bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCR7-CCL19/CCL21-Regulated Dendritic Cells Are Responsible for Effectiveness of Sublingual Vaccination
Authors: Song Joo-Hye , Kim Jung-Im , Kwon Hyung-Joon , Shim Doo-Hee , Parajuli Nirmala , Cuburu Nicolas , Czerkinsky Cecil , Kweon Mi-Na 
Published: May 2009

Abstract
Our previous studies demonstrated the potential of the sublingual (s.l.) route for delivering vaccines capable of inducing mucosal as well as systemic immune responses. Those findings prompted us to attempt to identify possible inductive mechanism of s.l. vaccination for immune responses. Within 2 h after s.l. administration with cholera toxin (CT), significantly higher numbers of MHC class II+ cells accumulated in the s.l. mucosa. Of note, there were brisk expression levels of both CCL19 and CCL21 in cervical lymph nodes (CLN) 24 h after s.l. vaccination with CT. In reconstitution experiments using OVA-specific CD4+ or CD8+ T cells, s.l. vaccination elicited strong Ag-specific T cell proliferation mainly in CLN. Interestingly, Ag-specific T cell proliferation completely disappeared in CD11c-depleted and CCR7−/− mice but not in Langerin-depleted, macrophage-depleted, and CCR6−/− mice. Similar to CD4+ T cell responses, induction of Ag-specific IgG (systemic) and IgA (mucosal) Ab responses were significantly reduced in CD11c-depleted and CCR7−/− mice after s.l. vaccination with OVA plus CT. Although CD8α− dendritic cells ferried Ag from the s.l. mucosa, both migratory CD8α− and resident CD8α+ dendritic cells were essential to prime CD4+ T cells in the CLN. On the basis of these findings, we believe that CCR7 expressed CD8α−CD11c+ cells ferry Ag in the s.l. mucosa, migrate into the CLN, and share the Ag with resident CD8α+CD11c+ cells for the initiation of Ag-specific T and B cell responses following s.l. challenge. We propose that the s.l. mucosa is one of the effective mucosal inductive sites regulated by the CCR7-CCL19/CCL21 pathway.
The Role of Intrapulmonary De Novo Lymphoid Tissue in Obliterative Bronchiolitis after Lung Transplantation
Authors: Sato Masaaki , Hirayama Shin , Hwang David M. , Lara-Guerra Humberto , Wagnetz Dirk , Waddell Thomas K. , Liu Mingyao , Keshavjee Shaf 
Published: May 2009

Abstract
Chronic rejection after lung transplantation is manifested as obliterative bronchiolitis (OB). The development of de novo lymphoid tissue (lymphoid neogenesis) may contribute to local immune responses in small airways. Compared with normal lungs, the lung tissue of 13 lung transplant recipients who developed OB demonstrated a significantly larger number of small, airway-associated, peripheral node addressin-positive (PNAd+) high endothelial venules (HEVs) unique to lymphoid tissue (p &lt; 0.001). HEVs were most abundant in lesions of lymphocytic bronchiolitis and “active” OB infiltrated by lymphocytes compared with those of “inactive” OB. T cells in lymphocytic bronchiolitis and active OB were predominantly of the CD45RO+CCR7− effector memory phenotype. Similar lymphoid tissue was also observed in the rat lung after intrapulmonary transplantation of allograft trachea (Brown Norway (BN) to Lewis), but not after isograft transplantation. Subsequent orthotopic transplantation of the recipient Lewis lung containing a BN trachea into an F1 (Lewis × BN) rat demonstrated stable homing of Lewis-derived T cells in the lung and their Ag-specific effector function against the secondary intrapulmonary BN trachea. In conclusion, we found de novo lymphoid tissue in the lung composed of effector memory T cells and HEVs but lacking delineated T cell and B cell zones. This de novo lymphoid tissue may play a critical role in chronic local immune responses after lung transplantation.
Airway Delivery of Silica Increases Susceptibility to Mycobacterial Infection in Mice: Potential Role of Repopulating Macrophages
Authors: Pasula Rajamouli , Britigan Bradley E. , Turner Joanne , Martin William J. 
Published: May 2009

