bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intraocular Tumor Antigen Drains Specifically to Submandibular Lymph Nodes, Resulting in an Abortive Cytotoxic T Cell Reaction
Authors: Boonman Zita F. H. M. , van Mierlo Geertje J. D. , Fransen Marieke F. , Franken Kees L. M. C. , Offringa Rienk , Melief Cornelis J. M. , Jager Martine J. , Toes René E. M. 
Published: April 2014

AbstractOcular immune privilege is considered essential in the protection against sight-threatening immune responses, as illustrated by the ability of the ocular environment to permit the growth of tumors that are rejected when implanted at other sites. Although several studies indicate that soluble Ag can drain directly into the spleen when injected into the anterior chamber, the primary site of intraocular tumor Ag presentation to tumor-specific CTLs has not been studied. To gain a better understanding of the mechanism involved in ocular immune privilege, we examined to which lymphoid organs anterior chamber tumor Ags primarily drain. Our data show that intraocular tumor Ag drains exclusively to the submandibular lymph nodes, resulting in activation of tumor-specific CTLs, whereas no Ag drainage was found in spleen. However, these tumor-specific CTLs do not distribute systemically and, as a consequence, intraocular tumor growth is unhampered. A similar lack of CTL efficacy has been observed in mice bearing s.c. tumors, which is converted to a systemic tumoricidal CTL response by administration of agonistic anti-CD40 mAb. In contrast, systemic anti-CD40 treatment of eye tumor-bearing mice did not result in mobilizing tumor-specific CTLs or tumor eradication. Together, these results show that intraocular tumor Ag drains to regional lymph nodes for activation of tumor-specific CTLs. However, the induced tumor-specific immunity is insufficient for tumor clearance, even combined with otherwise highly effective immune intervention protocols.
IFN-γ Promotes Fas Ligand- and Perforin-Mediated Liver Cell Destruction by Cytotoxic CD8 T Cells
Authors: Roth Evelyn , Pircher Hanspeter 
Published: April 2014

AbstractTo study liver cell damage by CTL, CD8 T cells from P14 TCR transgenic (tg) mice specific for the gp33 epitope of lymphocytic choriomeningitis virus with either deficiency in IFN-γ (P14.IFN-γ°), functional Fas ligand (P14.gld), or perforin (P14.PKO) were transferred into H8 tg mice ubiquitously expressing gp33 Ag. Treatment of H8 recipient mice with agonistic anti-CD40 Abs induced vigorous expansion of the transferred P14 T cells and led to liver cell destruction determined by increase of glutamate dehydrogenase serum levels and induction of caspase-3 in hepatocytes. Liver injury was mediated by the Fas/Fas ligand (FasL) pathway and by perforin, because P14.gld and P14.PKO T cells failed to induce increased glutamate dehydrogenase levels despite strong in vivo proliferation. In addition, H8 tg mice lacking Fas were resistant to the pathogenic effect of P14 T cells. Besides FasL and perforin, IFN-γ was also required for liver cell damage, because P14.IFN-γ° T cells adoptively transferred into H8 mice failed to induce disease. Moreover, Fas expression on hepatocytes from H8 recipient mice was increased after transfer of wild-type compared with P14.IFN-γ° T cells, and wild-type P14 T cells expressed higher levels of FasL than P14 T cells lacking IFN-γ. Thus, our data suggest that IFN-γ released by activated CD8 T cells upon Ag contact facilitates liver cell destruction.
Blockade of Lymphotoxin Signaling Inhibits the Clinical Expression of Murine Graft-versus-Host Skin Disease
Authors: Wu Qiang , Fu Yang-Xin , Sontheimer Richard D. 
Published: April 2014

