European Journal of Immunology (EUR J IMMUNOL)

Publications in this journal

• Article: Unexpected T-cell recognition of an altered peptide ligand is driven by reversed thermodynamics

  Allerbring EB, Duru AD, Uchtenhagen H, Madhurantakam C, Tomek MB, Grimm S, Mazumdar PA, Friemann R, Uhlin M, Sandalova T, Nygren PA, Achour A
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  ABSTRACT: The molecular basis underlying T-cell recognition of MHC molecules presenting altered peptide ligands is still not well-established. A hierarchy of T-cell activation by MHC class I-restricted altered peptide ligands has been defined using the T-cell receptor P14 specific for H-2D(b) in complex with the immunodominant lymphocytic choriomeningitis virus peptide gp33 (KAVYNFATM). While substitution of tyrosine to phenylalanine (Y4F) or serine (Y4S) abolished recognition by P14, the TCR unexpectedly recognized H-2D(b) in complex with the alanine-substituted semiagonist Y4A, which displayed the most significant structural modification. The observed functional hierarchy gp33 > Y4A > Y4S = Y4F was neither due to higher stabilization capacity nor to differences in structural conformation. However, thermodynamic analysis demonstrated that while recognition of the full agonist H-2D(b) /gp33 was strictly enthalpy driven, recognition of the weak agonist H-2D(b) /Y4A was instead entropy driven with a large reduction in the favorable enthalpy term. The fourfold larger negative heat capacity derived for the interaction of P14 with H-2D(b) /gp33 compared with H-2D(b) /Y4A can possibly be explained by higher water entrapment at the TCR/MHC interface, which is also consistent with the measured opposite entropy contributions for the interactions of P14 with both MHCs. In conclusion, this study demonstrates that P14 makes use of different strategies to adapt to structural modifications in the MHC/peptide complex.
  European Journal of Immunology 09/2012;
• Article: Stable antigen-specific T cell hyporesponsiveness induced by tolerogenic dendritic cells from multiple sclerosis patients

  Dàlia Raïch-Regué, Laia Grau-López, Mar Naranjo-Gómez, Cristina Ramo-Tello, Ricardo Pujol-Borrell, Eva Martínez-Cáceres, Francesc E. Borràs
  European Journal of Immunology 01/2012;
• Article: Phenotypic and functional characteristics of ATP-hydrolysing CD4+CD39+ Treg subsets in patients with cancer.

  Schuler P, Hoffmann T, Whiteside TL
  European Journal of Immunology 01/2012;
• Article: nonclassical

  robert j, goyos
  European Journal of Immunology 01/2011;
• Article: Correction: Autologous and allogeneic HLA KIR ligand environments and activating KIR control KIR NK-cell functions.

  Maelig Morvan, Gaëlle David, Véronique Sébille, Aurore Perrin, Katia Gagne, Catherine Willem, Nolwenn Kerdudou, Laure Denis, Béatrice Clémenceau, Gilles Folléa, Jean-Denis Bignon, Christelle Retière
  European Journal of Immunology 02/2009; 39(1):324.
• Article: Correction: Frontline: Control of Anaplasma phagocytophilum, an obligate intracellular pathogen, in the absence of inducible nitric oxide synthase, phagocyte NADPH oxidase, tumor necrosis factor, Toll-like receptor (TLR)2 and TLR4, or the TLR adaptor molecule MyD88.

  Friederike D von Loewenich, Diana G Scorpio, Udo Reischl, J Stephen Dumler, Christian Bogdan
  European Journal of Immunology 02/2009; 39(1):324.
• Article: Welcome address - congress president.

  Reinhold E Schmidt
  European Journal of Immunology 01/2009; 38(12):3254-6.
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  Available from: i-med.ac.at

  Article: Nramp1-functionality increases iNOS expression via repression of IL-10 formation.

