bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligoadenylate Synthetase/Protein Kinase R Pathways and αβ TCR+ T Cells Are Required for Adenovirus Vector: IFN-γ Inhibition of Herpes Simplex Virus-1 in Cornea
Authors: Austin Bobbie Ann , Halford William P. , Williams Bryan R. G. , Carr Daniel J. J. 
Published: April 2014

Abstract
An adenoviral (Ad) vector containing the murine IFN-γ transgene (Ad:IFN-γ) was evaluated for its capacity to inhibit HSV-1. To measure effectiveness, viral titers were analyzed in cornea and trigeminal ganglia (TG) during acute ocular HSV-1 infection. Ad:IFN-γ potently suppressed HSV-1 replication in a dose-dependent fashion, requiring IFN-γ receptor. Moreover, Ad:IFN-γ was effective when delivered −72 and −24 h before infection as well as 24 h postinfection. Associated with antiviral opposition, TG from Ad:IFN-γ-transduced mice harbored fewer T cells. Also related to T cell involvement, Ad:IFN-γ was effective but attenuated in TG from αβ TCR-deficient mice. In corneas, αβ TCR+ T cells were obligatory for protection against viral multiplication. Type I IFN involvement amid antiviral efficacy of Ad:IFN-γ was further investigated because types I and II IFN pathways have synergistic anti-HSV-1 activity. Ad:IFN-γ inhibited viral reproduction in corneas and TG from αβ IFNR-deficient (CD118−/−) mice, although viral titers were 2- to 3-fold higher in cornea and TG compared with wild-type mice. The absence of IFN-stimulated antiviral proteins, 2′-5′ oligoadenylate synthetase/RNase L, and dsRNA-dependent protein kinase R completely eliminated the antiviral effectiveness of Ad:IFN-γ. Collectively, the results demonstrate the following: 1) nonexistence of type I IFN receptor does not abolish defense of Ad:IFN-γ against HSV-1; 2) antiviral pathways oligoadenylate synthetase-RNase L and protein kinase R are mandatory; and 3) αβ TCR+ T cells are compulsory for Ad:IFN-γ effectiveness against HSV-1 in cornea but not in TG.
MyD88-Dependent Activation of B220−CD11b+LY-6C+ Dendritic Cells during Brucella melitensis Infection
Authors: Copin Richard , De Baetselier Patrick , Carlier Yves , Letesson Jean-Jacques , Muraille Eric 
Published: April 2014

Abstract
IFN-γ is a key cytokine controlling Brucella infection. One of its major function is the stimulation of Brucella-killing effector mechanisms, such as inducible NO synthase (iNOS)/NOS2 activity, in phagocytic cells. In this study, an attempt to identify the main cellular components of the immune response induced by Brucella melitensis in vivo is made. IFN-γ and iNOS protein were analyzed intracellularly using flow cytometry in chronically infected mice. Although TCRβ+CD4+ cells were the predominant source of IFN-γ in the spleen, we also identified CD11b+LY-6C+LY-6G−MHC-II+ cells as the main iNOS-producing cells in the spleen and the peritoneal cavity. These cells appear similar to inflammatory dendritic cells recently described in the mouse model of Listeria monocytogenes infection and human psoriasis: the TNF/iNOS-producing dendritic cells. Using genetically deficient mice, we demonstrated that the induction of iNOS and IFN-γ-producing cells due to Brucella infection required TLR4 and TLR9 stimulation coupled to Myd88-dependent signaling pathways. The unique role of MyD88 was confirmed by the lack of impact of Toll-IL-1R domain-containing adaptor inducing IFN-β deficiency. The reduction of IFN-γ+ and iNOS+ cell frequency observed in MyD88-, TLR4-, and TLR9-deficient mice correlated with a proportional lack of Brucella growth control. Taken together, our results provide new insight into how immune responses fight Brucella infection.
Disparity in IL-12 Release in Dendritic Cells and Macrophages in Response to Mycobacterium tuberculosis Is Due to Use of Distinct TLRs
Authors: Pompei Luca , Jang Sihyug , Zamlynny Beata , Ravikumar Sharada , McBride Amanda , Hickman Somia Perdow , Salgame Padmini 
Published: April 2014