AbstractAdhesion molecules are essential for the recruitment of T cells into the skin during the development of graft-vs-host skin disease (GVHSD). However, the mechanisms responsible for the regulation of expression of cutaneous adhesion molecules in this setting are still poorly understood. In this study we blocked lymphotoxin (LT) signaling in a murine model of minor histocompatibility Ag system mismatch GVHSD by using an LTβ receptor-Ig fusion protein (LTβR-Ig). The recipient mice treated with control human Ig developed clinically apparent, severe skin lesions. However, none of the mice treated with LTβR-Ig developed clinical skin disease. The expression of ICAM-1 in cutaneous tissue was also much lower in mice treated with LTβR-Ig than in mice treated with human Ig. Thus, the inhibition of LT signaling via LTβR-Ig treatment appears to be capable of markedly ameliorating the development of GVHSD, possibly by inhibiting the expression of adhesion molecules.
IFN-α Induced Adenosine Production on the Endothelium: A Mechanism Mediated by CD73 (Ecto-5′-Nucleotidase) Up-Regulation
Authors: Niemelä Jussi , Henttinen Tiina , Yegutkin Gennady G. , Airas Laura , Kujari Anna-Maija , Rajala Pertti , Jalkanen Sirpa 
Published: April 2014

Abstract
CD73 (ecto-5′-nucleotidase; EC 3.1.3.5) participates in lymphocyte binding to endothelial cells and converts extracellular AMP into a potent anti-inflammatory substance adenosine. However, the regulation of expression and function of CD73 has remained largely unknown. In this study, we show that IFN-α produces a time- and dose-dependent long-term up-regulation of CD73 on endothelial cells, but not on lymphocytes both at protein and RNA levels. Moreover, CD73-mediated production of adenosine is increased after IFN-α treatment on endothelial cells, resulting in a decrease in the permeability of these cells. Subsequent to induction with PMA, FMLP, dibutyryl cAMP, thrombin, histamine, IL-1β, TNF-α, and LPS, no marked changes in the level of CD73 expression on endothelial cells are observed. We also show that CD73 is up-regulated in vivo on the vasculature after intravesical treatment of urinary bladder cancers with IFN-α. In conclusion, distinct behavior of lymphocyte and endothelial CD73 subsequent to cytokine treatment further emphasizes the existence of cell type-specific mechanisms in the regulation of CD73 expression and function. Overall, these results suggest that IFN-α is a relevant in vivo regulator of CD73 in the endothelial-leukocyte microenvironment in infections/inflammations, and thus has a fundamental role in controlling the extent of inflammation via CD73-dependent adenosine production.
Nuclear Pro-IL-16 Regulation of T Cell Proliferation: p27KIP1-Dependent G0/G1 Arrest Mediated by Inhibition of Skp2 Transcription
Authors: Center David M. , Cruikshank William W. , Zhang Yujun 
Published: April 2014

AbstractThe precursor for IL-16 (pro-IL-16) is a nuclear and cytoplasmic PDZ domain-containing protein. In this study we have found that pro-IL-16 is absent or mutated in four T lymphoblastic leukemia cell lines examined. Ectopic expression of pro-IL-16 in pro-IL-16-negative Jurkat cells blocks cell cycle progression from G0/G1 to S phase associated with elevated levels of the cyclin-dependent kinase inhibitor p27KIP1. Pro-IL-16 decreases p27KIP1 degradation by reducing transcription and subsequent expression of Skp2, a key component of the SCFSkp2 ubiquitin E3 ligase complex. Taken together, these findings identify pro-IL-16 as a novel regulator of Skp2 expression and p27KIP1 levels and implicate a role for pro-IL-16 in T cell proliferation.
The Nonclassical MHC Class I Molecule Qa-1 Forms Unstable Peptide Complexes
Authors: Kambayashi Taku , Kraft-Leavy Jennifer R. , Dauner Joseph G. , Sullivan Barbara A. , Laur Oskar , Jensen Peter E. 
Published: April 2014