  Gernot Fritsche, Manfred Nairz, Ernst R Werner, Howard C Barton, Günter Weiss
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  ABSTRACT: In mice, resistance to certain intracellular microbes depends on the expression of a late phagosomal protein termed natural-resistance associated macrophage protein 1 (Nramp1, Slc11a1). Nramp1-functionality is associated with alterations of cellular iron homeostasis and a sustained pro-inflammatory immune response, including the formation of the antimicrobial effector molecule NO. To investigate the underlying mechanism we used RAW-264.7 murine macrophage cells stably transfected with a functional Nramp1 allele (RAW-37) or Nramp1 non-functional controls (RAW-21). We found that the production of and signalling by the anti-inflammatory cytokine IL-10 was significantly enhanced in macrophages lacking functional Nramp1. Upon infection of macrophages with Salmonella typhimurium pathogen survival was significantly better in RAW-21 than in RAW-37, which inversely correlated to NO and TNF-alpha formation. Addition of a neutralising anti-IL-10 antibody to RAW-21 cells led to a significantly reduced survival of S. typhimurium within these cells and enhanced formation of NO and TNF-alpha reaching levels comparable to that observed in cells bearing functional Nramp1. Oppositely, supplementation of iron to RAW-21 cells further increased IL-10 formation.Thus, Nramp1 mediates effective host defence in part via suppression of excessive IL-10 production which may relate to Nramp1-mediated reduction of cellular iron pools, thus strengthening antimicrobial effector mechanisms.
  European Journal of Immunology 12/2008; 38(11):3060-7.
• Article: Arginines in the CDR of anti-dsDNA autoantibodies facilitate cell internalization via electrostatic interactions.

  Ying-Chyi Song, Guang-Huan Sun, Tai-Ping Lee, Jason C Huang, Chia-Li Yu, Chia-Hung Chen, Shye-Jye Tang, Kuang-Hui Sun
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  ABSTRACT: Internalization of autoantibodies against double-stranded DNA (anti-dsDNA) is crucial to the pathogenesis of systemic lupus erythematosus. Anti-dsDNA may bind to cell-surface targets in order to facilitate the subsequent cell penetration of the anti-dsDNA. In this study, we observed that the 9D7 monoclonal anti-dsDNA autoantibody (9D7 mAb) penetrates into Jurkat cells via a novel alternative pathway. Endocytosis inhibitors or a lipid-raft inhibitor did not significantly change the penetration of 9D7 mAb into the Jurkat cells. However, heparin sulfate, chondroitin sulfate B, decaarginine and chondroitinase ABC significantly suppressed the internalization and the 9D7 mAb inhibited the internalization of Tat-GFP. Moreover, the penetration of the 9D7 mAb was significantly reduced in proteoglycan-deficient cells (pgs A-745). Positively charged amino acids including arginine are commonly found in the CDR of the 9D7 mAb. Point mutations to the arginine residues in the CDR of the H chain of the recombinant 9D7 mAb significantly attenuated its DNA-binding and cell-penetration abilities. These findings indicate that cell penetration of anti-dsDNA is due to the electrostatic interactions of arginine residues in the CDR with the negatively charged sulfated polysaccharides on the cell surface.
  European Journal of Immunology 12/2008; 38(11):3178-90.
• Article: Can NK cells be a therapeutic target in human cancer?

  Christopher J Chan, Daniel M Andrews, Mark J Smyth
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  ABSTRACT: Our current knowledge of NK-cell recognition and effector function suggests that it will be possible to design various new NK-cell-based immunotherapies against human cancer. The application of NK cells is already showing promise using HLA-mismatched haematopoietic stem cell transplantation for treatment of haematological malignancies. A better understanding of NK-cell heterogeneity and function will only broaden the applications for human cancer. Here we review the key developments that will propel this field.
  European Journal of Immunology 12/2008; 38(11):2964-8.
• Article: Killers and beyond: NK-cell-mediated control of immune responses.

  Christopher E Andoniou, Jérôme D Coudert, Mariapia A Degli-Esposti
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  ABSTRACT: Effective immunity requires coordinated activation of innate and adaptive immune responses. NK cells are principal mediators of innate immunity, able to respond to challenge quickly and generally without prior activation. The most acknowledged functions of NK cells are their cytotoxic potential and their ability to release large amounts of cytokines, especially IFN-gamma. Recently, it has become clear that NK cells are more than assassins. Indeed, NK cells play critical roles in shaping adaptive immunity.
  European Journal of Immunology 12/2008; 38(11):2938-42.
• Article: Non-cytotoxic protection by human NK cells in mucosal secondary lymphoid tissues.

