Milena Hasan
Pasteur Institute
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Publication
Featured researches published by Milena Hasan.
Nature Immunology | 2002
Astrid Krmpotić; Dirk H. Busch; Ivan Bubić; Friedemann Gebhardt; Hartmut Hengel; Milena Hasan; Anthony A. Scalzo; Ulrich H. Koszinowski; Stipan Jonjić
The susceptibility of certain inbred mouse strains to murine cytomegalovirus (MCMV) is related to their inability to generate a strong natural killer (NK) cell response. We addressed here whether the MCMV susceptibility of the BALB/c strain is due to viral functions that control NK cell activation in a strain-specific manner. MCMV expresses two proteins, gp48 and gp40, that are encoded by the genes m06 and m152, respectively; they down-regulate major histocompatibility complex (MHC) class I expression at the plasma membrane. Using MCMV deletion mutants and revertants, we found that gp40 but not gp48 controls NK cell activation. Absence of gp40 improved antiviral NK cell control in BALB/c, but not C57BL/6, mice. Down-regulation of H-60, the high-affinity ligand for the NKG2D receptor, was the mechanism by which gp40 modulates NK cell activation. Thus, a single herpesvirus protein has a dual function in inhibiting both the adaptive as well as the innate immune response.
Journal of Experimental Medicine | 2007
Christian A. J. Vosshenrich; Sarah Lesjean-Pottier; Milena Hasan; Odile Richard-Le Goff; Erwan Corcuff; Ofer Mandelboim; James P. Di Santo
Interferon-producing killer dendritic cells (IKDCs) are a recently described subset of CD11cloB220+ cells that share phenotypic and functional properties of DCs and natural killer (NK) cells (Chan, C.W., E. Crafton, H.N. Fan, J. Flook, K. Yoshimura, M. Skarica, D. Brockstedt, T.W. Dubensky, M.F. Stins, L.L. Lanier, et al. 2006. Nat. Med. 12:207–213; Taieb, J., N. Chaput, C. Menard, L. Apetoh, E. Ullrich, M. Bonmort, M. Pequignot, N. Casares, M. Terme, C. Flament, et al. 2006. Nat. Med. 12:214–219). IKDC development appears unusual in that cytokines using the interleukin (IL)-2 receptor β (IL-2Rβ) chain but not those using the common γ chain (γc) are necessary for their generation. By directly comparing Rag2−/−γc −/y, Rag2−/−IL-2Rβ−/−, Rag2−/−IL-15−/−, and Rag2−/−IL-2−/− mice, we demonstrate that IKDC development parallels NK cell development in its strict IL-15 dependence. Moreover, IKDCs uniformly express NK-specific Ncr-1 transcripts (encoding NKp46), whereas NKp46+ cells are absent in Ncr1gfp/+γc −/y mice. Distinguishing features of IKDCs (CD11cloB220+MHC-II+) were carefully examined on developing NK cells in the bone marrow and on peripheral NK cells. As B220 expression was heterogeneous, defining B220lo versus B220hi NK1.1+ NK cells could be considered as arbitrary, and few phenotypic differences were noted between NK1.1+ NK cells bearing different levels of B220. CD11c expression did not correlate with B220 or major histocompatibility complex (MHC) class II (MHC-II) expression, and most MHC-II+ NK1.1+ cells did not express B220 and were thus not IKDCs. Finally, CD11c, MHC-II, and B220 levels were up-regulated on NK1.1+ cells upon activation in vitro or in vivo in a proliferation-dependent fashion. Our data suggest that the majority of CD11cloB220+ “IKDC-like” cells represent activated NK cells.
Journal of Experimental Medicine | 2005
Astrid Krmpotić; Milena Hasan; Andrea Loewendorf; Tanja Saulig; Anne Halenius; Tihana Lenac; Bojan Polić; Ivan Bubić; Anja Kriegeskorte; Ester Pernjak-Pugel; Martin Messerle; Hartmut Hengel; Dirk H. Busch; Ulrich H. Koszinowski; Stipan Jonjić
The NK cell–activating receptor NKG2D interacts with three different cellular ligands, all of which are regulated by mouse cytomegalovirus (MCMV). We set out to define the viral gene product regulating murine UL16-binding protein-like transcript (MULT)-1, a newly described NKG2D ligand. We show that MCMV infection strongly induces MULT-1 gene expression, but surface expression of this glycoprotein is nevertheless completely abolished by the virus. Screening a panel of MCMV deletion mutants defined the gene m145 as the viral regulator of MULT-1. The MCMV m145-encoded glycoprotein turned out to be necessary and sufficient to regulate MULT-1 by preventing plasma membrane residence of MULT-1. The importance of MULT-1 in NK cell regulation in vivo was confirmed by the attenuating effect of the m145 deletion that was lifted after NK cell depletion. Our findings underline the significance of escaping MULT-1/NKG2D signaling for viral survival and maintenance.
