bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipids Including Cholesteryl Linoleate and Cholesteryl Arachidonate Contribute to the Inherent Antibacterial Activity of Human Nasal Fluid
Authors: Do Thai Q. , Moshkani Safiehkhatoon , Castillo Patricia , Anunta Suda , Pogosyan Adelina , Cheung Annie , Marbois Beth , Faull Kym F. , Ernst William , Chiang Su Ming , Fujii Gary , Clarke Catherine F. , Foster Krishna , Porter Edith 
Published: April 2014

Abstract
Mucosal surfaces provide first-line defense against microbial invasion through their complex secretions. The antimicrobial activities of proteins in these secretions have been well delineated, but the contributions of lipids to mucosal defense have not been defined. We found that normal human nasal fluid contains all major lipid classes (in micrograms per milliliter), as well as lipoproteins and apolipoprotein A-I. The predominant less polar lipids were myristic, palmitic, palmitoleic, stearic, oleic, and linoleic acid, cholesterol, and cholesteryl palmitate, cholesteryl linoleate, and cholesteryl arachidonate. Normal human bronchioepithelial cell secretions exhibited a similar lipid composition. Removal of less-polar lipids significantly decreased the inherent antibacterial activity of nasal fluid against Pseudomonas aeruginosa, which was in part restored after replenishing the lipids. Furthermore, lipids extracted from nasal fluid exerted direct antibacterial activity in synergism with the antimicrobial human neutrophil peptide HNP-2 and liposomal formulations of cholesteryl linoleate and cholesteryl arachidonate were active against P. aeruginosa at physiological concentrations as found in nasal fluid and exerted inhibitory activity against other Gram-negative and Gram-positive bacteria. These data suggest that host-derived lipids contribute to mucosal defense. The emerging concept of host-derived antimicrobial lipids unveils novel roads to a better understanding of the immunology of infectious diseases.
Trafficking of Antigen-Specific CD8+ T Lymphocytes to Mucosal Surfaces following Intramuscular Vaccination
Authors: Kaufman David R. , Liu Jinyan , Carville Angela , Mansfield Keith G. , Havenga Menzo J. E. , Goudsmit Jaap , Barouch Dan H. 
Published: April 2014

Abstract
A critical goal of vaccine development for a wide variety of pathogens is the induction of potent and durable mucosal immunity. However, it has been assumed that this goal would be difficult to achieve by systemic vaccination due to the anatomic and functional distinctness of the systemic and mucosal immune systems and the resultant compartmentalization of immune responses. In this study, we show that Ag-specific CD8+ T lymphocytes traffic efficiently to mucosal surfaces following systemic vaccination. Intramuscular immunization with recombinant adenovirus (rAd) vector-based vaccines expressing SIV Gag resulted in potent, durable, and functional CD8+ T lymphocyte responses at multiple mucosal effector sites in both mice and rhesus monkeys. In adoptive transfer studies in mice, vaccine-elicited systemic CD8+ T lymphocytes exhibited phenotypic plasticity, up-regulated mucosal homing integrins and chemokine receptors, and trafficked rapidly to mucosal surfaces. Moreover, the migration of systemic CD8+ T lymphocytes to mucosal compartments accounted for the vast majority of Ag-specific mucosal CD8+ T lymphocytes induced by systemic vaccination. Thus, i.m. vaccination can overcome immune compartmentalization and generate robust mucosal CD8+ T lymphocyte memory. These data demonstrate that the systemic and mucosal immune systems are highly coordinated following vaccination.
Elevated Numbers of FcγRIIIA+ (CD16+) Effector CD8 T Cells with NK Cell-Like Function in Chronic Hepatitis C Virus Infection
Authors: Björkström Niklas K. , Gonzalez Veronica D. , Malmberg Karl-Johan , Falconer Karolin , Alaeus Annette , Nowak Greg , Jorns Carl , Ericzon Bo-Göran , Weiland Ola , Sandberg Johan K. , Ljunggren Hans-Gustaf 
Published: April 2014

