bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Type I IFN-Dependent Pathway Induced by Schistosoma mansoni Eggs in Mouse Myeloid Dendritic Cells Generates an Inflammatory Signature
Authors: Trottein François , Pavelka Norman , Vizzardelli Caterina , Angeli Veronique , Zouain Claudia S. , Pelizzola Mattia , Capozzoli Monica , Urbano Matteo , Capron Monique , Belardelli Filippo , Granucci Francesca , Ricciardi-Castagnoli Paola 
Published: April 2014

Abstract
Schistosomes are helminth parasites that display a dual impact on the immune system of their hosts. Although the larval stage, also known as schistosomulum, appears to subvert the host defenses, the egg stage induces strong inflammatory reactions. Given the pivotal role of dendritic cells (DC) in initiating and regulating immune responses, we compared the distinct transcriptional programs induced in immature mouse DC by S. mansoni eggs or schistosomula. Although SLA abrogated the transcription of many genes implicated in DC functions, eggs caused myeloid DC to produce IFN-β. Autocrine/paracrine signaling through the type I IFN receptor in response to eggs was necessary for the induction of known IFN-responsive genes and enhanced the synthesis of key inflammatory products. Taken as a whole, our data provide molecular insights into the immune evasion mechanism of schistosomula and suggest an unexpected role for type I IFN in the innate response to helminth eggs.
The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo
Authors: Bellocchio Silvia , Montagnoli Claudia , Bozza Silvia , Gaziano Roberta , Rossi Giordano , Mambula Salamatu S. , Vecchi Annunciata , Mantovani Alberto , Levitz Stuart M. , Romani Luigina 
Published: April 2014

Abstract
In vitro studies have indicated the importance of Toll-like receptor (TLR) signaling in response to the fungal pathogens Candida albicans and Aspergillus fumigatus. However, the functional consequences of the complex interplay between fungal morphogenesis and TLR signaling in vivo remain largely undefined. In this study we evaluate the impact of the IL-1R/TLR/myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway on the innate and adaptive Th immunities to C. albicans and A. fumigatus in vivo. It was found that 1) the MyD88-dependent pathway is required for resistance to both fungi; 2) the involvement of the MyD88 adapter may occur through signaling by distinct members of the IL-1R/TLR superfamily, including IL-1R, TLR2, TLR4, and TLR9, with the proportional role of the individual receptors varying depending on fungal species, fungal morphotypes, and route of infection; 3) individual TLRs and IL-1R activate specialized antifungal effector functions on neutrophils, which correlates with susceptibility to infection; and 4) MyD88-dependent signaling on dendritic cells is crucial for priming antifungal Th1 responses. Thus, the finding that the innate and adaptive immunities to C. albicans and A. fumigatus require the coordinated action of distinct members of the IL-1R/TLR superfamily acting through MyD88 makes TLR manipulation amenable to the induction of host resistance to fungi.
Enhanced CD8+ T Cell Immune Responses and Protection Elicited against Plasmodium berghei Malaria by Prime Boost Immunization Regimens Using a Novel Attenuated Fowlpox Virus
Authors: Anderson Richard J. , Hannan Carolyn M. , Gilbert Sarah C. , Laidlaw Stephen M. , Sheu Eric G. , Korten Simone , Sinden Robert , Butcher Geoffrey A. , Skinner Michael A. , Hill Adrian V. S. 
Published: April 2014

Abstract
Sterile immunity can be provided against the pre-erythrocytic stages of malaria by IFN-γ-secreting CD8+ T cells that recognize parasite-infected hepatocytes. In this study, we have investigated the use of attenuated fowlpox virus (FPV) strains as recombinant vaccine vectors for eliciting CD8+ T cells against Plasmodium berghei. The gene encoding the P. berghei circumsporozoite (PbCS) protein was inserted into an FPV vaccine strain licensed for use in chickens, Webster’s FPV, and the novel FPV vaccine strain FP9 by homologous recombination. The novel FP9 strain proved more potent as a vaccine for eliciting CD8+ T cell responses against the PbCS Ag. Sequential immunization with rFP9 and recombinant modified vaccinia virus Anakara (MVA) encoding the PbCS protein, administered by clinically acceptable routes, elicited potent CD8+ T cell responses against the PbCS protein. This immunization regimen elicited substantial protection against a stringent liver-stage challenge with P. berghei and was more immunogenic and protective than DNA/MVA prime/boost immunization. However, further improvement was not achieved by sequential (triple) immunization with a DNA vaccine, FP9, and MVA.
The Effect of Innate Immunity on Autoimmune Diabetes and the Expression of Toll-Like Receptors on Pancreatic Islets
Authors: Wen Li , Peng Jian , Li Zhenjun , Wong F. Susan 
Published: April 2014