Journal of Virology | 2005
Milena Hasan; Astrid Krmpotić; Zsolt Ruzsics; Ivan Bubić; Tihana Lenac; Anne Halenius; Andrea Loewendorf; Martin Messerle; Hartmut Hengel; Stipan Jonjić; Ulrich H. Koszinowski
ABSTRACT Both human and mouse cytomegaloviruses (CMVs) encode proteins that inhibit the activation of NK cells by down-regulating cellular ligands for the activating NK cell receptor NKG2D. Up to now, three ligands for the NKG2D receptor, named RAE-1, H60, and MULT-1, have been identified in mice. The resistance of mouse strains to murine CMV (MCMV) infection is determined by their ability to generate an effective NK cell response. The MCMV gene m152, a member of the m145 gene family, down-regulates the expression of RAE-1 in order to avoid NK cell control in vivo. Here we report that the m155 gene, another member of the m145 gene family, encodes a protein that interferes with the expression of H60 on the surfaces of infected cells. Deletion of the m155 gene leads to an only partial restoration of H60 expression on the cell surface, suggesting the involvement of another, so far unknown, viral inhibitor. In spite of this, an m155 deletion mutant virus shows NK cell-dependent attenuation in vivo. The acquisition of endo-β-N-acetylglucosaminidase H resistance and the preserved half-life of H60 in MCMV-infected cells indicate that the m155-mediated effect must take place in a compartment after H60 exits from the ERGIC-cis-Golgi compartment.
Blood | 2010
Cécile Alanio; Fabrice Lemaître; Helen K. W. Law; Milena Hasan; Matthew L. Albert
The number of antigen-specific naive CD8(+) T cells is believed to be important in the shaping of adaptive immune responses, and is predictive for the magnitude of priming responses in mouse models. Because of extremely low precursor frequencies, knowledge about these cells comes from indirect techniques and estimations. Here, we present a strategy based on the combination of tetramer staining, magnetic-bead enrichment, and multiparametric cytometry, which permitted direct detection and analysis of CD8(+) T cells reactive for 6 different naive epitopes (MART-1(26-35), HIV-1 Gag p17(77-85), hepatitis C virus [HCV] NS3(1406-1415), HCV Core(132-140), NY-ESO-1(157-165), and cytomegalovirus [CMV] pp65(495-503)). Interestingly, we detected higher than 100-fold differences in precursor frequency across these epitopes (from 0.6 x 10(-6) to 1.3 x 10(-4)), but conserved frequencies among humans. Development of a procedure for direct assessment of T-cell precursor frequency in humans has important implications, with particular relevance to vaccine development and monitoring of tumor and self-reactive T cells.
Archives of Medical Research | 2002
Sonja Pezelj-Ribarić; Ivica Anić; Ivana Brekalo; Ivana Miletić; Milena Hasan; Marica Šimunović-Šoškić
Abstract Background The aim of this study was to determine concentrations of tumor necrosis factor-α (TNF-α) in normal, painful, and asymptomatic human dental pulps. Methods Pulps were obtained from three groups of teeth, including healthy teeth, asymptomatic teeth with caries and/or large restoration, and symptomatic teeth with clinical diagnosis of irreversible pulpitis. Pulpal tissues were collected, prepared, and analyzed for TNF-α concentration by ELISA technique. Results Nonparametric Kruskal-Wallis test revealed significant differences between TNF-α concentration in normal samples (64.01 ± 53.12 pg/g) and irreversible symptomatic pulpal tissue (1,962.99 ± 1,288.75 pg/g), between irreversible symptomatic and asymptomatic (1,120.09 ± 649.72 pg/g), and between normal and irreversible asymptomatic pulpal tissue ( p = 0.000). Conclusions TNF-α may be an objective marker for determining extent of pulpal inflammation associated with irreversible pulpitis.