Abstract
The control of IL-12 production from dendritic cells (DCs) and macrophages in response to Mycobacterium tuberculosis (Mtb) is not well understood. The objective of this study was to pursue the mechanism underlying our previous report that in response to Mtb infection, DCs release abundant IL-12, whereas secretion is limited in macrophages. An initial comparison of IL-12p35 and IL-12p40 gene induction showed that p35 transcription is similar in murine bone marrow-derived DCs and macrophages, but a rapid and enhanced IL-12p40 transcription occurs only in DCs. Consistent with the p40 gene transcription profile, Mtb-induced remodeling at nucleosome 1 of the p40 promoter also occurs rapidly and extensively in DCs in comparison to macrophages. Removal of IL-10 or addition of IFNγ enhances macrophage IL-12 release to Mtb, but without affecting the kinetics of remodeling at the macrophage p40 promoter. Furthermore, we show that Mtb-induced remodeling at the p40 promoter and IL-12 release in DCs is TLR9 dependent, and in contrast, TLR2 dependent, in macrophages. Data are also presented to demonstrate that a TLR9 agonist induces quantitatively more extensive remodeling at the IL-12p40 promoter and larger IL-12 release in comparison to a TLR2 agonist. Collectively, these findings suggest that DCs and macrophages handle Mtb differently resulting in only DCs being able to engage the more efficient TLR9 pathway for IL-12 gene induction. Our results also imply that TLR2 signaling is not a good inducer of IL-12, supporting the increasingly strong paradigm that TLR2 favors Th2 responses.
TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules
Authors: Gowen Brian B. , Wong Min-Hui , Jung Kie-Hoon , Sanders Andrew B. , Mitchell William M. , Alexopoulou Lena , Flavell Richard A. , Sidwell Robert W. 
Published: April 2014

Abstract
In the wake of RNA virus infections, dsRNA intermediates are often generated. These viral pathogen-associated molecular patterns can be sensed by a growing number of host cell cytosolic proteins and TLR3, which contribute to the induction of antiviral defenses. Recent evidence indicates that melanoma differentiation-associated gene-5 is the prominent host component mediating IFN production after exposure to the dsRNA analog, poly(I:C). We have previously reported that Punta Toro virus (PTV) infection in mice is exquisitely sensitive to treatment with poly(I:C12U), a dsRNA analog that has a superior safety profile while maintaining the beneficial activity of the parental poly(I:C) in the induction of innate immune responses. The precise host factor(s) mediating protective immunity following its administration remain to be elucidated. To assess the role of TLR3 in this process, mice lacking the receptor were used to investigate the induction of protective immunity, type I IFNs, and IL-6 following treatment. Unlike wild-type mice, those lacking TLR3 were not protected against PTV infection following poly(I:C12U) therapy and failed to produce IFN-α, IFN-β, and IL-6. In contrast, poly(I:C) treatment significantly protected TLR3−/− mice from lethal challenge despite some deficiencies in cytokine induction. There was no indication that the lack of protection was due to the fact that TLR3-deficient mice had a reduced capacity to fight infection because they were not found to be more susceptible to PTV. We conclude that TLR3 is essential to the induction of antiviral activity elicited by poly(I:C12U), which does not appear to be recognized by the cytosolic sensor of poly(I:C), melanoma differentiation-associated gene-5.
Role of the Indigenous Microbiota in Maintaining the Virus-Specific CD8 Memory T Cells in the Lung of Mice Infected with Murine Cytomegalovirus
Authors: Tanaka Kazuo , Sawamura Sadaaki , Satoh Tadayuki , Kobayashi Kiyoshi , Noda Satoshi 
Published: April 2014

