bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of CD83+CD14+ Nondendritic Antigen-Presenting Cells by Exposure of Monocytes to IFN-α
Authors: Gerlini Gianni , Mariotti Giulia , Chiarugi Alberto , Di Gennaro Paola , Caporale Roberto , Parenti Astrid , Cavone Leonardo , Tun-Kyi Adrian , Prignano Francesca , Saccardi Riccardo , Borgognoni Lorenzo , Pimpinelli Nicola 
Published: April 2014

Abstract
IFN-α is a well-known agent for treatment of viral and malignant diseases. It has several modes of actions, including direct influence on the immune system. We investigated IFN-α effects on PBMC in terms of dendritic cell (DC) differentiation, as PBMC are exposed to high IFN-α levels during treatment of infections and cancers. We show that in vitro IFN-α exposure induced rapid and strong up-regulation of the DC-maturation markers CD80, CD86, and CD83 in bulk PBMC. Consistently, IFN-α induced up-regulation of these molecules on purified monocytes within 24 h. Up-regulation of CD80 and CD83 expression was IFN-α concentration-dependent. In contrast to GM-CSF + IL-4-generated DCs, most of the IFN-α-challenged CD83+ cells coexpressed the monocyte marker CD14. Despite a typical mature DC immunophenotype, IFN-α-treated monocytes conserved phagocytic activity and never acquired a dendritic morphology. In mixed lymphocyte reactions IFN-α-treated monocytes were less potent than GM-CSF + IL-4-generated DCs but significantly more potent than untreated monocytes to induce T cell proliferation in bulk PBMC. However, only GM-CSF + IL-4-generated DCs were able to induce a significant proliferation of naive CD4+ T cells. Notably, autologous memory CD4+ T cells proliferated when exposed to tetanus toxoid-pulsed IFN-α-treated monocytes. At variance with untreated or GM-CSF + IL-4-exposed monocytes, those challenged with IFN-α showed long-lasting STAT-1 phosphorylation. Remarkably, CD83+CD14+ cells were present in varicella skin lesions in close contact with IFN-α-producing cells. The present findings suggest that IFN-α alone promptly generates nondendritic APCs able to stimulate memory immune responses. This may represent an additional mode of action of IFN-α in vivo.
Apoptotic Cell-Mediated Immunoregulation of Dendritic Cells Does Not Require iC3b Opsonization
Authors: Behrens Edward M. , Ning Yue , Muvarak Nidal , Zoltick Philip W. , Flake Alan W. , Gallucci Stefania 
Published: April 2014

Abstract
A number of recent studies show that activation of CR3 on dendritic cells (DCs) suppresses TLR-induced TNF-α and IL-12 production and inhibits effective Ag presentation. Although the proposed physiologic role for these phenomena is immune suppression due to recognition of iC3b opsonized apoptotic cells by CR3, all of the aforementioned investigations used artificial means of activating CR3. We investigated whether iC3b opsonized apoptotic cells could induce the same changes reported with artificial ligands such as mAbs or iC3b-opsonized RBC. We explored the kinetics of iC3b opsonization in two models of murine cell apoptosis, γ-irradiated thymocytes and cytokine deprivation of the IL-3 dependent cell line BaF3. Using a relatively homogenous population of early apoptotic cells (IL-3 deprived BaF3 cells), we show that iC3b opsonized apoptotic cells engage CR3, but this interaction is dispensable in mediating the anti-inflammatory effects of apoptotic cells. TLR-induced TNF-α and IL-12 production by bone marrow-derived DCs occurs heterogeneously, with apoptotic cells inhibiting only certain populations depending on the TLR agonist. In contrast, although apoptotic cells induced homogeneous IL-10 production by DCs, IL-10 was not necessary for the inhibition of TNF-α and IL-12. Furthermore, because the ability of iC3b opsonization to enhance phagocytosis of apoptotic cells has been controversial, we report that iC3b opsonization does not significantly affect apoptotic cell ingestion by DCs. We conclude that the apoptotic cell receptor system on DCs is sufficiently redundant such that the absence of CR3 engagement does not significantly affect the normal anti-inflammatory processing of apoptotic cells.
MUC1 Enhances Tumor Progression and Contributes Toward Immunosuppression in a Mouse Model of Spontaneous Pancreatic Adenocarcinoma
Authors: Tinder Teresa L. , Subramani Durai B. , Basu Gargi D. , Bradley Judy M. , Schettini Jorge , Million Arefayene , Skaar Todd , Mukherjee Pinku 
Published: April 2014