Abstract
CTL are crucial in the defense against viral infections. In the course of investigating peripheral blood and intrahepatic CD8 T cells in patients with chronic hepatitis C virus (HCV) infection, we observed a significant population of CD8 T cells expressing the FcγRIIIA (CD16) receptor. This observation led us to characterize these cells with respect to their phenotype and function in a cohort of patients with chronic HCV infection as well as in healthy blood donors. On average, 10% of peripheral blood CD8 T cells from HCV-infected patients expressed CD16 compared with only a few percent in healthy donors. CD16+ CD8 T cells displayed a late-stage effector phenotype with high levels of perforin. These cells exhibited a restricted TCR profile suggesting underlying clonal expansion. Stimulation of CD16 on CD8 T cells evoked a vigorous response similar to that of CD16 stimulation in NK cells. Our data suggest that CD8 T cells, during chronic HCV infection in humans, continue to differentiate beyond defined stages of terminal effector cells, acquiring CD16 and NK cell-like functional properties.
PIR-B-Deficient Mice Are Susceptible to Salmonella Infection
Authors: Torii Ikuko , Oka Satoshi , Hotomi Muneki , Benjamin William H. , Takai Toshiyuki , Kearney John F. , Briles David E. , Kubagawa Hiromi 
Published: April 2014

Abstract
Paired Ig-like receptors of activating (PIR-A) and inhibitory (PIR-B) isoforms are expressed by many hematopoietic cells, including B lymphocytes and myeloid cells. To determine the functional roles of PIR-A and PIR-B in primary bacterial infection, PIR-B-deficient (PIR-B−/−) and wild-type (WT) control mice were injected i.v. with an attenuated strain of Salmonella enterica Typhimurium (WB335). PIR-B−/− mice were found to be more susceptible to Salmonella infection than WT mice, as evidenced by high mortality rate, high bacterial loads in the liver and spleen, and a failure to clear bacteria from the circulation. Although blood levels of major cytokines and Salmonella-specific Abs were mostly comparable in the two groups of mice, distinct patterns of inflammatory lesions were found in their livers at 7–14 days postinfection: diffuse spreading along the sinusoids in PIR-B−/− mice vs nodular restricted localization in WT mice. PIR-B−/− mice have more inflammatory cells in the liver but fewer B cells and CD8+ T cells in the spleen than WT mice at 14 days postinfection. PIR-B−/− bone marrow-derived macrophages (BMMφ) failed to control intracellular replication of Salmonella in vitro, in part due to inefficient phagosomal oxidant production, when compared with WT BMMφ. PIR-B−/− BMMφ also produced more nitrite and TNF-α upon exposure to Salmonella than WT BMMφ did. These findings suggest that the disruption of PIR-A and PIR-B balance affects their regulatory roles in host defense to bacterial infection.
Identification of Functional Roles for Both IL-17RB and IL-17RA in Mediating IL-25-Induced Activities
Authors: Rickel Erika A. , Siegel Lori A. , Yoon Bo-Rin Park , Rottman James B. , Kugler David G. , Swart David A. , Anders Penny M. , Tocker Joel E. , Comeau Michael R. , Budelsky Alison L. 
Published: April 2014

