bluuebunny/crossref_metadata_2025_split huggingface dataset:
ICOS Costimulation Requires IL-2 and Can Be Prevented by CTLA-4 Engagement
Authors: Riley James L. , Blair Patrick J. , Musser John T. , Abe Ryo , Tezuka Katsunari , Tsuji Takashi , June Carl H. 
Published: April 2014

AbstractWe investigated the relationship between ICOS, CD28, CTLA-4, and IL-2 to gain a better understanding of this family of costimulatory receptors in the immune response. Using magnetic beads coated with anti-CD3 and varying amounts of anti-ICOS and anti-CTLA-4 Abs, we show that CTLA-4 ligation blocks ICOS costimulation. In addition to inhibiting cellular proliferation, CTLA-4 engagement prevented ICOS-costimulated T cells from producing IL-4, IL-10, and IL-13. Both an indirect and direct mechanism of CTLA-4’s actions were examined. First, CTLA-4 engagement on resting cells was found to indirectly block ICOS costimulation by interferring with the signals needed to induce ICOS cell surface expression. Second, on preactivated cells that had high levels of ICOS expression, CTLA-4 ligation blocked the ICOS-mediated induction of IL-4, IL-10, and IL-13, suggesting an interference with downstream signaling pathways. The addition of IL-2 not only overcame both mechanisms, but also greatly augmented the level of cellular activation suggesting synergy between ICOS and IL-2 signaling. This cooperation between ICOS and IL-2 signaling was explored further by showing that the minimum level of IL-2 produced by ICOS costimulation was required for T cell proliferation. Finally, exogenous IL-2 was required for sustained growth of ICOS-costimulated T cells. These results indicate that stringent control of ICOS costimulation is maintained initially by CTLA-4 engagement and later by a requirement for exogenous IL-2.
Class I MHC-Binding Characteristics of the 129/J Ly49 Repertoire
Authors: Makrigiannis Andrew P. , Pau Amanda T. , Saleh Ali , Winkler-Pickett Robin , Ortaldo John R. , Anderson Stephen K. 
Published: April 2014

AbstractThe Ly49 family of NK cell receptors and its MHC-binding characteristics have only been well characterized in C57BL/6 (B6) mice. Previous studies have shown that 129/J mice express unique Ly49 genes that are not found in the B6 strain. Screening of a 129/J cDNA library led to the discovery of 10 distinct full-length Ly49-related coding sequences (Ly49e, g, i, o, p, r, s, t, u, and v). Although 129/J mice share identical class I MHC (Kb and Db) transcripts with B6 mice, only one Ly49 is identical in the two strains (Ly49E). In addition to the previously characterized Ly49P, two new activating Ly49 proteins were discovered, Ly49R and U. The MHC specificity of the total 129/J Ly49 repertoire was evaluated with soluble class I MHC tetramers and found to be distinct compared with the B6 Ly49 repertoire. Ly49V bound to many types of class I MHC, suggesting that Ly49V+ NK cells may monitor host cells for a global down-regulation in MHC levels. An activating receptor, Ly49R, was shown to bind soluble class I molecules to a moderate degree, a result not previously observed for other activating Ly49 proteins. Furthermore, tetramer-binding results were confirmed functionally with cytotoxicity assays using sorted 129/J NK cells. This study shows that the Ly49 repertoire and its MHC-binding characteristics can be very different among inbred mouse strains. Ly49 divergence should be considered when using 129-derived embryonic stem cells for the production of gene-targeted mice, especially when an immune or NK-derived phenotype is under scrutiny.
Opposite Ability of Pre-TCR and αβTCR to Induce Apoptosis
Authors: Steff Ann-Muriel , Trop Sébastien , Maira Mario , Drouin Jacques , Hugo Patrice 
Published: April 2014