Abstract
Silica exposure results in an increased lifelong risk of developing mycobacterial pulmonary infections. To date, there are no animal models that replicate this finding to permit assessment of the mechanisms underlying susceptibility to mycobacterial infection. To test the hypothesis that prior silica exposure increases risk of mycobacterial infection, we intratracheally (I.T.) administered silica, a control dust (Al2O3) or saline into mechanically ventilated C57BL/6 mice. Later, the mice received Mycobacterium avium or Mycobacterium tuberculosis I.T. Mice were sacrificed at defined time points and mycobacteria in lung homogenates were quantified. M. avium or M. tuberculosis infection was markedly increased in silica-exposed mice compared with mice exposed to either Al2O3 or saline beginning 3 wk after silica exposure. Similarly, lung sections from silica-exposed mice had many more acid fast bacilli+ (AFB+) organisms than from control mice. Alveolar macrophages (AMs) from bronchoalveolar lavage of silica-exposed mice also revealed a higher number of mycobacteria compared with mice treated with Al2O3 or saline. In addition, passive transfer of AMs from silica-exposed mice to control mice increased M. tuberculosis susceptibility. These results indicate that silica exposure converts mycobacteria-resistant mice into mycobacteria-susceptible mice via a process that likely involves a new population of AMs that are more susceptible to mycobacterial infection.
Generation of T Cells from Human Embryonic Stem Cell-Derived Hematopoietic Zones
Authors: Timmermans Frank , Velghe Imke , Vanwalleghem Lieve , De Smedt Magda , Van Coppernolle Stefanie , Taghon Tom , Moore Harry D. , Leclercq Georges , Langerak Anton W. , Kerre Tessa , Plum Jean , Vandekerckhove Bart 
Published: May 2009

Abstract
Human embryonic stem cells (hESC) are pluripotent stem cells. A major challenge in the field of hESC is the establishment of specific differentiation protocols that drives hESC down a particular lineage fate. So far, attempts to generate T cells from hESC in vitro were unsuccessful. In this study, we show that T cells can be generated in vitro from hESC-derived hematopoietic precursor cells present in hematopoietic zones (HZs). These zones are morphologically similar to blood islands during embryonic development, and are formed when hESC are cultured on OP9 stromal cells. Upon subsequent transfer of these HZs on OP9 cells expressing high levels of Delta-like 1 and in the presence of growth factors, cells expand and differentiate to T cells. Furthermore, we show that T cells derive exclusively from a CD34highCD43low population, further substantiating the notion that hESC-derived CD34highCD43low cells are formed in HZs and are the only population containing multipotent hematopoietic precursor cells. Differentiation to T cells sequentially passes through the physiological intermediates: CD34+CD7+ T/NK committed, CD7+CD4+CD8− immature single positive, CD4+CD8+ double positive, and finally CD3+CD1−CD27+ mature T cell stages. TCRαβ+ and TCRγδ+ T cells are generated. Mature T cells are polyclonal, proliferate, and secrete cytokines in response to mitogens. This protocol for the de novo generation of T cells from hESC could be clinically and scientifically relevant.
The Golgi-Associated Protein p115 Mediates the Secretion of Macrophage Migration Inhibitory Factor
Authors: Merk Melanie , Baugh John , Zierow Swen , Leng Lin , Pal Utpal , Lee Seung Joon , Ebert Antje D. , Mizue Yuka , Trent John O. , Mitchell Robert , Nickel Walter , Kavathas Paula B. , Bernhagen Jürgen , Bucala Richard 
Published: May 2009