Abstract
IL-25 (IL-17E) is a unique IL-17 family ligand that promotes Th2-skewed inflammatory responses. Intranasal administration of IL-25 into naive mice induces pulmonary inflammation similar to that seen in patients with allergic asthma, including increases in bronchoalveolar lavage fluid eosinophils, bronchoalveolar lavage fluid IL-5 and IL-13 concentrations, goblet cell hyperplasia, and increased airway hyperresponsiveness. IL-25 has been reported to bind and signal through IL-17RB (IL-17BR, IL-17Rh1). It has been demonstrated recently that IL-17A signals through a heteromeric receptor composed of IL-17RA and IL-17RC. We sought to determine whether other IL-17 family ligands also utilize heteromeric receptor complexes. The required receptor subunits for IL-25 biological activities were investigated in vitro and in vivo using a combination of knockout (KO) mice and antagonistic Abs. Unlike wild-type mice, cultured splenocytes from either IL-17RB KO or IL-17RA KO mice did not produce IL-5 or IL-13 in response to IL-25 stimulation, and both IL-17RB KO and IL-17RA KO mice did not respond to intranasal administration of IL-25. Furthermore, treatment with antagonistic mAbs to either IL-17RB or IL-17RA completely blocked IL-25-induced pulmonary inflammation and airway hyperresponsiveness in naive BALB/c mice, similar to the effects of an antagonistic Ab to IL-25. Finally, a blocking Ab to human IL-17RA prevented IL-25 activity in a primary human cell-based assay. These data demonstrate for the first time that IL-25-mediated activities require both IL-17RB and IL-17RA and provide another example of an IL-17 family ligand that utilizes a heteromeric receptor complex.
Serum Amyloid A Induces CCL2 Production via Formyl Peptide Receptor-Like 1-Mediated Signaling in Human Monocytes
Authors: Lee Ha Young , Kim Sang Doo , Shim Jae Woong , Lee Sun Young , Lee Hwahyung , Cho Kyung-Hyun , Yun Jeanho , Bae Yoe-Sik 
Published: April 2014

Abstract
Although the presence of an elevated level of serum amyloid A (SAA) has been regarded as a cardiovascular risk factor, the role of SAA on the progress of atherosclerosis has not been fully elucidated. In the present study, we investigated the effect of SAA on the production of CCL2, an important mediator of monocyte recruitment, and the mechanism underlying the action of SAA in human monocytes. The stimulation of human monocytes with SAA elicited CCL2 production in a concentration-dependent manner. The production of CCL2 by SAA was found to be mediated by the activation of NF-κB. Moreover, the signaling events induced by SAA included the activation of ERK and the induction of cyclooxygenase-2, which were required for the production of CCL2. Moreover, SAA-induced CCL2 induction was inhibited by a formyl peptide receptor-like 1 (FPRL1) antagonist. We also found that the stimulation of FPRL1-expressing RBL-2H3 cells induced CCL2 mRNA accumulation, but the vector-expressing RBL-2H3 cells combined with SAA did not. Taken together, our findings suggest that SAA stimulates CCL2 production and, thus, contributes to atherosclerosis. Moreover, FPRL1 was found to be engaged in SAA-induced CCL2 induction, and cyclooxygenase-2 induction was found to be essential for SAA-induced CCL2 expression. These results suggest that SAA and FPRL1 offer a developmental starting point for the treatment of atherosclerosis.
Potent Tumor-Specific Protection Ignited by Adoptively Transferred CD4+ T Cells
Authors: Liu Zuqiang , Noh Hae S. , Chen Janet , Kim Jin H. , Falo Louis D. , You Zhaoyang 
Published: April 2014

Abstract
Administration of anti-CD25 mAb before an aggressive murine breast tumor inoculation provoked effective antitumor immunity. Compared with CD4+ T cells purified from anti-CD25 mAb-pretreated mice that did not reject tumor, CD4+ T cells purified from anti-CD25 mAb-pretreated mice that rejected tumor stimulated by dendritic cells (DCs) produced more IFN-γ and IL-2, and less IL-17 in vitro, and ignited protective antitumor immunity in vivo in an adoptive transfer model. Tumor Ag-loaded DCs activated naive CD8+ T cells in the presence of these CD4+ T cells in vitro. Tumor Ag and adoptively transferred CD4+ T cells were both required for inducing a long-term tumor-specific IFN-γ-producing cellular response and potent protective antitumor activity. Although adoptively transferred CD4+ T cells ignited effective tumor-specific antitumor immunity in wild-type mice, they failed to do so in endogenous NK cell-depleted, Gr-1+ cell-depleted, CD40−/−, CD11c+ DC-depleted, B cell−/−, CD8+ T cell-depleted, or IFN-γ−/− mice. Collectively, the data suggest that adoptively transferred CD4+ T cells orchestrate both endogenous innate and adaptive immunity to generate effective tumor-specific long-term protective antitumor immunity. The data also demonstrate the pivotal role of endogenous DCs in the tumor-specific protection ignited by adoptively transferred CD4+ T cells. Thus, these findings highlight the importance of adoptively transferred CD4+ T cells, as well as host immune components, in generating effective tumor-specific long-term antitumor activity.
Rapid Deletional Peripheral CD8 T Cell Tolerance Induced by Allogeneic Bone Marrow: Role of Donor Class II MHC and B Cells
Authors: Fehr Thomas , Wang Sophia , Haspot Fabienne , Kurtz Josef , Blaha Peter , Hogan Timothy , Chittenden Meredith , Wekerle Thomas , Sykes Megan 
Published: April 2014