Abstract
In early CD4−CD8− pro-thymocytes, signaling through the pre-TCR is crucial for survival and differentiation into CD4+CD8+ cells. At this more mature stage, interactions between αβTCR and self-Ag/MHC complexes in turn lead either to cell survival and differentiation (positive selection) or to cell death (negative selection). Intrinsic differences must therefore exist between pre-TCR signals in CD4−CD8− thymocytes and αβTCR signals in CD4+CD8+ cells, since only the latter can mediate a death signal. In this work, we directly compared the capability of pre-TCR and αβTCR to induce apoptosis in a CD4−CD8− thymoma cell line following receptor cross-linking with mAbs. Cross-linking of αβTCR triggered high levels of programmed cell death, mimicking the negative selection signal usually induced in CD4+CD8+ thymocytes. In contrast, pre-TCR was very inefficient at inducing apoptosis upon cross-linking, despite similar levels of surface receptor expression. Importantly, inefficient apoptosis induction by the pre-TCR did not result from its weak association with TCRζ chain, since TCRs containing α-pTα chimeric chains, binding weakly to TCRζ, were still able to induce apoptosis. Although similar tyrosine phosphorylation and calcium influx were induced after either pre-TCR or αβTCR cross-linking, the two pathways diverged at the level of Fas ligand induction. Among putative transcription factors involved in Fas ligand mRNA induction, Nur77 and NFAT transcriptional activities were readily induced after αβTCR, but not pre-TCR, stimulation. Together, these results support the view that the structure of the pre-TCR and αβTCR directly influences their apoptosis-inducing capabilities by activating distinct signaling pathways.
Relaxed DM Requirements During Class II Peptide Loading and CD4+ T Cell Maturation in BALB/c Mice
Authors: Bikoff Elizabeth K. , Wutz Gordana , Kenty George A. , Koonce Chad H. , Robertson Elizabeth J. 
Published: April 2014

AbstractCurrent ideas about DM actions have been strongly influenced by studies of mutant strains expressing the H-2b haplotype. To evaluate DM contributions to class II activities in BALB/c mice, we generated a novel mutation at the DMa locus via embryonic stem cell technology. Unlike long-lived Ab/class II-associated invariant chain-derived peptide (CLIP) complexes, mature Ad and Ed molecules are loosely occupied by class II-associated invariant chain-derived peptide and are SDS unstable. BALB/c DM mutants weakly express BP107 conformational epitopes and toxic shock syndrome toxin-1 superantigen-binding capabilities, consistent with partial occupancy by wild-type ligands. Near normal numbers of mature CD4+ T cells fail to undergo superantigen-mediated negative selection, as judged by TCR Vβ usage. Ag presentation assays reveal consistent differences for Ad- and Ed-restricted T cells. Indeed, the mutation leads to decreased peptide capture by Ad molecules, and in striking contrast causes enhanced peptide loading by Ed molecules. Thus, DM requirements differ for class II structural variants coexpressed under physiological conditions in the intact animal.
LOX-1 Supports Adhesion of Gram-Positive and Gram-Negative Bacteria
Authors: Shimaoka Takeshi , Kume Noriaki , Minami Manabu , Hayashida Kazutaka , Sawamura Tatsuya , Kita Toru , Yonehara Shin 
Published: April 2014