Abstract
Viral infections have previously been implicated as a trigger of autoimmune diabetes. In this study, we compared a viral mimic with other microbial components derived from bacteria in triggering diabetes development in C57BL/6-rat insulin promoter-B7.1 mice that do not normally develop diabetes. It is striking that only the viral mimic induced the development of diabetes in our model system. Further mechanistic studies suggest that diabetes is induced, in part, by the combination of direct recognition of this virus-like stimulus by pancreatic islets through the expression of the innate immune receptor, Toll-like receptor 3. In addition, the functions of APCs are up-regulated, and this could stimulate islet Ag-reactive T cells that will attack β cells leading to autoimmune diabetes.
Acidosis Improves Uptake of Antigens and MHC Class I-Restricted Presentation by Dendritic Cells
Authors: Vermeulen Mónica , Giordano Mirta , Trevani Analía S. , Sedlik Christine , Gamberale Romina , Fernández-Calotti Paula , Salamone Gabriela , Raiden Silvina , Sanjurjo Julieta , Geffner Jorge R. 
Published: April 2014

Abstract
It is widely appreciated that inflammatory responses in peripheral tissues are usually associated to the development of acidic microenvironments. Despite this, there are few studies aimed to analyze the effect of extracellular pH on immune cell functions. We analyzed the impact of acidosis on the behavior of dendritic cells (DCs) derived from murine bone marrow. We found that extracellular acidosis (pH 6.5) markedly stimulated the uptake of FITC-OVA, FITC-dextran, and HRP by DCs. In fact, to reach similar levels of endocytosis, DCs cultured at pH 7.3 required concentrations of Ag in the extracellular medium almost 10-fold higher compared with DCs cultured at pH 6.5. Not only the endocytic capacity of DCs was up-regulated by extracellular acidosis, but also the expression of CD11c, MHC class II, CD40, and CD86 as well as the acquisition of extracellular Ags by DCs for MHC class I-restricted presentation. Importantly, DCs pulsed with Ag under acidosis showed an improved efficacy to induce both specific CD8+ CTLs and specific Ab responses in vivo. Our results suggest that extracellular acidosis improves the Ag-presenting capacity of DCs.
CD40 on Adult Human Airway Epithelial Cells: Expression and Proinflammatory Effects
Authors: Cagnoni Francesca , Oddera Susanna , Giron-Michel Julien , Riccio Anna Maria , Olsson Susanna , Dellacasa Palmiro , Melioli Giovanni , Canonica G. Walter , Azzarone Bruno 
Published: April 2014

Abstract
CD40/CD40 ligand interaction is an important pathway for B and T cell cooperation and function; functional CD40 molecules have recently been found on nonhematopoietic cells. We detected CD40 in vivo on normal human respiratory epithelial cells and showed that its expression is increased on inflamed airway epithelium. Subsequently, we analyzed its expression and function on primary cultures of human airway epithelial cells. Our data show that CD40 is up-regulated by IFN-β and IFN-γ, its ligation increases the surface expression of CD54 and CD106 and it may stimulate the release of IL-6 and IL-8. The use of Janus kinase 3 (JAK3) and NF-κB inhibitors suggests that both basal and CD40-induced release of the two cytokines is JAK3-dependent. Using colocalization techniques, we revealed the existence of CD40/JAK3 and CD40/TNFR-associated factor 2 interplay. The extent of these interactions may be partial (2–40% of the cells) or massive (80–90% of the cells) in cultured cells. Stimulation via CD40 causes a significant increase in the number of cells expressing colocalization only in the cultures displaying low frequency of initial colocalization. Thus, airway epithelial cells, activated by CD40, may behave as effector cells of the inflammation process and should be considered priority targets for anti-inflammatory therapy. This work identifies CD40 and the correlated JAK3 signaling molecule as potential molecular targets to block the inflammatory functions of epithelial cells.
Direct In Vivo Monitoring of Acute Allergic Reactions in Human Conjunctiva
Authors: Helintö Maaret , Renkonen Risto , Tervo Timo , Vesaluoma Minna , Saaren-Seppälä Heikki , Haahtela Tari , Kirveskari Juha 
Published: April 2014