AbstractThe MHC class Ib molecule Qa-1 is the primary ligand for mouse CD94/NKG2A inhibitory receptors expressed on NK cells, in addition to presenting Ags to a subpopulation of T cells. CD94/NKG2A receptors specifically recognize Qa-1 bound to the MHC class Ia leader sequence-derived peptide Qdm. Qdm is the dominant peptide loaded onto Qa-1 under physiological conditions and this peptide has an optimal sequence for binding to Qa-1. Peptide dissociation experiments demonstrated that Qdm dissociates from soluble or cell surface Qa-1b molecules with a t1/2 of ∼1.5 h at 37°C. In comparison, complexes of an optimal peptide (SIINFEKL) bound to the MHC class Ia molecule H-2Kb dissociated with a t1/2 in the range from 11 to 31 h. In contrast to Kb, the stability of cell surface Qa-1b molecules was independent of bound peptides, and several observations suggested that empty cell surface Qa-1b molecules might be unusually stable. Consistent with the rapid dissociation rate of Qdm from Qa-1b, cells become susceptible to lysis by CD94/NKG2A+ NK cells under conditions in which new Qa-1b/Qdm complexes cannot be continuously generated at the cell surface. These results support the hypothesis that Qa-1 has been selected as a specialized MHC molecule that is unable to form highly stable peptide complexes. We propose that the CD94/NKG2A-Qa-1/Qdm recognition system has evolved as a rapid sensor of the integrity of the MHC class I biosynthesis and Ag presentation pathway.
The C4A and C4B Isotypic Forms of Human Complement Fragment C4b Have the Same Intrinsic Affinity for Complement Receptor 1 (CR1/CD35)
Authors: Clemenza Liliana , Isenman David E. 
Published: April 2014

AbstractSeveral previous reports concluded that the C4b fragment of human C4A (C4Ab) binds with higher affinity to CR1 than does C4Bb. Because the isotypic residues, 1101PCPVLD and 1101LSPVIH in C4A and C4B, respectively, are located within the C4d region, one may have expected a direct binding contribution of C4d to the interaction with CR1. However, using surface plasmon resonance as our analytical tool, with soluble rCR1 immobilized on the biosensor chip, we failed to detect significant binding of C4d of either isotype. By contrast, binding of C4c was readily detectable. C4A and C4B, purified from plasma lacking one of the isotypes, were C1̄s converted to C4Ab and C4Bb. Spontaneously formed disulfide-linked dimers were separated from monomers and higher oligomers by sequential chromatographic steps. The binding sensorgrams of C4Ab and C4Bb monomers as analytes reached steady state plateaus, and these equilibrium data yielded essentially superimposable saturation curves that were well fit by a one-site binding model. Although a two-site model was required to fit the equilibrium-binding data for the dimeric forms of C4b, once again there was little difference in the KD values obtained for each isotype. Independent verification of our surface plasmon resonance studies came from ELISA-based inhibition experiments in which monomers of C4Ab and C4Bb were equipotent in inhibiting the binding of soluble CR1 to plate-bound C4b. Although divergent from previous reports, our results are consistent with recent C4Ad structural data that raised serious doubts about there being a conformational basis for the previously reported isotypic differences in the C4b-CR1 interaction.
Pervasive Influence of Hepatitis C Virus on the Phenotype of Antiviral CD8+ T Cells
Authors: Lucas Michaela , Vargas-Cuero Ana L. , Lauer Georg M. , Barnes Eleanor , Willberg Christian B. , Semmo Nasser , Walker Bruce D. , Phillips Rodney , Klenerman Paul 
Published: April 2014