Abstract
Adhesion of bacteria to vascular endothelial cells as well as mucosal cells and epithelial cells appears to be one of the initial steps in the process of bacterial infection, including infective endocarditis. We examined whether lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), a member of scavenger receptor family molecules with C-type lectin-like structure, can support adhesion of Gram-positive and Gram-negative bacteria. Chinese hamster ovary-K1 (CHO-K1) cells stably expressing LOX-1 can support binding of FITC-labeled Staphylococcus aureus and Escherichia coli, which was suppressed by poly(I) and an anti-LOX-1 mAb. Adhesion of these bacteria to LOX-1 does not require divalent cations or serum factors and can be supported under both static and nonstatic conditions. Cultured bovine aortic endothelial cells (BAEC) can also support adhesion of FITC-labeled S. aureus, which was similarly suppressed by poly(I) and an anti-LOX-1 mAb. In contrast, binding of FITC-labeled E. coli to BAEC was partially inhibited by the anti-LOX-1 mAb, and poly(I) did not block FITC-labeled E. coli adhesion to BAEC, but, rather, enhanced it under a static condition. TNF-α increased LOX-1-dependent adhesion of E. coli, but not that of S. aureus, suggesting that S. aureus adhesion to BAEC may require additional molecules, which cooperate with LOX-1 and suppressed by TNF-α. Taken together, LOX-1 can work as a cell surface receptor for Gram-positive and Gram-negative bacteria, such as S. aureus and E. coli, in a mechanism similar to that of class A scavenger receptors; however, other unknown molecules may also be involved in the adhesion of E. coli to BAEC, which is enhanced by poly(I).
The Potency and Durability of DNA- and Protein-Based Vaccines Against Leishmania major Evaluated Using Low-Dose, Intradermal Challenge
Authors: Méndez Susana , Gurunathan Sanjay , Kamhawi Shaden , Belkaid Yasmine , Moga Michael A. , Skeiky Yasir A. W. , Campos-Neto Antonio , Reed Steven , Seder Robert A. , Sacks David 
Published: April 2014

Abstract
DNA- and protein- based vaccines against cutaneous leishmaniasis due to Leishmania major were evaluated using a challenge model that more closely reproduces the pathology and immunity associated with sand fly-transmitted infection. C57BL/6 mice were vaccinated s.c. with a mixture of plasmid DNAs encoding the Leishmania Ags LACK, LmSTI1, and TSA (AgDNA), or with autoclaved L. major promastigotes (ALM) plus rIL-12, and the mice were challenged by inoculation of 100 metacyclic promastigotes in the ear dermis. When challenged at 2 wk postvaccination, mice receiving AgDNA or ALM/rIL-12 were completely protected against the development of dermal lesions, and both groups had a 100-fold reduction in peak dermal parasite loads compared with controls. When challenged at 12 wk, mice vaccinated with ALM/rIL-12 maintained partial protection against dermal lesions and their parasite loads were no longer significantly reduced, whereas the mice vaccinated with AgDNA remained completely protected and had a 1000-fold reduction in dermal parasite loads. Mice vaccinated with AgDNA also harbored few, if any, parasites in the skin during the chronic phase, and their ability to transmit L. major to vector sand flies was completely abrogated. The durable protection in mice vaccinated with AgDNA was associated with the recruitment of both CD8+ and CD4+ T cells to the site of intradermal challenge and with IFN-γ production by CD8+ T cells in lymph nodes draining the challenge site. These data suggest that under conditions of natural challenge, DNA vaccination has the capacity to confer complete protection against cutaneous leishmaniasis and to prevent the establishment of infection reservoirs.
Fibronectin Binding Protein A of Staphylococcus aureus Can Mediate Human T Lymphocyte Adhesion and Coactivation
Authors: Miyamoto Yuko J. , Wann Elisabeth R. , Fowler Trent , Duffield Eric , Höök Magnus , McIntyre Bradley W. 
Published: April 2014