Abstract
MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in &gt;80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.
OX40/OX40L Costimulation Affects Induction of Foxp3+ Regulatory T Cells in Part by Expanding Memory T Cells In Vivo
Authors: Xiao Xiang , Kroemer Alexander , Gao Wenda , Ishii Naoto , Demirci Gulcin , Li Xian Chang 
Published: April 2014

Abstract
OX40 is a member of the TNFR superfamily and has potent T cell costimulatory activities. OX40 also inhibits the induction of Foxp3+ regulatory T cells (Tregs) from T effector cells, but the precise mechanism of such inhibition remains unknown. In the present study, we found that CD4+ T effector cells from OX40 ligand-transgenic (OX40Ltg) mice are highly resistant to TGF-β mediated induction of Foxp3+ Tregs, whereas wild-type B6 and OX40 knockout CD4+ T effector cells can be readily converted to Foxp3+ T cells. We also found that CD4+ T effector cells from OX40Ltg mice are heterogeneous and contain a large population of CD44highCD62L− memory T cells. Analysis of purified OX40Ltg naive and memory CD4+ T effector cells showed that memory CD4+ T cells not only resist the induction of Foxp3+ T cells but also actively suppress the conversion of naive CD4+ T effector cells to Foxp3+ Tregs. This suppression is mediated by the production of IFN-γ by memory T cells but not by cell-cell contact and also involves the induction of T-bet. Importantly, memory CD4+ T cells have a broad impact on the induction of Foxp3+ Tregs regardless of their origins and Ag specificities. Our data suggest that one of the mechanisms by which OX40 inhibits the induction of Foxp3+ Tregs is by inducing memory T cells in vivo. This finding may have important clinical implications in tolerance induction to transplanted tissues.
The Suppression of Murine Lupus by a Tolerogenic Peptide Involves Foxp3-Expressing CD8 Cells That Are Required for the Optimal Induction and Function of Foxp3-Expressing CD4 Cells
Authors: Sharabi Amir , Mozes Edna 
Published: April 2014

Abstract
A peptide, designated human CDR1 (hCDR1), that is based on the CDR1 of an anti-DNA Ab ameliorates systemic lupus erythematosus (SLE) in murine models via the induction of CD4+CD25+ regulatory T cells (Tregs). In the present study, the involvement of CD8 Tregs in the mode of action of hCDR1 was investigated in SLE-afflicted (NZB × NZW)F1 mice and in SJL mice following immunization with the lupus-inducing anti-DNA mAb that bears a common Id, 16/6Id. Treatment with hCDR1 up-regulated Foxp3-expressing CD8+CD28− Tregs in association with clinical amelioration of lupus manifestations. Furthermore, the in vivo depletion of the latter cells diminished the clinical improvement and the inhibitory effects of hCDR1 on the secretion of IFN-γ and resulted in the up-regulation of IL-10. However, the stimulatory effect of hCDR1 on the secretion of TGF-β was not affected by the CD8 Tregs. In the absence of CD8 Tregs, CD4+CD25+ Tregs were unable to expand in the hCDR1-treated mice, and the expression of Foxp3 was reduced, thereby interfering further with the suppressive function of CD4+CD25+ Tregs as determined in the in vitro assays. However, CD8 cells from hCDR1-treated mice that were adoptively transferred into SLE-afflicted mice led to up-regulation of CD4+CD25+ cells with intensified Foxp3 expression in the recipient mice. Thus, a functional link between two subsets of Tregs is demonstrated in which CD8+CD28− Tregs are required for both the optimal expansion and function of lupus ameliorating hCDR1-induced CD4+CD25+ Tregs.
Rap1b Regulates B Cell Development, Homing, and T Cell-Dependent Humoral Immunity
Authors: Chu Haiyan , Awasthi Aradhana , White Gilbert C. , Chrzanowska-Wodnicka Magdalena , Malarkannan Subramaniam 
Published: April 2014