Abstract
Macrophage migration inhibitory factor (MIF) is a leaderless protein that is secreted from cells by a specialized, nonclassical export pathway. The release of MIF nevertheless is regulated and its production in response to different inflammatory, mitogenic, and hormonal stimuli plays an important role in diverse physiologic and pathologic processes. We report herein the identification of the Golgi complex-associated protein p115 as an intracellular binding partner for MIF. MIF interacts with p115 in the cytoplasm and the stimulated secretion of MIF results in the accumulation of both proteins in supernatants, which is consistent with MIF release from cells in conjunction with p115. The depletion of p115 from monocytes/macrophages decreases the release of MIF but not other cytokines following inflammatory stimulation or intracellular bacterial infection. Notably, the small molecule MIF inhibitor 4-iodo-6-phenylpyrimidine inhibits MIF secretion by targeting the interaction between MIF and p115. These data reveal p115 to be a critical intermediary component in the regulated secretion of MIF from monocytes/macrophages.
Cutting Edge: CD28 Engagement Releases Antigen-Activated Invariant NKT Cells from the Inhibitory Effects of PD-1
Authors: Wang Jianxiong , Cheng Lu , Wondimu Zenebech , Swain Mark , Santamaria Pere , Yang Yang 
Published: May 2009

Abstract
Costimulatory and coinhibitory signals are important for the maintenance of immune homeostasis both in the steady state and during immune responses. In this study, we explore the relative contributions of these signals to the rapid production of large amounts of cytokines by activated invariant NKT cells (iNKT cells). We find that upon antigenic stimulation, iNKT cells rapidly up-regulate programmed death (PD)-1 and induce high levels of PD ligand 1 and costimulatory molecules on the surface of cognate Ag-presenting dendritic cells and that iNKT cells require a CD28 signal to secrete cytokines in the presence of a PD-1/PD ligand 1 interaction. CD28-deficient iNKT cells synthesized but failed to secrete cytokines during activation, and blockade of the PD-1 pathway restored the ability of CD28-deficient iNKT cells to secrete cytokines. The opposing functions of CD28 and PD-1 thus tightly regulate the unique effector function iNKT cells.
Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells
Authors: Grosso Joseph F. , Goldberg Monica V. , Getnet Derese , Bruno Tullia C. , Yen Hung-Rong , Pyle Kristin J. , Hipkiss Edward , Vignali Dario A. A. , Pardoll Drew M. , Drake Charles G. 
Published: May 2009

Abstract
Lymphocyte Activation Gene-3 (LAG-3) is a transmembrane protein that binds MHC class II, enhances regulatory T cell activity, and negatively regulates cellular proliferation, activation, and homeostasis of T cells. Programmed Death 1 (PD-1) also negatively regulates T cell function. LAG-3 and PD-1 are both transiently expressed on CD8 T cells that have been stimulated during acute activation. However, both LAG-3 and PD-1 remain on CD8 T cells at high levels after stimulation within tolerizing environments. Our previous data demonstrated that blockade of either LAG-3 or PD-1 using mAb therapy in combination with vaccination restores the function of tolerized Ag-specific CD8 T cells in models of self and tumor tolerance. It is unclear whether tolerized CD8 T cells coexpress PD-1 and LAG-3 or whether PD-1 and LAG-3 mark functionally distinct populations of CD8 T cells. In this study, we describe three populations of CD8 T cells activated under tolerizing conditions based on LAG-3 and PD-1 staining, each with distinct phenotypic and functional characteristics. From a mechanistic perspective, both Ag concentration and proinflammatory signals control the expression of LAG-3 and PD-1 phenotypes on CD8 T cells under activating and tolerizing conditions. These results imply that signaling through the PD-1 and LAG-3 pathways have distinct functional consequences to CD8 T cells under tolerizing conditions and manipulation of both Ag and cytokine signaling can influence CD8 tolerance through LAG-3 and PD-1.
Antiviral Antibodies Target Adenovirus to Phagolysosomes and Amplify the Innate Immune Response
Authors: Zaiss Anne K. , Vilaysane Akosua , Cotter Matthew J. , Clark Sharon A. , Meijndert H. Christopher , Colarusso Pina , Yates Robin M. , Petrilli Virginie , Tschopp Jurg , Muruve Daniel A. 
Published: May 2009