Abstract
The extracellular matrix protein fibronectin (FN) mediates the adhesion of bacteria as well as T lymphocytes. Mammalian cells express integrins α4β1 and α5β1 as the major FN-binding cell surface receptors. Bacteria such as Staphylococcus aureus, also express FN-binding receptors that are important for adherence to host tissue and initiation of infection. The S. aureus FN-binding protein, FnbpA, has been previously identified, and recombinant proteins that correspond to distinct functional regions of this protein have been made. Three recombinant truncated forms of FnbpA, rFnbpA(37-881), rFnbpA(37-605), and rFnbpA(620-881), were examined for effects on in vitro adhesion and coactivation of human T lymphocytes. These proteins, when coimmobilized with anti-CD3 mAb, activated T lymphocyte proliferation. The coactivation signal generated by the rFnbpA proteins required medium containing serum with FN. Furthermore, the costimulatory signal could be restored in FN-depleted serum when the rFnbpAs were preloaded with soluble FN. Monoclonal Ab blocking studies revealed that integrin α5β1 is the major receptor responsible for the rFnbpA costimulatory signal. Shear flow cell detachment assays confirmed that lymphocytes can bind to FN captured by the rFnbpA proteins. These results suggest that the S. aureus rFnbpA can interact with integrin α5β1 via an FN bridge to mediate adhesion and costimulatory signals to T lymphocytes.
Platelet-Activating Factor-Induced Early Activation of NF-κB Plays a Crucial Role for Organ Clearance of Candida albicans
Authors: Choi Jung Hwa , Ko Hyun Mi , Kim Jung-Woo , Lee Hern-Ku , Han Sang Seop , Chun Soon-Bai , Im Suhn Young 
Published: April 2014

Abstract
In this study, we have investigated the mechanisms underlying organ susceptibility to candida infection. Infection of BALB/c mice with Candida albicans led to both an early (1–8 h) and late (24–48 h) activation of NF-κB in the organs resistant to C. albicans, including the lung and spleen. In susceptible organs such as the kidneys, early activation of NF-κB was not observed. The kinetics of TNF-α mRNA expression paralleled those of NF-κB activation in all organs examined. Blocking the effects of endogenous platelet-activating factor (PAF) by pretreatment with the PAF antagonist BN50739 or antioxidants significantly reduced the early activity of NF-κB and TNF-α mRNA expression, and increased the recovery of C. albicans in the lung and spleen. Importantly, administration of PAF 5 min prior to the infection resulted in the appearance of early activities of NF-κB and TNF-α mRNA expression, followed by a nearly complete clearance of the organisms in the kidneys. Pretreatment with anti-TNF-α Ab resulted in an enhanced susceptibility to C. albicans, and the PAF-mediated resistance was abrogated by anti-TNF-α in all organs examined. These data indicated that endogenously produced PAF in response to C. albicans is a key molecule involved in the early activation of NF-κB, which, in turn, renders the organ resistant to the fungus by promoting the production of anti-candidal proinflammatory cytokines such as TNF-α. Susceptible organs, including the kidneys, lack the capacity to generate a sufficient PAF-induced early NF-κB response.
Resident and Infiltrating Central Nervous System APCs Regulate the Emergence and Resolution of Experimental Autoimmune Encephalomyelitis
Authors: Juedes Amy E. , Ruddle Nancy H. 
Published: April 2014

AbstractDuring experimental autoimmune encephalomyelitis (EAE), autoreactive Th1 T cells invade the CNS. Before performing their effector functions in the target organ, T cells must recognize Ag presented by CNS APCs. Here, we investigate the nature and activity of the cells that present Ag within the CNS during myelin oligodendrocyte glycoprotein-induced EAE, with the goal of understanding their role in regulating inflammation. Both infiltrating macrophages (Mac-1+CD45high) and resident microglia (Mac-1+CD45int) expressed MHC-II, B7-1, and B7-2. Macrophages and microglia presented exogenous and endogenous CNS Ags to T cell lines and CNS T cells, resulting in IFN-γ production. In contrast, Mac-1− cells were inefficient APCs during EAE. Late in disease, after mice had partially recovered from clinical signs of disease, there was a reduction in Ag-presenting capability that correlated with decreased MHC-II and B7-1 expression. Interestingly, although CNS APCs induced T cell cytokine production, they did not induce proliferation of either T cell lines or CNS T cells. This was attributable to production by CNS cells (mainly by macrophages) of NO. T cell proliferation was restored with an NO inhibitor, or if the APCs were obtained from inducible NO synthase-deficient mice. Thus, CNS APCs, though essential for the initiation of disease, also play a down-regulatory role. The mechanisms by which CNS APCs limit the expansion of autoreactive T cells in the target organ include their production of NO, which inhibits T cell proliferation, and their decline in Ag presentation late in disease.
Production of Chemokines In Vivo in Response to Microbial Stimulation
Authors: Coates Nicholas J. , McColl Shaun R. 
Published: April 2014