Abstract
Rap1 is a small GTPase that belongs to Ras superfamily. This ubiquitously expressed GTPase is a key regulator of integrin functions. Rap1 exists in two isoforms: Rap1a and Rap1b. Although Rap1 has been extensively studied, its isoform-specific functions in B cells have not been elucidated. In this study, using gene knockout mice, we show that Rap1b is the dominant isoform in B cells. Lack of Rap1b significantly reduced the absolute number of B220+IgM− pro/pre-B cells and B220+IgM+ immature B cells in bone marrow. In vitro culture of bone marrow-derived Rap1b−/− pro/pre-B cells with IL-7 showed similar proliferation levels but reduced adhesion to stromal cell line compared with wild type. Rap1b−/− mice displayed reduced splenic marginal zone (MZ) B cells, and increased newly forming B cells, whereas the number of follicular B cells was normal. Functionally, Rap1b−/− mice showed reduced T-dependent but normal T-independent humoral responses. B cells from Rap1b−/− mice showed reduced migration to SDF-1, CXCL13 and in vivo homing to lymph nodes. MZ B cells showed reduced sphingosine-1-phosphate-induced migration and adhesion to ICAM-1. However, absence of Rap1b did not affect splenic B cell proliferation, BCR-mediated activation of Erk1/2, p38 MAPKs, and AKT. Thus, Rap1b is crucial for early B cell development, MZ B cell homeostasis and T-dependent humoral immunity.
Molecular Requirements for MHC Class II α-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C
Authors: Kasper Katherine J. , Xi Wang , Nur-ur Rahman A. K. M. , Nooh Mohammed M. , Kotb Malak , Sundberg Eric J. , Madrenas Joaquín , McCormick John K. 
Published: April 2014

Abstract
Superantigens (SAgs) are microbial toxins that bind to both TCR β-chain variable domains (Vβs) and MHC class II molecules, resulting in the activation of T cells in a Vβ-specific manner. It is now well established that different isoforms of MHC II molecules can play a significant role in the immune response to bacterial SAgs. In this work, using directed mutational studies in conjunction with functional analyses, we provide a complete functional map of the low-affinity MHC II α-chain binding interface of the SAg streptococcal pyrogenic exotoxin C (SpeC) and identify a functional epitope in the β-barrel domain that is required for the activation of T cells. Using cell lines that exclusively express individual MHC II isoforms, our studies provide a molecular basis for the selectivity of SpeC-MHC II recognition, and provide one mechanism by how SAgs are capable of distinguishing between different MHC II alleles.
Congenic Analysis of the NKT Cell Control Gene Nkt2 Implicates the Peroxisomal Protein Pxmp4
Authors: Fletcher Julie M. , Jordan Margaret A. , Snelgrove Sarah L. , Slattery Robyn M. , Dufour François D. , Kyparissoudis Konstantinos , Besra Gurdyal S. , Godfrey Dale I. , Baxter Alan G. 
Published: April 2014

Abstract
Type 1 NKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. Herein, we report the production and characterization of a NOD.Nkrp1b.Nkt2bb congenic mouse strain, which has increased thymic and peripheral NKT cells, a decreased incidence of type 1 diabetes, and enhanced cytokine responses in vivo and increased proliferative responses in vitro following challenge with α-galactosylceramide. The 19 highly differentially expressed candidate genes within the congenic region identified by microarray expression analyses included Pxmp4. This gene encodes a peroxisome-associated integral membrane protein whose only known binding partner is Pex19, an intracellular chaperone and component of the peroxisomal membrane insertion machinery encoded by a candidate for the NKT cell control gene Nkt1. These findings raise the possibility that peroxisomes play a role in modulating glycolipid availability for CD1d presentation, thereby influencing NKT cell function.
Adoptive Transfer of Gene-Modified Primary NK Cells Can Specifically Inhibit Tumor Progression In Vivo
Authors: Pegram Hollie J. , Jackson Jacob T. , Smyth Mark J. , Kershaw Michael H. , Darcy Phillip K. 
Published: April 2014

Abstract
NK cells hold great potential for improving the immunotherapy of cancer. Nevertheless, tumor cells can effectively escape NK cell-mediated apoptosis through interaction of MHC molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against tumors, we used Amaxa gene transfer technology to gene-modify primary mouse NK cells with a chimeric single-chain variable fragment (scFv) receptor specific for the human erbB2 tumor-associated Ag. The chimeric receptor was composed of the extracellular scFv anti-erbB2 Ab linked to the transmembrane and cytoplasmic CD28 and TCR-ζ signaling domains (scFv-CD28-ζ). In this study we demonstrated that mouse NK cells gene-modified with this chimera could specifically mediate enhanced killing of an erbB2+ MHC class I+ lymphoma in a perforin-dependent manner. Expression of the chimera did not interfere with NK cell-mediated cytotoxicity mediated by endogenous NK receptors. Furthermore, adoptive transfer of gene-modified NK cells significantly enhanced the survival of RAG mice bearing established i.p. RMA-erbB2+ lymphoma. In summary, these data suggest that use of genetically modified NK cells could broaden the scope of cancer immunotherapy for patients.
Teleost TLR22 Recognizes RNA Duplex to Induce IFN and Protect Cells from Birnaviruses
Authors: Matsuo Aya , Oshiumi Hiroyuki , Tsujita Tadayuki , Mitani Hiroshi , Kasai Hisae , Yoshimizu Mamoru , Matsumoto Misako , Seya Tsukasa 
Published: April 2014