Abstract
Immediate allergic reactions are initiated by allergen-induced, specific IgE-mediated mast cell degranulation and involve leukocyte recruitment into the inflamed site. We compared conjunctival signs, symptoms, and in vivo leukocyte rolling and extravasation into sites of inflammation in five patients allergic to birch pollen and in 10 nonallergic controls who received a challenge to birch allergen or histamine. Both the specific allergen in allergic patients and histamine, both in patients and in healthy controls, induced symptoms and signs of an immediate allergic reaction together with leukocyte rolling within the conjunctival blood vessels. However, only allergen, not histamine, caused leukocyte extravasation into the site of inflammation in the allergic patients. Allergen also increased expression of endothelial P-selectin in conjunctival vessels and slowed the rolling of leukocytes which is required for their extravasation from blood circulation into the target tissue. Finally, i.v. heparin strongly reduced the number of slowly rolling cells during allergen- or histamine-induced reactions and this can probably hinder the leukocyte extravasation after allergen exposure. These findings suggest that slow rolling is required for leukocyte extravasation in acute allergic reactions, and it can be inhibited by heparin in vivo in therapeutically relevant conditions.
Grass Pollen Immunotherapy Induces Mucosal and Peripheral IL-10 Responses and Blocking IgG Activity
Authors: Nouri-Aria Kayhan T. , Wachholz Petra A. , Francis James N. , Jacobson Mikila R. , Walker Samantha M. , Wilcock Louisa K. , Staple Steven Q. , Aalberse Robert C. , Till Stephen J. , Durham Stephen R. 
Published: April 2014

Abstract
T regulatory cells and IL-10 have been implicated in the mechanism of immunotherapy in patients with systemic anaphylaxis following bee stings. We studied the role of IL-10 in the induction of clinical, cellular, and humoral tolerance during immunotherapy for local mucosal allergy in subjects with seasonal pollinosis. Local and systemic IL-10 responses and serum Ab concentrations were measured before/after a double-blind trial of grass pollen (Phleum pratense, Phl P) immunotherapy. We observed local increases in IL-10 mRNA-positive cells in the nasal mucosa after 2 years of immunotherapy, but only during the pollen season. IL-10 protein-positive cells were also increased and correlated with IL-10 mRNA+ cells. These changes were not observed in placebo-treated subjects or in healthy controls. Fifteen and 35% of IL-10 mRNA signals were colocalized to CD3+ T cells and CD68+ macrophages, respectively, whereas only 1–2% of total CD3+ cells and 4% of macrophages expressed IL-10. Following immunotherapy, peripheral T cells cultured in the presence of grass pollen extract also produced IL-10. Immunotherapy resulted in blunting of seasonal increases in serum allergen Phl p 5-specific IgE, 60- to 80-fold increases in Phl p 5-specific IgG, and 100-fold increases in Phl p 5-specific IgG4. Post-immunotherapy serum exhibited inhibitory activity, which coeluted with IgG4, and blocked IgE-facilitated binding of allergen-IgE complexes to B cells. Both the increases in IgG and the IgG “blocking” activity correlated with the patients’ overall assessment of improvement. Thus, grass pollen immunotherapy may induce allergen-specific, IL-10-dependent “protective” IgG4 responses.
Molecular and Immunological Evaluation of the Transcription Factor SOX-4 as a Lung Tumor Vaccine Antigen
Authors: Friedman Rachel S. , Bangur Chaitanya S. , Zasloff Eden J. , Fan Liqun , Wang Tongtong , Watanabe Yoshihiro , Kalos Michael 
Published: April 2014

Abstract
The developmental transcription factor SOX-4 has been shown to be highly and differentially overexpressed in primary small cell lung carcinomas (SCLC). To examine the potential of SOX-4 for broad use as a lung cancer vaccine, we have evaluated the expression of SOX-4 in a panel of primary adenocarcinoma, squamous, and large cell tumor samples as well as in a panel of established small cell and non-small cell lung carcinoma tumor cell lines. SOX-4 mRNA is shown to be overexpressed in a substantial fraction of each of these lung tumor types. To examine the immunological potential of SOX-4, we have evaluated the presence of SOX-4-specific CD4 and CD8 T cells in PBMC of healthy donors and the presence of SOX4-specific Abs in sera from SCLC patients. We demonstrate the presence of both CD4 and CD8 T cells that recognize naturally processed epitopes derived from SOX-4 as well as the presence of SOX-4-specific Abs in sera from SCLC patients, but not in sera from healthy donors. The lung tumor-specific overexpression and demonstration of a comprehensive Ag-specific immune response specific for SOX-4 support the use of this molecule in the development of whole gene-, peptide-, or protein-based vaccination strategies against lung cancer. Furthermore, the identification of naturally processed T cell and Ab epitopes from SOX-4 provides valuable tools for the development of peptide-based vaccination strategies against lung cancer as well as to monitor SOX-4-specific responses in vaccinated patients.
Textbook Germinal Centers?
Authors: Manser Tim 
Published: April 2014