  Christian Münz
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  ABSTRACT: Even though NK cells have been named for their spontaneous cytotoxicity, a large subpopulation of human NK cells primarily responds to activation with cytokine secretion and not killing. These CD56brightCD16(-) NK cells are abundant in secondary lymphoid tissues, can restrict pathogens that have breached mucosal barriers, and assist Th1 polarization during immune response priming. This exciting new aspect of NK-cell biology is discussed in this viewpoint.
  European Journal of Immunology 12/2008; 38(11):2946-8.
• Article: Experimental immunology in Zürich: the legacy of studying disease-related Ag.

  Christian Münz, Burkhard Becher
  European Journal of Immunology 12/2008; 38(11):2924-6.
• Article: IFN regulatory factor (IRF) 3/7-dependent and -independent gene induction by mammalian DNA that escapes degradation.

  Yasutaka Okabe, Kohki Kawane, Shigekazu Nagata
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  ABSTRACT: DNase II in macrophages cleaves the DNA of engulfed apoptotic cells and of nuclei expelled from erythroid precursor cells. Macrophages in DNase II-deficient mice accumulate undigested DNA and constitutively produce IFN-beta as well as TNF-alpha. The IFN-beta causes severe anemia in the DNase II(-/-) embryos, which die prenatally. On the other hand, when the DNase II gene is inactivated postnatally, mice develop polyarthritis owing to the TNF-alpha produced by macrophages. Here, we showed that the IFN-beta gene activation in DNase II(-/-) mice is dependent on IFN regulatory factor (IRF) 3 and 7. Accordingly, DNase II(-/-)IRF3(-/-)IRF7(-/-) mice do not suffer from anemia, but they still produce TNF-alpha, and age-dependently develop chronic polyarthritis. A microarray analysis of the gene expression in the fetal liver revealed a set of genes that is induced in DNase II(-/-) mice in an IRF3/IRF7-dependent manner, and another set that is induced independent of these factors. These results indicate that the mammalian chromosomal DNA that accumulates in macrophages due to inefficient degradation activates genes in both IRF3/IRF7-dependent and -independent manners.
  European Journal of Immunology 12/2008; 38(11):3150-8.
• Article: Excessive CpG 1668 stimulation triggers IL-10 production by cDC that inhibits IFN-alpha responses by pDC.

  Zoe Waibler, Martina Anzaghe, Abdo Konur, Shizuo Akira, Werner Müller, Ulrich Kalinke
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  ABSTRACT: Upon stimulation with a wide range of concentrations of CpG oligodeoxynucleotide 2216 (CpG 2216), plasmacytoid DC are induced to produce type I IFN (IFN-alpha/beta). In contrast, CpG 1668 shows a bell-shaped dose-response correlation, i.e. only intermediate but not high doses of CpG 1668 induce IFN-alpha/beta. Interestingly, high-dose CpG 1668 completely inhibited IFN-alpha responses induced by CpG 2216. Experiments using supernatant of high-dose CpG-1668-treated cells indicated that secreted inhibitor(s) mediated the IFN-alpha shut-off. Among modulating cytokines, IL-10 turned out to be one important negative regulator. In line with this, supernatants of IL-10-deficient DC cultures stimulated with high-dose CpG 1668 did not inhibit IFN-alpha production. Interestingly, high-dose CpG 1668 also inhibited IFN-alpha responses induced by the DNA-encoded mouse cytomegalovirus, whereas IFN-alpha responses induced by negative-strand RNA-encoded vesicular stomatitis virus were only marginally affected. Experiments with DC cultures devoid of TLR9 indicated that TLR9 was critically required to mediate stimulatory and modulatory signals by low and high concentrations of CpG 1668, respectively. Analysis of purified DC subsets showed that conventional DC were the main IL-10 producers, whereas plasmacytoid DC hardly produced any IL-10.
  European Journal of Immunology 12/2008; 38(11):3127-37.
• Article: Galectin-1 functions as a Th2 cytokine that selectively induces Th1 apoptosis and promotes Th2 function.