Abstract
Recent studies using MHC class I tetramers have shown that CD8+ T cell responses against different persistent viruses vary considerably in magnitude and phenotype. At one extreme, hepatitis C virus (HCV)-specific CD8+ T cell responses in blood are generally weak and have a phenotype that is perforin low and CCR7 high (early memory). At the other, specific responses to CMV are strong, perforin high, and CCR7 low (mature or effector memory). To examine the potential mechanisms behind this diversity, we compared CMV-specific responses in HCV-infected and healthy individuals. We find a striking difference in the phenotype of CMV-specific CD8+ T cells between these groups. In the HCV-infected cohort, CMV-specific CD8+ T cells lost markers associated with maturity; they had increased expression of CCR7 and reduced expression of Fas and perforin. They nevertheless responded to Ag in vitro in a manner similar to controls, with strong proliferation and appropriate acquisition of effector memory markers. The reduction in mature CD8 T cells in HCV-infected individuals may arise through either impairment or regulation of T cell stimulation, or through the early loss of mature T cells. Whatever the mechanism, HCV has a pervasive influence on the circulating CD8+ T cell population, a novel feature that may be a hallmark of this infection.
Distinct Modulatory Effects of LPS and CpG on IL-18-Dependent IFN-γ Synthesis
Authors: Gould Meetha P. , Greene Jennifer A. , Bhoj Vijay , DeVecchio Jennifer L. , Heinzel Frederick P. 
Published: April 2014

AbstractInnate cellular production of IFN-γ is suppressed after repeated exposure to LPS, whereas CpG-containing DNA potentiates IFN-γ production. We compared the modulatory effects of LPS and CpG on specific cellular and cytokine responses necessary for NK-cell dependent IFN-γ synthesis. C3H/HeN mice pretreated with LPS for 2 days generated 5-fold less circulating IL-12 p70 and IFN-γ in response to subsequent LPS challenge than did challenged control mice. In contrast, CpG-pretreated mice produced 10-fold more circulating IFN-γ without similar changes in IL-12 p70 levels, but with 10-fold increases in serum IL-18 relative to LPS-challenged control or endotoxin-tolerant mice. The role of IL-18 in CpG-induced immune potentiation was studied in splenocyte cultures from control, LPS-conditioned, or CpG-conditioned mice. These cultures produced similar amounts of IFN-γ in response to rIL-12 and rIL-18. However, only CpG-conditioned cells produced IFN-γ when cultured with LPS or CpG, and production was ablated in the presence of anti-IL-18R Ab. Anti-IL-18R Ab also reduced in vivo IFN-γ production by &gt;2-fold in CpG-pretreated mice. Finally, combined pretreatment of mice with LPS and CpG suppressed the production of circulating IFN-γ, IL-12 p70, and IL-18 after subsequent LPS challenge. We conclude that CpG potentiates innate IFN-γ production from NK cells by increasing IL-18 availability, but that the suppressive effects of LPS on innate cellular immunity dominate during combined LPS and CpG pretreatment. Multiple Toll-like receptor engagement in vivo during infection can result in functional polarization of innate immunity dominated by a specific Toll-like receptor response.
Nonmethylated CG Motifs Packaged into Virus-Like Particles Induce Protective Cytotoxic T Cell Responses in the Absence of Systemic Side Effects
Authors: Storni Tazio , Ruedl Christiane , Schwarz Katrin , Schwendener Reto A. , Renner Wolfgang A. , Bachmann Martin F. 
Published: April 2014

AbstractDNA rich in nonmethylated CG motifs (CpGs) greatly facilitates induction of immune responses against coadministered Ags. CpGs are therefore among the most promising adjuvants known to date. Nevertheless, CpGs are characterized by two drawbacks. They have unfavorable pharmacokinetics and may exhibit systemic side effects, including splenomegaly. We show in this study that packaging CpGs into virus-like particles (VLPs) derived from the hepatitis B core Ag or the bacteriophage Qβ is a simple and attractive method to reduce these two problems. CpGs packaged into VLPs are resistant to DNase I digestion, enhancing their stability. In addition, and in contrast to free CpGs, packaging CpGs prevents splenomegaly in mice, without affecting their immunostimulatory capacity. In fact, vaccination with CpG-loaded VLPs was able to induce high frequencies of peptide-specific CD8+ T cells (4–14%), protected from infection with recombinant vaccinia viruses, and eradicated established solid fibrosarcoma tumors. Thus, packaging CpGs into VLPs improves both their immunogenicity and pharmacodynamics.
Overproduction of TNF-α by CD8+ Type 1 Cells and Down-Regulation of IFN-γ Production by CD4+ Th1 Cells Contribute to Toxic Shock-Like Syndrome in an Animal Model of Fatal Monocytotropic Ehrlichiosis
Authors: Ismail Nahed , Soong Lynn , McBride Jere W. , Valbuena Gustavo , Olano Juan P. , Feng Hui-Min , Walker David H. 
Published: April 2014