Abstract
Mixed chimerism and donor-specific tolerance are achieved in mice receiving 3 Gy of total body irradiation and anti-CD154 mAb followed by allogeneic bone marrow (BM) transplantation. In this model, recipient CD4 cells are critically important for CD8 tolerance. To evaluate the role of CD4 cells recognizing donor MHC class II directly, we used class II-deficient donor marrow and were not able to achieve chimerism unless recipient CD8 cells were depleted, indicating that directly alloreactive CD4 cells were necessary for CD8 tolerance. To identify the MHC class II+ donor cells promoting this tolerance, we used donor BM lacking certain cell populations or used positively selected cell populations. Neither donor CD11c+ dendritic cells, B cells, T cells, nor donor-derived IL-10 were critical for chimerism induction. Purified donor B cells induced early chimerism and donor-specific cell-mediated lympholysis tolerance in both strain combinations tested. In contrast, positively selected CD11b+ monocytes/myeloid cells did not induce early chimerism in either strain combination. Donor cell preparations containing B cells were able to induce early deletion of donor-reactive TCR-transgenic 2C CD8 T cells, whereas those devoid of B cells had reduced activity. Thus, induction of stable mixed chimerism depends on the expression of MHC class II on the donor marrow, but no requisite donor cell lineage was identified. Donor BM-derived B cells induced early chimerism, donor-specific cell-mediated lympholysis tolerance, and deletion of donor-reactive CD8 T cells, whereas CD11b+ cells did not. Thus, BM-derived B cells are potent tolerogenic APCs for alloreactive CD8 cells.
CD8+ T Cells Targeting a Single Immunodominant Epitope are Sufficient for Elimination of Established SV40 T Antigen-Induced Brain Tumors
Authors: Tatum Angela M. , Mylin Lawrence M. , Bender Susan J. , Fischer Matthew A. , Vigliotti Beth A. , Tevethia M. Judith , Tevethia Satvir S. , Schell Todd D. 
Published: April 2014

Abstract
Immunotherapy of established solid tumors is rarely achieved, and the mechanisms leading to success remain to be elucidated. We previously showed that extended control of advanced-stage autochthonous brain tumors is achieved following adoptive transfer of naive C57BL/6 splenocytes into sublethally irradiated line SV11 mice expressing the SV40 T Ag (T Ag) oncoprotein, and was associated with in vivo priming of CD8+ T cells (TCD8) specific for the dominant epitope IV (T Ag residues 404–411). Using donor lymphocytes derived from mice that are tolerant to epitope IV or a newly characterized transgenic mouse line expressing an epitope IV-specific TCR, we show that epitope IV-specific TCD8 are a necessary component of the donor pool and that purified naive epitope IV-specific TCD8 are sufficient to promote complete and rapid regression of established tumors. While transfer of naive TCR-IV cells alone induced some initial tumor regression, increased survival of tumor-bearing mice required prior conditioning of the host with a sublethal dose of gamma irradiation and was associated with complete tumor eradication. Regression of established tumors was associated with rapid accumulation of TCR-IV T cells within the brain following initial priming against the endogenous T Ag in the peripheral lymphoid organs. Additionally, persistence of functional TCR-IV cells in both the brain and peripheral lymphoid organs was associated with long-term tumor-free survival. Finally, we show that production of IFN-γ, but not perforin or TNF-α, by the donor lymphocytes is critical for control of autochthonous brain tumors.
Elevated Maternal IL-16 Levels, Enhanced IL-16 Expressions in Endothelium and Leukocytes, and Increased IL-16 Production by Placental Trophoblasts in Women with Preeclampsia
Authors: Gu Yang , Lewis David F. , Deere Kelli , Groome Lynn J. , Wang Yuping 
Published: April 2014