Abstract
Adenovirus is a nonenveloped dsDNA virus that activates intracellular innate immune pathways. In vivo, adenovirus-immunized mice displayed an enhanced innate immune response and diminished virus-mediated gene delivery following challenge with the adenovirus vector AdLacZ suggesting that antiviral Abs modulate viral interactions with innate immune cells. Under naive serum conditions in vitro, adenovirus binding and internalization in macrophages and the subsequent activation of innate immune mechanisms were inefficient. In contrast to the neutralizing effect observed in nonhematopoietic cells, adenovirus infection in the presence of antiviral Abs significantly increased FcR-dependent viral internalization in macrophages. In direct correlation with the increased viral internalization, antiviral Abs amplified the innate immune response to adenovirus as determined by the expression of NF-κB-dependent genes, type I IFNs, and caspase-dependent IL-1β maturation. Immune serum amplified TLR9-independent type I IFN expression and enhanced NLRP3-dependent IL-1β maturation in response to adenovirus, confirming that antiviral Abs specifically amplify intracellular innate pathways. In the presence of Abs, confocal microscopy demonstrated increased targeting of adenovirus to LAMP1-positive phagolysosomes in macrophages but not epithelial cells. These data show that antiviral Abs subvert natural viral tropism and target the adenovirus to phagolysosomes and the intracellular innate immune system in macrophages. Furthermore, these results illustrate a cross-talk where the adaptive immune system positively regulates the innate immune system and the antiviral state.
Lipoproteins in Staphylococcus aureus Mediate Inflammation by TLR2 and Iron-Dependent Growth In Vivo
Authors: Schmaler Mathias , Jann Naja J. , Ferracin Fabrizia , Landolt Lea Z. , Biswas Lalitha , Götz Friedrich , Landmann Regine 
Published: May 2009

Abstract
Lipoproteins (Lpp) are ligands of TLR2 and signal by the adaptor MyD88. As part of the bacterial cell envelope, Lpp are mainly involved in nutrient acquisition for Staphylococcus aureus. The impact of Lpp on TLR2-MyD88 activation for S. aureus in systemic infection is unknown. S. aureus strain SA113 deficient in the enzyme encoded by the prolipoprotein diacylglyceryl transferase gene (Δlgt), which attaches the lipid anchor to pro-Lpp, was used to study benefits and costs of Lpp maturation. Lpp in S. aureus induced early and strong cytokines by TLR2-MyD88 signaling in murine peritoneal macrophages. Lpp contributed via TLR2 to pathogenesis of sepsis in C57BL/6 mice with IL-1β, chemokine-mediated inflammation, and high bacterial numbers. In the absence of MyD88-mediated inflammation, Lpp allowed bacterial clearing from liver devoid of infiltrating cells, but still conferred a strong growth advantage in mice, which was shown to rely on iron uptake and storage in vitro and in vivo. With iron-restricted bacteria, the Lpp-related growth advantage was evident in infection of MyD88−/−, but not of C57BL/6, mice. On the other hand, iron overload of the host restored the growth deficit of Δlgt in MyD88−/−, but not in immunocompetent C57BL/6 mice. These results indicate that iron acquisition is improved by Lpp of S. aureus but is counteracted by inflammation. Thus, lipid anchoring is an evolutionary advantage for S. aureus to retain essential proteins for better survival in infection.
CD27 Expression on CD4+ T Cells Differentiates Effector from Regulatory T Cell Subsets in the Lung
Authors: Mack Douglas G. , Lanham Allison M. , Palmer Brent E. , Maier Lisa A. , Fontenot Andrew P. 
Published: May 2009