AbstractHuman monocytotropic ehrlichiosis (HME) is an emerging, life-threatening, infectious disease caused by Ehrlichia chaffeensis, an obligate intracellular bacterium that lacks cell wall LPS. We have previously developed an animal model of severe HME using a strain of Ehrlichia isolated from Ixodes ovatus ticks (IOE). To understand the basis of susceptibility to severe monocytotropic ehrlichiosis, we compared low and high doses of the highly virulent IOE strain and the less virulent Ehrlichia muris strain that are closely related to E. chaffeensis in C57BL/6 mice. Lethal infections caused by high or low doses of IOE were accompanied by extensive liver damage, extremely elevated levels of TNF-α in the serum, high frequency of Ehrlichia-specific, TNF-α-producing CD8+ T cells in the spleen, decreased Ehrlicha-specific CD4+ T cell proliferation, low IL-12 levels in the spleen, and a 40-fold decrease in the number of IFN-γ-producing CD4+ Th1 cells. All groups contained negligible numbers of IL-4-producing cells in the spleen. Transfer of Ehrlichia-specific polyclonal Abs and IFN-γ-producing Ehrlichia-specific CD4+ and CD8+ type 1 cells protected naive mice against lethal IOE challenge. Interestingly, infection with high dose E. muris provided protection against rechallenge with a lethal dose of IOE. Cross-protection was associated with substantial expansion of IFN-γ-producing CD4+ and CD8+ cells, but not TNF-α-producing CD8+ T cells, a high titer of IgG2a, and a low serum level of TNF-α. In conclusion, uncontrolled TNF-α production by CD8+ T cells together with a weak CD4+ Th1 cell response are associated with immunopathology and failure to clear IOE in the fatal model of HME.
Leptin Indirectly Activates Human Neutrophils via Induction of TNF-α
Authors: Zarkesh-Esfahani Hamid , Pockley Alan G. , Wu Zida , Hellewell Paul G. , Weetman Anthony P. , Ross Richard J. M. 
Published: April 2014

Abstract
Leptin, the satiety hormone, appears to act as a link between nutritional status and immune function. It has been shown to elicit a number of immunoregulatory effects, including the promotion of T cell proliferative responses, and the induction of proinflammatory cytokines. Leptin deficiency is associated with an increased susceptibility to infection. As polymorphonuclear neutrophils (PMN) play a major role in innate immunity and host defense against infection, this study evaluated the influence of leptin on PMN activation. The presence of leptin receptor in human PMN was determined both at mRNA and protein levels, and the effect of leptin on PMN activation, as assessed by CD11b expression, was evaluated using flow cytometry. In contrast to monocytes, which express both the short and long forms of the leptin receptor (Ob-Ra and Ob-Rb, respectively), PMN expressed only Ob-Ra. Leptin up-regulated the expression of CD11b, an early marker of PMN activation, on PMN in whole blood, yet it had no effect on purified PMN, even those treated by submaximal doses of TNF-α or PMA. The kinetics of leptin-induced activation in whole blood were consistent with an indirect effect mediated by monocytes, and 71% of the leptin-stimulatory effect on PMN was blocked by a TNF-α inhibitor. Leptin-mediated induction of CD11b expression was observed when purified PMN were coincubated with purified monocytes. In conclusion, although leptin activates PMN, it does so indirectly via TNF-α release from monocytes. These findings provide an additional link among the obesity-derived hormone leptin, innate immune function, and infectious disease.
Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-γ and Lipopolysaccharide
Authors: Morrison Amy C. , Wilson Caleph B. , Ray Manujendra , Correll Pamela H. 
Published: April 2014