Abstract
TLR22 occurs exclusively in aquatic animals and its role is unknown. Herein we show that the fugu (Takifugu rubripes) (fg)TLR3 and fgTLR22 link the IFN-inducing pathway via the fg Toll-IL-1R homology domain-containing adaptor protein 1(fgTICAM-1, or TRIF) adaptor in fish cells. fgTLR3 resides in endoplasmic reticulum and recognizes relatively short-sized dsRNA, whereas fgTLR22 recognizes long-sized dsRNA on the cell surface. On poly(I:C)-stimulated fish cells, both recruit fgTICAM-1, which in turn moves from the TLR to a cytoplasmic signalosome region. Thus, fgTICAM-1 acts as a shuttling platform for IFN signaling. When fish cells expressing fgTLR22 are exposed to dsRNA or aquatic dsRNA viruses, cells induce IFN responses to acquire resistance to virus infection. Thus, fish have a novel TICAM-1-coupling TLR that is distinct from the mammalian TLR3 in cellular localization, ligand selection, and tissue distribution. TLR22 may be a functional substitute of human cell-surface TLR3 and serve as a surveillant for infection with dsRNA virus to alert the immune system for antiviral protection in fish.
Inchoate CD8+ T Cell Responses in Neonatal Mice Permit Influenza-Induced Persistent Pulmonary Dysfunction
Authors: You Dahui , Ripple Michael , Balakrishna Shrilatha , Troxclair Dana , Sandquist Dane , Ding Liren , Ahlert Terry A. , Cormier Stephania A. 
Published: April 2014

AbstractInfluenza infection remains a significant cause of pulmonary morbidity and mortality worldwide, with the highest hospitalization and mortality rates occurring in infants and elder adults. The mechanisms inducing this considerable morbidity and mortality are largely unknown. To address this question, we established a neonatal mouse model of influenza infection to test the hypothesis that the immaturity of the neonatal immune system is responsible for the severe pulmonary disease observed in infants. Seven-day-old mice were infected with influenza A virus (H1N1) and allowed to mature. As adults, these mice showed enhanced airway hyperreactivity, chronic pulmonary inflammation, and diffuse emphysematous-type lesions in the lungs. The adaptive immune responses of the neonates were much weaker than those of adults. This insufficiency appeared to be in both magnitude and functionality and was most apparent in the CD8+ T cell population. To determine the role of neonatal CD8+ T cells in disease outcome, adult, naive CD8+ T cells were adoptively transferred into neonates before infection. Neonatal mice receiving the adult CD8+ T cells had significantly lower pulmonary viral titers and greatly improved pulmonary function as adults (airway resistance similar to SHAM). Additional adoptive transfer studies using adult CD8+ T cells from IFN-γ-deficient mice demonstrated the importance of IFN-γ from CD8+ T cells in controlling the infection and in determining disease outcome. Our data indicate that neonates are more vulnerable to severe infections due to immaturity of their immune system and emphasize the importance of vaccination in infants.
PKCβΙΙ Augments NF-κB-Dependent Transcription at the CCL11 Promoter via p300/CBP-Associated Factor Recruitment and Histone H4 Acetylation
Authors: Clarke Deborah L. , Sutcliffe Amy , Deacon Karl , Bradbury Dawn , Corbett Lisa , Knox Alan J. 
Published: April 2014