Abstract
The potent role of indigenous microbiota in maintaining murine CMV (MCMV)-specific memory T cells, which were measured by multimer staining, was investigated using germfree (GF) mice. When the BALB/c mice bred under specific pathogen-free (SPF) conditions were i.p. infected with 0.2 LD50 of MCMV, high frequencies of CD69+/CD44+ MCMV-specific CD8 T cells were noted in the lungs even at 6–12 mo after infection (11.1 ± 3.2 and 9.8 ± 0.9%, respectively). In contrast, even though the viral load and expression levels of mRNA of such cytokines as IL-2, IL-7, IL-15, and IFN-γ in the lungs of MCMV-infected GF mice were comparable to those of infected SPF mice, the frequencies of MCMV-specific CD8 T cells in the lungs of infected GF mice were kept lower than 1% at 6–12 mo after infection. In addition, the reconstitution of microbiota of MCMV-infected GF mice by orally administering a fecal suspension prepared from SPF mice restored the frequencies of both CD8+/multimer+ and CD8+/multimer− T cells to levels similar to those found in SPF mice. These results suggested the indigenous microbiota to play a crucial role in the expansion and maintenance of viral-specific CD8 memory T cells, probably by cross-reactivity between the antigenic epitope of the MCMV-specific memory T cells and the variety of peptides derived from the members of the microbiota. Such cross-reactivity may thus be a major feature of those cells.
Granulocyte-Macrophage Colony-Stimulating Factor (CSF) and Macrophage CSF-Dependent Macrophage Phenotypes Display Differences in Cytokine Profiles and Transcription Factor Activities: Implications for CSF Blockade in Inflammation
Authors: Fleetwood Andrew J. , Lawrence Toby , Hamilton John A. , Cook Andrew D. 
Published: April 2014

Abstract
GM-CSF and M-CSF (CSF-1) can enhance macrophage lineage numbers as well as modulate their differentiation and function. Of recent potential significance for the therapy of inflammatory/autoimmune diseases, their blockade in relevant animal models leads to a reduction in disease activity. What the critical actions are of these CSFs on macrophages during inflammatory reactions are unknown. To address this issue, adherent macrophages (GM-BMM and BMM) were first derived from murine bone marrow precursors by GM-CSF and M-CSF, respectively, and stimulated in vitro with LPS to measure secreted cytokine production, as well as NF-κB and AP-1 activities. GM-BMM preferentially produced TNF-α, IL-6, IL-12p70, and IL-23 whereas, conversely, BMM generated more IL-10 and CCL2; strikingly the latter population could not produce detectable IL-12p70 and IL-23. Following LPS stimulation, GM-BMM displayed rapid IκBα degradation, RelA nuclear translocation, and NF-κB DNA binding relative to BMM, as well as a faster and enhanced AP-1 activation. Each macrophage population was also pretreated with the other CSF before LPS stimulation and found to adopt the phenotype of the other population to some extent as judged by cytokine production and NF-κB activity. Thus, GM-CSF and M-CSF demonstrate, at the level of macrophage cytokine production, different and even competing responses with implications for their respective roles in inflammation, including a possible dampening or suppressive role for M-CSF in certain circumstances.
Free Cholesterol Alters Lipid Raft Structure and Function Regulating Neutrophil Ca2+ Entry and Respiratory Burst: Correlations with Calcium Channel Raft Trafficking
Authors: Kannan Kolenkode B. , Barlos Dimitrios , Hauser Carl J. 
Published: April 2014

Abstract
Recent studies associate cholesterol excess and atherosclerosis with inflammation. The link between these processes is not understood, but cholesterol is an important component of lipid rafts. Rafts are thought to concentrate membrane signaling molecules and thus regulate cell signaling through G protein-coupled pathways. We used methyl β-cyclodextrin to deplete cholesterol from polymorphonuclear neutrophil (PMN) rafts and thus study the effects of raft disruption on G protein-coupled Ca2+ mobilization. Methyl β-cyclodextrin had no effect on Ca2+ store depletion by the G protein-coupled agonists platelet-activating factor or fMLP, but abolished agonist-stimulated Ca2+ entry. Free cholesterol at very low concentrations regulated Ca2+ entry into PMN via nonspecific Ca2+ channels in a biphasic fashion. The specificity of cholesterol regulation for Ca2+ entry was confirmed using thapsigargin studies. Responses to cholesterol appear physiologic because they regulate respiratory burst in a proportional biphasic fashion. Investigating further, we found that free cholesterol accumulated in PMN lipid raft fractions, promoting formation and polarization of membrane rafts. Finally, the transient receptor potential calcium channel protein TRPC1 redistributed to raft fractions in response to cholesterol. The uniformly biphasic relationships between cholesterol availability, Ca2+ signaling and respiratory burst suggest that Ca2+ influx and PMN activation are regulated by the quantitative relationships between cholesterol and other environmental lipid raft components. The association between symptomatic cholesterol excess and inflammation may therefore in part reflect free cholesterol- dependent changes in lipid raft structure that regulate immune cell Ca2+ entry. Ca2+ entry-dependent responses in other cell types may also reflect cholesterol bioavailability and lipid incorporation into rafts.
Chemokine Receptor CCR2 but Not CCR5 or CCR6 Mediates the Increase in Pulmonary Dendritic Cells during Allergic Airway Inflammation
Authors: Robays Lander J. , Maes Tania , Lebecque Serge , Lira Sergio A. , Kuziel William A. , Brusselle Guy G. , Joos Guy F. , Vermaelen Karim V. 
Published: April 2014