Abstract
Beryllium exposure in the workplace can result in chronic beryllium disease, a granulomatous lung disorder characterized by CD4+ T cell alveolitis and progressive lung fibrosis. A large number of the CD4+ T cells recruited to the lung in chronic beryllium disease recognize beryllium in an Ag-specific manner and express Th1-type cytokines following T cell activation. Beryllium-responsive CD4+ T cells in the bronchoalveolar lavage (BAL) express an effector memory T cell phenotype and recognize beryllium in a CD28-independent manner. In this study, we show that the majority of beryllium-responsive CD4+ T cells in BAL have lost CD27 expression, whereas a subset of beryllium-responsive cells in blood retains expression of this costimulatory molecule. In addition, loss of CD27 on BAL CD4+ T cells inversely correlates with markers of lung inflammation. A small population of BAL CD4+ T cells retains CD27 expression, and these CD4+CD27+ T cells contain the FoxP3-expressing, naturally occurring regulatory T (Treg) cell subset. Coexpression of CD27 and CD25 identifies the majority of FoxP3-expressing Treg cells in blood and BAL, and these cells express potent suppressor function. Taken together, these findings suggest that CD27 is differentially expressed between effector T cells from the inflamed lung and can be used in conjunction with CD25 to isolate Treg cells and assess their functional capacity in an ongoing adaptive immune response in a target organ.
Inhibition and Genetic Deficiency of p38 MAPK Up-Regulates Heme Oxygenase-1 Gene Expression via Nrf2
Authors: Naidu Srivatsava , Vijayan Vijith , Santoso Sentot , Kietzmann Thomas , Immenschuh Stephan 
Published: May 2009

Abstract
Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. The HO products carbon monoxide and bilirubin not only provide antioxidant cytoprotection, but also have potent anti-inflammatory and immunomodulatory functions. Although HO-1 has previously been shown to be induced by various stimuli via activation of the p38 MAPK signaling pathway, the role of this protein kinase for HO-1 gene regulation is largely unknown. In the present study, it is demonstrated that pharmacological inhibitors of p38 induced HO-1 expression in monocytic cells. Moreover, basal HO-1 gene expression levels were markedly higher in untreated murine embryonic fibroblasts (MEF) from p38α−/− mice compared with those from wild-type mice. Transfection studies with luciferase reporter gene constructs indicate that increased HO-1 gene expression via inhibition of p38 was mediated by the transcription factor Nrf2, which is a central regulator of the cellular oxidative stress response. Accordingly, inhibitors of p38 induced binding of nuclear proteins to a Nrf2 target sequence of the HO-1 promoter, but did not affect HO-1 protein expression and promoter activity in Nrf2−/− MEF. Genetic deficiency of p38 led to enhanced phosphorylation of ERK and increased cellular accumulation of reactive oxygen species. In addition, pharmacological blockage of ERK and scavenging of reactive oxygen species with N-acetylcysteine reduced HO-1 gene expression in p38−/− MEF, respectively. Taken together, it is demonstrated that pharmacological inhibition and genetic deficiency of p38 induce HO-1 gene expression via a Nrf2-dependent mechanism in monocytic cells and MEF.
Osteopontin Enhances Phagocytosis through a Novel Osteopontin Receptor, the αXβ2 Integrin
Authors: Schack Lotte , Stapulionis Romualdas , Christensen Brian , Kofod-Olsen Emil , Skov Sørensen Uffe B. , Vorup-Jensen Thomas , Sørensen Esben S. , Höllsberg Per 
Published: May 2009

Abstract
Osteopontin (OPN) is a cytokine with multiple functions, including immune defense mechanisms against invading microorganisms. OPN-deficient mice are impaired in clearing intracellular pathogens, suggesting an important role of OPN during phagocytosis, but it remains to be defined how OPN may enhance this innate immune process. Here, we demonstrate that OPN binds to monocytes, but not resting T cells, NK cells, or B cells, and mediates chemoattraction of IL-1-activated human monocytes. Moreover, OPN binds in a specific manner to all known serotypes of the two bacterial species Streptococcus agalactiae and Staphylococcus aureus and opsonizes these bacteria for phagocytosis. We identify the integrin αXβ2 (CD11c/CD18), which is highly expressed on the cell surface of monocytes, as a novel OPN receptor. To eliminate the contribution from other molecular interactions between the bacteria and the phagocyte, we show that OPN-coated synthetic beads are phagocytosed in an αXβ2 integrin-dependent manner. The ligand recognition does not involve the RGD motif previously reported to support binding of OPN to integrins. Taken together, these data identify the αXβ2 integrin as a novel OPN receptor that is required for OPN-mediated phagocytosis, thereby elucidating an important mechanism of an innate immune function of OPN.
Ig Synthesis and Class Switching Do Not Require the Presence of the hs4 Enhancer in the 3′ IgH Regulatory Region
Authors: Vincent-Fabert Christelle , Truffinet Véronique , Fiancette Remi , Cogné Nadine , Cogné Michel , Denizot Yves 
Published: May 2009