AbstractMembers of the chemokine gene superfamily are known to play a central role in leukocyte extravasation; however, their involvement in acute inflammation in response to micro-organisms has not yet been well studied. We have therefore investigated the role of murine macrophage-inflammatory protein (muMIP) 1α and muMIP-2 in the inflammatory response mounted against the bacteria Salmonella enteritidis and the Sacchromyces cerevisiae cell wall component, zymosan. Leukocyte extravasation was monitored in murine s.c. air pouches. Both agonists induced accumulation of leukocytes in a dose- and time-dependent manner, with the response peaking after 4 h and declining thereafter. The inflammatory exudate comprised mainly neutrophils; however, an increase in eosinophil accumulation was also observed in response to zymosan. The production of both muMIP-1α and muMIP-2 increased with time in response to both the agonists, although production was more sustained in response to the bacteria. Prior treatment of mice with neutralizing Abs against muMIP-1α or muMIP-2, either alone or in combination, failed to attenuate the accumulation of leukocytes in response to the agonists. In contrast, the anti-muMIP-2 Abs significantly inhibited leukocyte recruitment in response to S. enteritidis in complement-deficient mice. Taken together, these data show that while muMIP-1α and muMIP-2 are produced in response to phagocytosis of micro-organisms in s.c. tissue, under these circumstances components of the complement pathway appear to play a dominant role in the recruitment of neutrophils.
Intracellular Pool of IL-10 Receptors in Specific Granules of Human Neutrophils: Differential Mobilization by Proinflammatory Mediators
Authors: Elbim Carole , Reglier Hélène , Fay Michèle , Delarche Charlotte , Andrieu Valérie , El Benna Jamel , Gougerot-Pocidalo Marie-Anne 
Published: April 2014

Abstract
IL-10 has a wide range of effects tending to control inflammatory responses. We used flow cytometry to study IL-10 binding at the polymorphonuclear neutrophil (PMN) surface and its modulation by various proinflammatory agents. Little IL-10 bound to the surface of resting PMN. However, binding was strongly increased after stimulation with LPS and proinflammatory cytokines such as TNF and GM-CSF. IL-1 and IL-8 did not significantly modify IL-10 binding. Cycloheximide had no effect on TNF-induced IL-10 binding, strongly suggesting the release of a pre-existing pool of IL-10R rather than de novo receptor synthesis by PMN. This was confirmed by the inhibitory effect of pentoxifylline, an inhibitor of degranulation. The existence of an intracellular pool of IL-10R was shown by flow cytometry, immunocytochemical staining, and Western blotting with several anti-human IL-10R Abs. In subcellular fractions of resting PMN, IL-10R was mainly located in the specific granule fraction, and was absent from azurophil granules and cytosol. We also tested the mobilization of specific granules by measuring the release of lactoferrin, their reference marker. The differential effects of the proinflammatory agents on IL-10 binding matched their effects on lactoferrin release and may therefore be related to differential mobilization of specific granules by these agents. Furthermore, the kinetics of TNF-induced up-regulation of IL-10 binding to PMN ran parallel to the kinetics of the inhibitory effect of IL-10 on the oxidative burst, suggesting a key role of IL-10R mobilization from specific granules to the membranes in optimal regulation of inflammatory responses.
Lethal Hepatitis After Gene Transfer of IL-4 in the Liver Is Independent of Immune Responses and Dependent on Apoptosis of Hepatocytes: A Rodent Model of IL-4-Induced Hepatitis
Authors: Guillot Cécile , Coathalem Hélène , Chetritt Jérôme , David Anne , Lowenstein Pedro , Gilbert Emmanuelle , Tesson Laurent , van Rooijen Nico , Cuturi Maria Cristina , Soulillou Jean-Paul , Anegon Ignacio 
Published: April 2014