AbstractIL-12, produced by APCs during the initial stages of an immune response, plays a pivotal role in the induction of IFN-γ by NK and γδT cells and in driving the differentiation of Th1 cells, thus providing a critical link between innate and acquired immunity. Due to the unique position occupied by IL-12 in the regulation of immunity, many mechanisms have evolved to modulate IL-12 production. We have shown previously that macrophage-stimulating protein (MSP), the ligand for the stem cell-derived tyrosine kinase/recepteur d’origine nantais (RON) receptor, inhibits NO production by macrophages in response to IFN-γ and enhances the expression of arginase. Mice lacking RON exhibit increased inflammation in a delayed-type hypersensitivity reaction and increased susceptibility to endotoxic shock. In this study we demonstrate that pretreatment of macrophages with MSP before IFN-γ and LPS results in the complete inhibition of IL-12 production due to suppression of p40 expression. This response is mediated by the RON receptor, and splenocytes from RON−/− animals produce increased levels of IFN-γ. MSP pretreatment of macrophages resulted in decreased tyrosine phosphorylation of Stat-1 and decreased expression of IFN consensus sequence binding protein in response to inflammatory cytokines. In addition to IL-12, the expression of IL-15 and IL-18, cytokines that are also dependent on IFN consensus sequence binding protein activation, is inhibited by pretreatment with MSP before IFN-γ and LPS. We also show that the ability of MSP to inhibit IL-12 production is independent of IL-10. Taken together, these results suggest that MSP may actively suppress cell-mediated immune responses through its ability to down-regulate IL-12 production and thus inhibit classical activation of macrophages.
Kinin B1 Receptor Up-Regulation after Lipopolysaccharide Administration: Role of Proinflammatory Cytokines and Neutrophil Influx
Authors: Passos Giselle F. , Fernandes Elizabeth S. , Campos Maria M. , Araújo José G. V. C. , Pesquero Jorge L. , Souza Glória E. P. , Avellar Maria C. W. , Teixeira Mauro M. , Calixto João B. 
Published: April 2014

Abstract
Several studies have now clearly established the ability of LPS to induce bradykinin B1 receptor up-regulation in vivo and the functional relevance of this up-regulation for the pathophysiological effects of LPS. Using an in vivo system in which LPS is injected locally into the rat paw, we have examined the potential contribution of proinflammatory cytokines, NF-κB activation, and neutrophil influx for the functional and molecular up-regulation of the bradykinin B1 receptor. Treatment with LPS resulted in a rapid and sustained functional up-regulation of B1 receptors in the rat paw that correlated with the increase in B1 receptor mRNA levels. B1 receptor up-regulation is preceded by the rapid activation of the transcription factor NF-κB and the production of proinflammatory cytokines, including TNF-α and IL-1β. More importantly, blockade of NF-κB translocation, TNF-α, or IL-1β prevented the functional and molecular up-regulation of B1 receptors. Injection of LPS also induced the influx of neutrophils that followed the peak of cytokine production and associated with the persistent activation of NF-κB and functional B1 receptor up-regulation. Blockade of neutrophil influx with platelet-activating factor receptor antagonists or cell adhesion molecule blockers prevented B1 receptor up-regulation. Thus, by acting in cooperation and in a coordinated, timely manner, TNF-α, IL-1β, neutrophils, and the transcription factor NF-κB are major and essential players in the ability of LPS to induce B1 receptor expression in vivo.