AbstractModels for the development and function of germinal centers (GCs) have been so widely discussed in the original literature that they now appear in immunology textbooks. Unfortunately, many of the tenets of these models have not yet been subjected to adequate experimental scrutiny. Indeed, recent studies have called several of their principal assumptions into question. In addition, the term germinal center has been applied to a diverse assortment of focal processes of B cell proliferation and differentiation. This variability might be explained by alterations in the progression of a single textbook GC process. Alternatively, distinct developmental pathways may create unique classes of GCs with specialized functions.
Suppression of CD4+ T Lymphocyte Effector Functions by CD4+CD25+ Cells In Vivo
Authors: Martin Bruno , Banz Alice , Bienvenu Boris , Cordier Corinne , Dautigny Nicole , Bécourt Chantal , Lucas Bruno 
Published: April 2014

Abstract
CD4+CD25+ regulatory T cells have been extensively studied during the last decade, but how these cells exert their regulatory function on pathogenic effector T cells remains to be elucidated. Naive CD4+ T cells transferred into T cell-deficient mice strongly expand and rapidly induce inflammatory bowel disease (IBD). Onset of this inflammatory disorder depends on IFN-γ production by expanding CD4+ T cells. Coinjection of CD4+CD25+ regulatory T cells protects recipient mice from IBD. In this study, we show that CD4+CD25+ regulatory T cells do not affect the initial activation/proliferation of injected naive T cells as well as their differentiation into Th1 effectors. Moreover, naive T cells injected together with CD4+CD25+ regulatory T cells into lymphopenic hosts are still able to respond to stimuli in vitro when regulatory T cells are removed. In these conditions, they produce as much IFN-γ as before injection or when injected alone. Finally, when purified, they are able to induce IBD upon reinjection into lymphopenic hosts. Thus, prevention of IBD by CD4+CD25+ regulatory T cells is not due to deletion of pathogenic T cells, induction of a non reactive state (anergy) among pathogenic effector T cells, or preferential induction of Th2 effectors rather than Th1 effectors; rather, it results from suppression of T lymphocyte effector functions, leading to regulated responses to self.
Prolonged Antigen Presentation, APC-, and CD8+ T Cell Turnover during Mycobacterial Infection: Comparison withListeria monocytogenes
Authors: van Faassen Henk , Dudani Renu , Krishnan Lakshmi , Sad Subash 
Published: April 2014

AbstractWe expressed the CTL epitope of OVA (OVA257–264) in an acute (Listeria monocytogenes (LM)-OVA) and a chronic intracellular pathogen (Mycobacterium bovis (BCG)-OVA), to evaluate the kinetics of Ag presentation. LM-OVA proliferated rapidly in vivo, resulting in profound LM-OVA expansion within the first 24 h of infection, culminating in the generation of a potent CD8+ T cell response, which peaked on day 7 but underwent a rapid attrition subsequently. In contrast, BCG-OVA exhibited reduced growth in vivo, resulting in a delayed CD8+ T cell response that increased progressively with time. Relative to LM-OVA, BCG-OVA induced persistently increased numbers of apoptotic (annexin V+) CD8+ T cells. Ag presentation in vivo was evaluated by transferring Thy1.2+ carboxyfluorescein-labeled OT1 transgenic CD8+ T cells into infected Thy1.1+ congeneic recipient mice. LM-OVA induced rapid Ag presentation that was profound in magnitude, with most of the transferred cells getting activated within 4 days and resulting in a massive accumulation of activated donor CD8+ T cells. In contrast, Ag presentation induced by BCG-OVA was delayed, weaker in magnitude, which peaked around the second week of infection and declined to a low level subsequently. Increasing the dose of BCG-OVA while enhancing the magnitude of Ag presentation did not change the kinetics. Furthermore, a higher dose of BCG-OVA also accelerated the attrition of OVA257–264-specific CD8+ T cells. Relative to LM-OVA, the dendritic cells in BCG-OVA-infected mice were apoptotic for prolonged periods, suggesting that the rapid death of APCs may limit the magnitude of Ag presentation during chronic stages of mycobacterial infection.
The Cell-Cell Adhesion Molecule Carcinoembryonic Antigen-Related Cellular Adhesion Molecule 1 Inhibits IL-2 Production and Proliferation in Human T Cells by Association with Src Homology Protein-1 and Down-Regulates IL-2 Receptor
Authors: Chen Charng-Jui , Shively John E. 
Published: April 2014