AbstractIncreased numbers of pulmonary dendritic cells (DCs) are recruited to the lungs during allergic airway inflammation and contribute to the maintenance of the inflammatory immune response. The chemokine receptors that directly control DC accumulation into the lungs are largely unknown. To explore this issue, we generated mixed bone marrow chimeric mice containing both wild-type and knockout cells for a given chemokine receptor. After induction of allergic airway inflammation, we specifically tracked and compared chemokine receptor knockout vs wild-type DC populations through various lung compartments. Using this approach, we show that CCR2, but not CCR5 or CCR6, directly controls the accumulation of DCs into allergic lungs. Furthermore, the size of inflammatory monocyte populations in peripheral blood was strikingly CCR2 dependent, suggesting that CCR2 primarily mediates the release of monocytic DC precursors into the bloodstream.
The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells
Authors: Wu Henry D. , Maurer Mathew S. , Friedman Richard A. , Marboe Charles C. , Ruiz-Vazquez Elena M. , Ramakrishnan Rajasekhar , Schwartz Allan , Tilson M. David , Stewart Allan S. , Winchester Robert 
Published: April 2014

Abstract
Valve lesions in degenerative calcific aortic stenosis (CAS), a disorder affecting 3% of those older than 75 years, are infiltrated by T lymphocytes. We sought to determine whether the αβ TCR repertoire of these valve-infiltrating lymphocytes exhibited features either of a polyclonal nonselective response to inflammation or contained expanded clones suggesting a more specific immune process. TCR β-chain CDR3-length distribution analysis using PCR primers specific for 23 Vβ families performed in eight individuals with CAS affecting tri- or bileaflet aortic valves revealed considerable oligoclonal T cell expansion. In five cases, β-chain nucleotide sequencing in five selected Vβ families showed that an average of 92% of the valve-infiltrating T cell repertoire consisted of expanded T cell clones, differing markedly in composition from the relatively more polyclonal peripheral CD8 or CD4 T cell subsets found even in this elderly population. Twenty-four of the valve-infiltrating T cell clones also had the same clone identified in blood, some of which were highly expanded. Interestingly, 22 of these 24 shared clones were CD8 in lineage (p = 1.5 × 10−12), suggesting a possible relationship to the expanded CD8+CD28− T cell clones frequently present in the elderly. Additionally, the sequences of several TCR β-chain CDR3 regions were homologous to TCR β-chains identified previously in allograft arteriosclerosis. We infer that these findings are inconsistent with a nonselective secondary response of T cells to inflammation and instead suggest that clonally expanded αβ T cells are implicated in mediating a component of the valvular injury responsible for CAS.
Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection
Authors: Fluur Caroline , De Milito Angelo , Fry Terry J. , Vivar Nancy , Eidsmo Liv , Atlas Ann , Federici Cristina , Matarrese Paola , Logozzi Mariantonia , Rajnavölgyi Eva , Mackall Crystal L. , Fais Stefano , Chiodi Francesca , Rethi Bence 
Published: April 2014

AbstractIL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.
Overexpression of Activation-Induced Cytidine Deaminase in B Cells Is Associated with Production of Highly Pathogenic Autoantibodies
Authors: Hsu Hui-Chen , Wu Yalei , Yang PingAr , Wu Qi , Job Godwin , Chen Jian , Wang John , Accavitti-Loper Mary Ann V. , Grizzle William E. , Carter Robert H. , Mountz John D. 
Published: April 2014

