKT-cell-deficient mice, we demonstrate an enhanced Th(17) response in mice lacking iNKT cells. This invigorated Th(17) response reverts to physiological levels when iNKT cells are introduced into Jalpha18(-/-) mice by adoptive transfer, indicating that iNKT cells control the Th(17) compartment at steady state. We conclude that iNKT cells play an important role in limiting development of the Th(17) lineage and suggest that iNKT cells provide a natural barrier against Th(17) responses.
    Proceedings of the National Academy of Sciences 04/2009; 106(15):6238-43. · 9.81 Impact Factor
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    ABSTRACT: Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.
    Immunity 03/2009; 30(2):289-99. · 19.80 Impact Factor
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    ABSTRACT: Introduction Bien que l’incidence du diabète soit supérieure chez les femelles que chez les mâles «non obese diabetic» (NOD), l’influence des estrogènes n’a jamais été clairement identifiée dans ce modèle classique de diabète auto-immun. Compte tenu de leurs effets immunomodulateurs reconnus, notre objectif a été d’étudier si l’exposition chronique aux estrogènes influence la survenue d’un diabète chez la souris NOD. Matériels et méthodes Des souris NOD femelles ont été traitées de l’âge de 4 à 20 semaines par 17β-estradiol (E2, dose physiologique par voie sous-cutanée). L’influence des estrogènes endogènes a été étudiée en comparant des souris ovariectomisées à des souris intactes. Résultats Tandis que 80 % des souris contrôles non traitées développent un diabète durant la période de suivi, aucune des souris traitées par E2 n’est affectée (p < 0,001). Un effet protecteur total est également observé dans le modèle de diabète exacerbé par l’injection de cyclophosphamide (p < 0,001). L’administration d’E2 s’accompagne d’une réduction significative de l’insulite spontanée et du titre des anticorps anti-insuline. Suggérant que l’E2 n’altère pas le développement des lymphocytes T diabétogènes, le transfert de splénocytes provenant de souris NOD traitées ou non par E2 induit un diabète de façon similaire chez des souris NOD immunodéficientes (RAG-/-). Écartant l’hypothèse d’un rôle majeur des populations lymphocytaires régulatrices, un effet protecteur complet de l’E2 est retrouvé chez des souris NOD déficientes en lymphocytes Natural Killer T (Ja18-/-) ou en T régulateurs (CD28-/-). Enfin, bien que l’incidence du diabète spontané ne soit pas modifiée, la réalisation d’une ovariectomie se traduit par l’accélération de l’apparition du diabète induit par cyclophosphamide, révélant l’effet protecteur des estrogènes endogènes. Conclusion Les estrogènes préviennent l’insulite et l’apparition du diabète chez la souris NOD, permettant d’expliquer que, pour certaines tranches d’âge, l’incidence du diabète type 1 soit soumise à un dimorphisme sexuel. L’activation de la voie de signalisation des estrogènes pourrait donc représenter une nouvelle cible pour la prévention du diabète auto-immun.
    Diabetes & Metabolism - DIABETES METAB. 01/2009; 35.

Publication Stats

3k Citations
428.76 Total Impact Points

Institutions

  • 2012
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2011
    • Hôpital Paul-Brousse – Hôpitaux universitaires Paris-Sud
      Île-de-France, France
  • 2000–2011
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2010
    • Pierre and Marie Curie University - Paris 6
      • Centre de recherche des Cordeliers - UMR_S 872
      Paris, Ile-de-France, France
  • 2005–2010
    • Université Paris 13 Nord
      Île-de-France, France
  • 2009
    • Université Paris Descartes
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
  • 1995–2009
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Paris, Ile-de-France, France
    • Hôpital Universitaire Necker
      Lutetia Parisorum, Île-de-France, France
  • 2007
    • Centre Hospitalier Universitaire de Poitiers
      Poitiers, Poitou-Charentes, France
  • 2001
    • Robarts Research Institute
      London, Ontario, Canada
  • 1994–2001
    • French Institute of Health and Medical Research
      • Toulouse Purpan Pathophysiology Center CPTP
      Lutetia Parisorum, Île-de-France, France