Abstract
The cell adhesion molecule, carcinoembryonic Ag-related cellular adhesion molecule 1, shown by others to both activate and inhibit T cell proliferation, exhibits a reciprocal relationship to IL-2R expression over the time course of activation of PBMCs, and upon Ab ligation, inhibits both the production of IL-2 and cell proliferation. Carcinoembryonic Ag-related cellular adhesion molecule 1 associates with CD3 and is found in lipid rafts of PBMCs, is phosphorylated on the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of the -4L isoform, and associates with Src homology protein-1, providing an explanation for its inhibitory activity. When the ITIM-containing -4L and non-ITIM-containing -4S isoforms are transfected into Jurkat cells that produce, but do not depend on IL-2 for growth, both IL-2 production and cell proliferation are differentially inhibited, demonstrating that the two isoforms signal via different pathways. When the two isoforms are transfected into Kit-225 cells that depend on IL-2 for growth, IL-2Rβ and γ, but not α subunits are down-regulated, and the -4L, but not the -4S isoform inhibits cell proliferation by 6-fold in an IL-2 dose-response study.
A Keratinocyte-Responsive γδ TCR Is Necessary for Dendritic Epidermal T Cell Activation by Damaged Keratinocytes and Maintenance in the Epidermis
Authors: Jameson Julie M. , Cauvi Gabrielle , Witherden Deborah A. , Havran Wendy L. 
Published: April 2014

AbstractA unique population of T lymphocytes, designated dendritic epidermal T cells (DETC), homes to the murine epidermis during fetal development. DETC express a canonical γδ TCR, Vγ3/Vδ1, which recognizes Ag expressed on damaged, stressed, or transformed keratinocytes. Recently, DETC were shown to play a key role in the complex process of wound repair. To examine the role of the DETC TCR in DETC localization to the epidermis, maintenance in the skin, and activation in vivo, we analyzed DETC in the TCRδ−/− mouse. Unlike previous reports in which the TCRδ−/− skin was found to be devoid of any DETC, we discovered that TCRδ−/− mice have αβ TCR-expressing DETC with a polyclonal Vβ chain repertoire. The αβ DETC are not retained over the life of the animal, suggesting that the γδ TCR is critical for the maintenance of DETC in the skin. Although the αβ DETC can be activated in response to direct stimulation, they do not respond to keratinocyte damage. Our results suggest that a keratinocyte-responsive TCR is necessary for DETC activation in response to keratinocyte damage and for DETC maintenance in the epidermis.
Inhibition of NFAT Specifically in T Cells Prevents Allergic Pulmonary Inflammation
Authors: Diehl Sean , Krahl Troy , Rinaldi Lisa , Norton Ryan , Irvin Charles G. , Rincón Mercedes 
Published: April 2014

AbstractNFAT is a family of transcription factors important in the regulation of cytokine genes and is widely expressed in different lymphoid and nonlymphoid tissues. Consequently, the role of NFAT in CD4+ T cells during an in vivo immune response is not completely clear. In this study, we use transgenic mice expressing a dominant negative NFAT mutant exclusively in T cells to address the role of NFAT in T cells during a Th2 immune response in a model of allergic airway inflammation. We have observed that inhibition of NFAT in T cells results in a reduction of Ag-specific Th2 Ab levels and IL-4 production by CD4+ T cells. The accumulation of eosinophils in the bronchoalveolar lavage is delayed in dominant negative NFAT-transgenic mice. These mice are also more resistant to the development of lung pathology in response to allergen exposure. We, therefore, conclude that activation of NFAT in CD4+ T cells is required for the development of a Th2 immune response in vivo and allergic airway inflammation.