Abstract
The putative role of IL-4 in human and animal models of hepatitis has not yet been directly determined. We now report that direct expression of IL-4 in the liver of rats or mice using recombinant adenoviruses coding for rat or mouse IL-4 (AdrIL-4 and AdmIL-4, respectively) results in a lethal, dose-dependent hepatitis. The hepatitis induced by IL-4 was characterized by hepatocyte apoptosis and a massive monocyte/macrophage infiltrate. IL-4-induced hepatitis was independent of T cell-mediated immune responses. Hepatitis occurred even after gene transfer of IL-4 into nude rats, CD8-depleted rats, cyclosporine A-treated rats, or recombinase-activating gene 2−/− immunodeficient mice. Peripheral depletion of leukocytes using high doses of cyclophosphamide, and/or the specific depletion of liver macrophages with liposome-encapsulated dichloromethylene diphosphonate in rats did not block lethal IL-4-induced hepatitis. Direct transduction of hepatocytes with adenoviruses was not essential, since injection of AdrIL-4 into the hind limb induced an identical hepatitis. Finally, primary rat hepatocytes in culture also showed apoptosis when cultured in the presence of rIL-4. IL-4-dependent hepatitis was associated with increases in the intrahepatic levels of IFN-γ, TNF-α, and Fas ligand. Administration of AdmIL-4 to IFN-γ, TNF-α receptor type I, or TNF-α receptor type II knockout mice also resulted in lethal hepatitis, whereas a moderate protection was observed in Fas-deficient lpr mice. IL-4-dependent hepatocyte apoptosis could be abolished by treatment with caspase inhibitory peptides. Our results thus demonstrate that IL-4 causes hepatocyte apoptosis, which is only partially dependent on the activation of Apo-1-Fas signaling and is largely independent of any immune cells in the liver.
Highly Efficient Transduction of Human Monocyte-Derived Dendritic Cells with Subgroup B Fiber-Modified Adenovirus Vectors Enhances Transgene-Encoded Antigen Presentation to Cytotoxic T Cells
Authors: Rea Delphine , Havenga Menzo J. E. , van den Assem Maayke , Sutmuller Roger P. M. , Lemckert Angelique , Hoeben Rob C. , Bout Abraham , Melief Cornelis J. M. , Offringa Rienk 
Published: April 2014

Abstract
The efficiency of dendritic cells (DC) as immunotherapeutic vaccines critically depends on optimal delivery of target Ags. Although DC modified by subgroup C type 5 recombinant adenoviruses (rAd5) provide encouraging results, their clinical application is hampered by the need for high viral titers to achieve sufficient gene transfer, due to the lack of the Ad5 fiber receptor. We now demonstrate that rAd5 carrying subgroup B Ad fibers are up to 100-fold more potent than classical rAd5 for gene transfer and expression in human DC, rAd5 with a type 35 fiber (rAd5F35) being the most efficient vector. This improvement relates to a greater and faster virus entry and to an increased transgene expression especially following DC maturation. Furthermore, these new vectors possess enhanced synergistic effects with other activation signals to trigger DC maturation. Consequently, rAd5F35-infected DC engineered to express the gp100 melanoma-associated Ag largely exceed rAd5-infected DC in activating gp100-specific CTL. Finally, the DC infection pattern of rAd5F35 is fully conserved when DC are in the vicinity of primary skin-derived fibroblasts, suggesting this vector as a candidate for in vivo targeting of DC. Thus, subgroup B fiber-modified rAd5 constitute a major breakthrough in the exploitation of ex vivo rAd-targeted DC as clinically relevant vaccines and may also be suitable for in vivo genetic modification of DC.