Abstract
Cytokine IL-16 plays an important role in innate immune responses. However, little information is available about IL-16 function in human pregnancy. In this study, we collected maternal blood samples from 125 pregnant women between 26 and 41 wk of gestation, 63 from normal pregnant women and 62 from women with preeclampsia (PE). Serum IL-16C levels were measured by ELISA. We also examined IL-16C and IL-16N immunostaining in maternal vessels and protein expression in leukocytes from normal and PE pregnant women. In addition, IL-16C production by placental trophoblasts was also determined. Our results showed that IL-16C levels were significantly higher in severe PE than in mild PE and normal pregnant controls, 515 ± 58 vs 287 ± 46 (p &lt; 0.05) and 163 ± 9 pg/ml (p &lt; 0.01), respectively, indicating that increased IL-16 levels in PE is associated with the severity of the disease. There was no difference for the IL-16C levels in normal pregnant women throughout the third trimester. The correlation of maternal IL-16C levels with labor and body mass index was also analyzed. IL-16C levels were neither associated with labor nor associated with body mass index. Moreover, increased IL-16C immunostaining in maternal vessel endothelium and enhanced IL-16C protein expression in leukocytes were observed in PE. We also found that IL-16C production was increased by trophoblasts from PE placentas. Our study demonstrated up-regulation of the IL-16 profile in both the maternal and the placental systems in PE, suggesting that IL-16 could be an important cytokine engaged in the altered immune system and exaggerated inflammatory response in PE syndrome.
Transcriptional Outcome of Wnt-Frizzled Signal Transduction in Inflammation: Evolving Concepts
Authors: Sen Malini , Ghosh Gourisankar 
Published: April 2014

Abstract
Wnt-Frizzled signaling was first identified as a key event in Drosophila development. Over the years, ample evidence has accumulated regarding the multiple roles of Wnt-Frizzled signaling in mammalian cell differentiation and tissue/organ morphogenesis. It is thus not surprising that variations in the regulatory network of the Wnt signaling scheme would lead to alterations in cellular organization and cell activation and to the development of pathogenic conditions. Several reports have accordingly implied the involvement of Wnt-Frizzled signaling in the activation of proinflammatory mediators in inflammatory disorders. We will discuss how Wnt-Frizzled signaling may initiate/augment inflammation, focusing on its transcriptional outcome.
Only a Subset of Phosphoantigen-Responsive γ9δ2 T Cells Mediate Protective Tuberculosis Immunity
Authors: Spencer Charles T. , Abate Getahun , Blazevic Azra , Hoft Daniel F. 
Published: April 2014