Abstract
The transcription factor NF-κB plays a pivotal role in regulating inflammatory gene expression. Its effects are optimized by various coactivators, including histone acetyltransferases (HATs) such as CREB-binding protein/p300 and p300/CBP-associated factor (p/CAF). The molecular mechanisms regulating cofactor recruitment are poorly understood. In this study, we describe a novel role for protein kinase C (PKC) βΙΙ in augmenting NF-κB-mediated TNF-α-induced transcription of the target gene CCL11 in human airway smooth muscle cells by phosphorylating the HAT p/CAF. Studies using reporters, overexpression strategies, kinase-dead and HAT-defective mutants, and chromatin immunoprecipitation showed that PKCβII activation was not involved in NF-κB translocation, but facilitated NF-κB-mediated CCL11 transcription by colocalizing with and phosphorylating p/CAF, and thereby acetylating histone H4 and promoting p65 association with the CCL11 promoter. The effect was dependent on p/CAF’s HAT activity. Furthermore, mouse embryonic fibroblasts from PKCβ knockout mice showed markedly reduced TNF-α-induced CCL11 expression and NF-κB reporter activity that was restored on PKCβII overexpression, suggesting a critical role for this pathway. These data suggest a novel important biological role for PKCβΙΙ in NF-κB-mediated CCL11 transcription by p/CAF activation and histone H4 acetylation.
Gp130 Signaling Promotes Development of Acute Experimental Colitis by Facilitating Early Neutrophil/Macrophage Recruitment and Activation
Authors: Sander Leif E. , Obermeier Florian , Dierssen Uta , Kroy Daniela C. , Singh Anurag K. , Seidler Ursula , Streetz Konrad L. , Lutz Holger H. , Müller Werner , Tacke Frank , Trautwein Christian 
Published: April 2014

Abstract
IL-6 is known to play a crucial role in the pathogenesis of chronic intestinal inflammation by modulating T cell functions. In this study, we investigated the role of gp130, the common signal transducer for all IL-6 cytokines, in a murine model of acute T cell independent colitis to better characterize the impact of gp130 on innate immune cells and the early stages of inflammation. Experimental colitis was induced by dextran sulfate sodium treatment of mice with inducible systemic deletion of gp130 (MxCre/gp130−/−), macrophage/neutrophil-specific gp130-deficiency (LysCre/gp130−/−), or bone marrow chimeric mice and compared with wild-type controls (gp130f/f). Systemic deletion of gp130 (MxCre/gp130−/−) protected mice from severe colitis and wasting and attenuated the mucosal inflammatory infiltrate as well as local cytokine, chemokine, and adhesion molecule expression. Experiments in newly generated macrophage/neutrophil-specific gp130-deleted animals (LysCre/gp130−/−) and gp130 bone marrow chimeric mice, revealed a dual mechanism of proinflammatory effects mediated by gp130. Leukocyte recruitment was impaired in gp130-deleted animals and gp130-deleted recipients of wild-type bone marrow, demonstrating a central role of gp130-dependent signals in nonmyeloid cells for directing leukocytes to sites of inflammation, which was further confirmed in a model of sterile peritonitis. In contrast, macrophage/neutrophil-specific gp130 deficiency delayed and attenuated the disease but only marginally affected the inflammatory infiltrate, indicating a defective activation of mucosal leukocytes. We provide evidence that IL-6 cytokines acting via gp130 are required in the acute stages of intestinal inflammation by modulating the dynamics of innate immune cell recruitment and activation.
Production of C5a by ASP, a Serine Protease Released from Aeromonas sobria
Authors: Nitta Hidetoshi , Imamura Takahisa , Wada Yoshihiro , Irie Atsushi , Kobayashi Hidetomo , Okamoto Keinosuke , Baba Hideo 
Published: April 2014

Abstract
Aeromonas sobria causes pus and edema at sites of infection. However, the mechanisms underlying these effects have not been elucidated. C5a, the amino-terminal fragment of the complement 5th component (C5), mimics these events. To investigate the involvement of C5a in the pathophysiology of A. sobria infection, we examined release of C5a from human C5 by a serine protease (ASP), a putative virulence factor secreted by this bacterium. C5 incubated with enzymatically active ASP induced neutrophil migration in a dose-dependent manner from an ASP concentration of 3 nM and in an incubation time-dependent manner in as little as 7 min, with neutrophil accumulation in guinea pigs at intradermal injection sites and neutrophil superoxide release. These effects on neutrophils were inhibited by a C5a-receptor antagonist. The ASP incubation mixture with C5 but not C3 elicited vascular leakage in a dose- and incubation time-dependent manner, which was inhibited by a histamine H1-receptor antagonist. Together with these C5a-like activities, ASP cleaved C5 to release only one C5a Ag, the m.w. of which was similar to that of C5a. Immunoblotting using an anti-C5a Ab revealed generation of a C5a-like fragment from human plasma incubated with ASP. These results suggest that ASP-elicited neutrophil migration and vascular leakage via C5a production from C5 could occur in vivo, which was supported by that ASP did not affect functions of C5a and neutrophil C5a receptor. Through C5a generation, ASP could be associated with the induction of pus and edema caused by infection with this bacterium.