AbstractDefective receptor editing or defective B cell checkpoints have been associated with increased frequency of multireactive autoantibodies in autoimmune disease. However, Ig somatic hypermutation and/or class switch recombination may be mechanisms enabling the development of pathogenic multireactive autoantibodies. In this study, we report that, in the BXD2 mouse model of autoimmune disease, elevated expression of activation-induced cytidine deaminase (AID) in recirculating follicular CD86+ subsets of B cells and increased germinal center B cell activity are associated with the production of pathogenic multireactive autoantibodies. CD4 T cells from BXD2 mice that expressed increased levels of CD28 and an increased proliferative response to anti-CD3 and anti-CD28 stimulation are required for this process. Inhibition of the CD28-CD86 interaction in BXD2 mice with AdCTLA4-Ig resulted in normalization of AID in the B cells and suppression of IgG autoantibodies. This treatment also prevented the development of germinal center autoantibody-producing B cells, suggesting that an optimal microenvironment enabling AID function is important for the formation of pathogenic autoantibodies. Taken together, our data indicate that AID expression in B cells is a promising therapeutic target for the treatment of autoimmune diseases and that suppression of this gene may be a molecular target of CTLA4-Ig therapy.
Airway Exposure Levels of Lipopolysaccharide Determine Type 1 versus Type 2 Experimental Asthma
Authors: Kim Yoon-Keun , Oh Sun-Young , Jeon Seong Gyu , Park Heung-Woo , Lee Soo-Yeon , Chun Eun-Young , Bang Boram , Lee Hyun-Seung , Oh Min-Hee , Kim You-Sun , Kim Jong-Hoon , Gho Yong Song , Cho Sang-Heon , Min Kyung-Up , Kim You-Young , Zhu Zhou 
Published: April 2014

Abstract
Allergic asthma is characterized by airway inflammation initiated by adaptive immune responses to aeroallergens. Recent data suggest that severe asthma may be a different form of asthma rather than an increase in asthma symptoms and that innate immune responses to LPS can modulate adaptive immune responses to allergens. In this study, we evaluated the hypothesis that airway exposure to different doses of LPS induces different form of asthma. Our study showed that neutrophilic inflammation and IFN-γ expression were higher in induced sputum from severe asthma patients than from mild to moderate asthmatics. Animal experiments indicated that allergen sensitization with low-dose LPS (0.1 μg) induced type 2 asthma phenotypes, i.e., airway hyperresponsiveness, eosinophilic inflammation, and allergen-specific IgE up-regulation. In contrast, allergen sensitization with high-dose LPS (10 μg) induced asthma phenotypes, i.e., airway hyperresponsiveness and noneosinophilic inflammation that were not developed in IFN-γ-deficient mice, but unaffected in the absence of IL-4. During the allergen sensitization period, TNF-α expression was found to be enhanced by both low- and high-dose LPS, whereas IL-12 expression was only enhanced by high-dose LPS. Interestingly, the asthma phenotypes induced by low-dose LPS, but not by high-dose LPS, were completely inhibited in TNF-α receptor-deficient mice, whereas the asthma phenotypes induced by high-dose LPS were abolished in the homozygous null mutation of the STAT4 gene. These findings suggest that airway exposure levels of LPS induces different forms of asthma that are type 1 and type 2 asthma phenotypes by high and low LPS levels, respectively.
Clinical Transplantation Tolerance: Many Rivers to Cross
Authors: Salama Alan D. , Womer Karl L. , Sayegh Mohamed H. 
Published: April 2014

Abstract
Modern immunosuppressive regimens for organ transplantation have resulted in excellent short-term results but less dramatic improvements in long-term outcomes. Moreover, they are associated with significant deleterious effects. One solution that should avoid the adverse drug effects and result in improved graft and patient longevity as well as positively impacting on the organ shortage is the establishment of transplantation tolerance. Ever since the original description of transplantation tolerance in rodent allografts, there have been significant efforts made to translate tolerance-promoting strategies to the clinical arena. However, &gt;50 years later, we are still faced with significant barriers that are preventing such a goal from being widely attained. Nonetheless, pilot clinical tolerance protocols are underway in selected transplant recipients. In this review, we discuss the scientific and nonscientific issues that must be overcome for successful transplantation tolerance to become a clinical reality.