Immunity | 2014
Darragh Duffy; Vincent Rouilly; Valentina Libri; Milena Hasan; Benoît Beitz; Mikael David; Alejandra Urrutia; Aurélie Bisiaux; Samuel T. LaBrie; Annick Dubois; Ivo G. Boneca; Cécile Delval; Stéphanie Thomas; Lars Rogge; Manfred Schmolz; Lluis Quintana-Murci; Matthew L. Albert; Laurent Abel; Andrés Alcover; Philippe Bousso; Ana Cumano; Marc Daëron; Caroline Demangel; Ludovic Deriano; James P. Di Santo; Françoise Dromer; Gérard Eberl; Jost Enninga; Antonio A. Freitas; Ivo Gomperts-Boneca
Standardization of immunophenotyping procedures has become a high priority. We have developed a suite of whole-blood, syringe-based assay systems that can be used to reproducibly assess induced innate or adaptive immune responses. By eliminating preanalytical errors associated with immune monitoring, we have defined the protein signatures induced by (1) medically relevant bacteria, fungi, and viruses; (2) agonists specific for defined host sensors; (3) clinically employed cytokines; and (4) activators of T cell immunity. Our results provide an initial assessment of healthy donor reference values for induced cytokines and chemokines and we report the failure to release interleukin-1α as a common immunological phenotype. The observed naturally occurring variation of the immune response may help to explain differential susceptibility to disease or response to therapeutic intervention. The implementation of a general solution for assessment of functional immune responses will help support harmonization of clinical studies and data sharing.
Journal of Virology | 2010
Cinzia Nobile; Dominika Rudnicka; Milena Hasan; Nathalie Aulner; Françoise Porrot; Christophe Machu; Olivier Renaud; Marie-Christine Prévost; Claire Hivroz; Olivier Schwartz; Nathalie Sol-Foulon
ABSTRACT The HIV-1 Nef protein is a pathogenic factor modulating the behavior of infected cells. Nef induces actin cytoskeleton changes and impairs cell migration toward chemokines. We further characterized the morphology, cytoskeleton dynamics, and motility of HIV-1-infected lymphocytes. By using scanning electron microscopy, confocal immunofluorescence microscopy, and ImageStream technology, which combines flow cytometry and automated imaging, we report that HIV-1 induces a characteristic remodeling of the actin cytoskeleton. In infected lymphocytes, ruffle formation is inhibited, whereas long, thin filopodium-like protrusions are induced. Cells infected with HIV with nef deleted display a normal phenotype, and Nef expression alone, in the absence of other viral proteins, induces morphological changes. We also used an innovative imaging system to immobilize and visualize living individual cells in suspension. When combined with confocal “axial tomography,” this technique greatly enhances three-dimensional optical resolution. With this technique, we confirmed the induction of long filopodium-like structures in unfixed Nef-expressing lymphocytes. The cytoskeleton reorganization induced by Nef is associated with an important impairment of cell movements. The adhesion and spreading of infected cells to fibronectin, their spontaneous motility, and their migration toward chemokines (CXCL12, CCL3, and CCL19) were all significantly decreased. Therefore, Nef induces complex effects on the lymphocyte actin cytoskeleton and cellular morphology, which likely impacts the capacity of infected cells to circulate and to encounter and communicate with bystander cells.
European Journal of Immunology | 2002
Milena Hasan; Bojan Polić; Marina Bralic; Stipan Jonjić; Klaus Rajewsky
The expression of the preB cell receptor (preBCR), composed of the μ chain, surrogate light chains and the Igα /Igβ signal transduction unit, permits further differentiation of Bcell precursors. C57BL/6 mice homozygous for an inactivating mutation of the membrane exon of the μ chain gene (C57BL/6μ MT/μ MT) cannot form a preBCR and are, consequently, devoid of mature B lymphocytes. Here we present evidence that the block of B cell development by the μ MT mutation is incomplete in BALB/c mice. Unlike C57BL/6μ MT/μ MT, BALB/cμ MT/μ MT mice generate small numbers of mature B cells, accumulate plasma cells and produce high levels of all immunoglobulin isotypes, except IgM. The observed phenomenon seems to be controlled by a single genetic locus that is not linked to IgH.
Blood | 2013
Marcos García; Roel G. J. Klein Wolterink; Fabrice Lemâitre; Carine Le Goff; Milena Hasan; Rudi W. Hendriks; Ana Cumano; James P. Di Santo
Transcription factors orchestrate T-lineage differentiation in the thymus. One critical checkpoint involves Notch1 signaling that instructs T-cell commitment at the expense of the B-lineage program. While GATA-3 is required for T-cell specification, its mechanism of action is poorly understood. We show that GATA-3 works in concert with Notch1 to commit thymic progenitors to the T-cell lineage via 2 distinct pathways. First, GATA-3 orchestrates a transcriptional “repertoire” that is required for thymocyte maturation up to and beyond the pro-T-cell stage. Second, GATA-3 critically suppresses a latent B-cell potential in pro–T cells. As such, GATA-3 is essential to sealing in Notch-induced T-cell fate in early thymocyte precursors by promoting T-cell identity through the repression of alternative developmental options.