  Claudia C Motran, Karen M Molinder, Scot D Liu, Françoise Poirier, M Carrie Miceli
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  ABSTRACT: Galectin-1 has been implicated in regulating T-cell survival, function, and Th1/Th2 balance in several mouse models, though the molecular and cellular basis of its immuno-modulatory activity has not been completely elucidated. Therefore, we examined galectin-1 expression and activity within differentiated murine Th1 and Th2 subsets. While recombinant galectin-1 specifically bound to both T-cell subsets, Th1 and Th2 T cells expressed distinct combinations of galectin-1-reactive epitopes and were differentially responsive to galectin-1 exposure. Indeed, Th1 cells were more susceptible to galectin-1-induced death than Th2 cells. Th2 protection from apoptosis was correlated with expression of anti-apoptotic galectin-3. Further, galectin-1 promoted TCR-induced type 2 cytokine production by Th2 cells. Differentiated Th2 cells constitutively expressed high levels of galectin-1 and can be induced to produce even higher levels of galectin-1 with restimulation, whereas comparable levels of galectin-1 in Th1 cells were only observed after restimulation. Co-culturing experiments using galectin-1(-/-) and galectin-1+/+ Th1 and Th2 T cells demonstrated that Th2-derived galectin-1 induced Th1 apoptosis, whereas Th1-derived galectin-1 promoted Th2 cytokine production. These studies identify galectin-1 as a cross-regulatory cytokine that selectively antagonizes Th1 survival, while promoting TCR-induced Th2 cytokine production.
  European Journal of Immunology 12/2008; 38(11):3015-27.
• Article: The role of the PI3K-AKT kinase pathway in T-cell development beyond the beta checkpoint.

  Ling Xue, Leslie Chiang, Chulho Kang, Astar Winoto
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  ABSTRACT: The PI3K-AKT pathway can mediate diverse biological responses and is crucial for optimal immune responses and lymphocyte development. Deletion of PI3K subunits or AKT leads to blockage of T-cell development at the TCR-beta checkpoint. Studies with over-expression of constitutively activated AKT have implicated this pathway in anti-apoptosis of developing thymocytes and in development of regulatory T cells. However, the role of endogenous PI3K-AKT in T-cell development beyond the TCR-beta checkpoint remains unclear. Here, we inhibited the endogenous PI3K-AKT pathway in thymocytes after double negative stages by expressing the negative regulator, PTEN. These mice exhibit normal early T-cell development, but the transition from intermediate single positive to double positive (DP) thymocytes is inhibited, leading to a significantly decreased number of DP, single positive thymocytes and peripheral T cells. Proliferation of peripheral T cells is reduced but apoptosis of DP cells and subsequent T-cell maturation, including regulatory T cells, are normal. AKT phosphorylation can be readily observed in most WT T-cell compartments but not DP thymocytes in response to TCR activation. Thus, the PI3K-AKT pathway is crucial for the transition of intermediate single positive to DP thymocytes but is dispensable for apoptosis and maturation of developing thymocytes.
  European Journal of Immunology 12/2008; 38(11):3200-7.
• Article: Passive immunization with monoclonal antibody against a 70-kDa putative adhesin of Sporothrix schenckii induces protection in murine sporotrichosis.

  Rosana C Nascimento, Noeli M Espíndola, Rafaela A Castro, Pedro A C Teixeira, Carla V Loureiro y Penha, Leila M Lopes-Bezerra, Sandro R Almeida
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  ABSTRACT: Cell-mediated and innate immunity are considered the most important mechanisms of host defense against fungus infections. However, recent studies demonstrated that specific antibodies show different degrees of protection against mycosis. In a previous study, antigens secreted by Sporothrix schenckii induced a specific humoral response in infected animals, mainly against the 70-kDa molecule, indicating a possible participation of antibodies to this antigen in infection control. In the present study, an IgG1 mAb was produced against a 70-kDa glycoprotein of S. schenckii in order to better understand the effect of passive immunization of mice infected with S. schenckii. Results showed a significant reduction in the number of CFU in organs of mice when the mAb was injected before and during S. schenckii infection. Similar results were observed when T-cell-deficient mice were used. Moreover, in a second schedule treatment, the mAb was injected after infection was established, and again we observed a significant reduction in CFU associated with an increase of IFN-gammaproduction. Also, the 70-kDa antigen is shown to be a putative adhesin present on the surface of this fungus. In conclusion, we report for the first time the protective effect of a specific antibody against S. schenckii.
  European Journal of Immunology 12/2008; 38(11):3080-9.