Abstract
Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guérin (BCG) induce potent expansions of human memory Vγ9+Vδ2+ T cells capable of IFN-γ production, cytolytic activity, and mycobacterial growth inhibition. Certain phosphoantigens expressed by mycobacteria can stimulate γ9δ2 T cell expansions, suggesting that purified or synthetic forms of these phosphoantigens may be useful alone or as components of new vaccines or immunotherapeutics. However, we show that while mycobacteria-activated γ9δ2 T cells potently inhibit intracellular mycobacterial growth, phosphoantigen-activated γ9δ2 T cells fail to inhibit mycobacteria, although both develop similar effector cytokine and cytolytic functional capacities. γ9δ2 T cells receiving TLR-mediated costimulation during phosphoantigen activation also failed to inhibit mycobacterial growth. We hypothesized that mycobacteria express Ags, other than the previously identified phosphoantigens, that induce protective subsets of γ9δ2 T cells. Testing this hypothesis, we compared the TCR sequence diversity of γ9δ2 T cells expanded with BCG-infected vs phosphoantigen-treated dendritic cells. BCG-stimulated γ9δ2 T cells displayed a more restricted TCR diversity than phosphoantigen-activated γ9δ2 T cells. In addition, only a subset of phosphoantigen-activated γ9δ2 T cells functionally responded to mycobacteria-infected dendritic cells. Furthermore, differential inhibitory functions of BCG- and phosphoantigen-activated γ9δ2 T cells were confirmed at the clonal level and were not due to differences in TCR avidity. Our results demonstrate that BCG infection can activate and expand protective subsets of phosphoantigen-responsive γ9δ2 T cells, and provide the first indication that γ9δ2 T cells can develop pathogen specificity similar to αβ T cells. Specific targeting of protective γ9δ2 T cell subsets will be important for future tuberculosis vaccines.
Hepatitis C Virus-Specific Th17 Cells Are Suppressed by Virus-Induced TGF-β
Authors: Rowan Aileen G. , Fletcher Jean M. , Ryan Elizabeth J. , Moran Barry , Hegarty John E. , O'Farrelly Cliona , Mills Kingston H. G. 
Published: April 2014

Abstract
IL-17-secreting T (Th17) cells play a protective role in certain bacterial infections, but they are major mediators of inflammation and are pathogenic in organ-specific autoimmune diseases. However, human Th17 cells appear to be resistant to suppression by CD4+CD25+FoxP3+ regulatory T cells, suggesting that they may be regulated by alternative mechanisms. Herein we show that IL-10 and TGF-β suppressed IL-17 production by anti-CD3-stimulated PBMC from normal individuals. TGF-β also suppressed IL-17 production by purified CD4+ T cells, whereas the inhibitory effect of IL-10 on IL-17 production appears to be mediated predominantly by its effect on APC. An examination of patients infected with hepatitis C virus (HCV) demonstrated that Ag-specific Th17 cells are induced during infection and that these cells are regulated by IL-10 and TGF-β. PBMC from HCV Ab-positive donors secreted IL-17, IFN-γ, IL-10, and TGF-β in response to stimulation with the HCV nonstructural protein 4 (NS4). Furthermore, NS4 induced innate TGF-β and IL-10 expression by monocytes from normal donors and at higher levels from HCV-infected patients. Neutralization of TGF-β, and to a lesser extent IL-10, significantly enhanced NS4-specific IL-17 and IFN-γ production by T cells from HCV-infected donors. Our findings suggest that both HCV-specific Th1 and Th17 cells are suppressed by NS4-induced production of the innate anti-inflammatory cytokines IL-10 and TGF-β. This may represent a novel immune subversion mechanism by the virus to evade host-protective immune responses. Our findings also suggest that TGF-β and IL-10 play important roles in constraining the function of Th17 cells in general.
Lentiviral-Mediated Transcriptional Targeting of Dendritic Cells for Induction of T Cell Tolerance In Vivo
Authors: Dresch Christiane , Edelmann Stephanie L. , Marconi Peggy , Brocker Thomas 
Published: April 2014

Abstract
Dendritic cells (DCs) are important APCs able to induce both tolerance and immunity. Therefore, DCs are attractive targets for immune intervention. However, the ex vivo generation and manipulation of DCs at sufficient numbers and without changing their original phenotypic and functional characteristics are major obstacles. To manipulate DCs in vivo, we developed a novel DC-specific self-inactivating lentiviral vector system using the 5′ untranslated region from the DC-STAMP gene as a putative promoter region. We show that a gene therapy approach with these DC-STAMP-lentiviral vectors yields long-term and cell-selective transgene expression in vivo. Furthermore, transcriptionally targeted DCs induced functional, Ag-specific CD4 and CD8 T cell tolerance in vivo, which could not be broken by viral immunization. Tolerized CTL were unable to induce autoimmune diabetes in a murine autoimmune model system. Therefore, delivering transgenes specifically to DCs by using viral vectors might be a promising tool in gene therapy.