Abstract
Several studies have reported that regulatory elements located 3′ of the IgH locus (namely hs3a, hs1,2, hs3b, and hs4) might play a role during class switch recombination (CSR) and Ig synthesis. While individual deletion of hs3a or hs1,2 had no effect, pairwise deletion of hs3b (an inverted copy of hs3a) and hs4 markedly affected CSR and Ig expression. Among these two elements, hs4 was tentatively presented with the master role due to its unique status within the 3′ regulatory region: distal position outside repeated regions, early activation in pre-B cells, strong activity throughout B cell ontogeny. To clarify its role, we generated mice with a clean deletion of the hs4 after replacement with a floxed neoR cassette. Surprisingly, and as for previous deletion of hs3a or hs1,2, deletion of hs4 did not affect either in vivo CSR or the secretion level of any Ig isotype. In vitro CSR and Ig secretion in response to LPS and cytokines was not affected either. The only noticeable effects of the hs4 deletion were a decrease in the number of B splenocytes and a decreased membrane IgM expression. In conclusion, while dispensable for CSR and Ig transcription in plasma cells, hs4 mostly appears to contribute to Ig transcription in resting B lymphocytes.
Control of Thymic T Cell Maturation, Deletion and Egress by the RNA-Binding Protein HuR
Authors: Papadaki Olympia , Milatos Stavros , Grammenoudi Sofia , Mukherjee Neelanjan , Keene Jack D. , Kontoyiannis Dimitris L. 
Published: May 2009

Abstract
HuR emerged as a posttranscriptional regulator of mRNAs involved in cellular control, stress, and immunity but its role in governing such responses remains elusive. In this study, we assessed HuR’s role in the staged progression of thymic T cell differentiation by means of its genetic ablation. Mice with an early deletion of HuR in thymocytes possess enlarged thymi but display a substantial loss of peripheral T cells. We show that this discordant phenotype related to specific defects in thymic cellular processes, which demonstrated HuR’s involvement in: 1) intrinsic checkpoint signals suppressing the cell cycle of immature thymocyte progenitors, 2) TCR and antigenic signals promoting the activation and positive selection of mature thymocytes, 3) antigenic and death-receptor signals promoting thymocyte deletion, and 4) chemokine signals driving the egress of postselection thymocytes to the periphery. The cellular consequences of HuR’s dysfunction were underlined by the aberrant expression of selective cell cycle regulators, TCR, and death-receptor signaling components. Our studies reveal the signal-dependent context of HuR’s cellular activities in thymocytes and its importance in the generation of a physiological T cell pool.
Lithiumdotierung eines hydroxymodifizierten MIL‐53‐Strukturanalogons zur Verbesserung der Wasserstoffadsorption
Authors: Himsl Dieter , Wallacher Dirk , Hartmann Martin 
Published: May 2009

AbstractEine einfache Strategie für die Herstellung eines lithiumdotierten, porösen, metall‐organischen Gerüsts (MOF; siehe Struktur; schwarz C, rot O, blau AlO6‐Oktaeder) wurde entwickelt, die den Weg zur Synthese weiterer Mitglieder dieser Stoffklasse ebnet. In Übereinstimmung mit Vorhersagen adsorbierte das untersuchte dotierte MOF Wasserstoff deutlich besser als sein undotiertes Gegenstück.magnified image