bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kit Regulates Maintenance of Quiescent Hematopoietic Stem Cells
Authors: Thorén Lina A. , Liuba Karina , Bryder David , Nygren Jens M. , Jensen Christina T. , Qian Hong , Antonchuk Jennifer , Jacobsen Sten-Eirik W. 
Published: April 2014

Abstract
Hematopoietic stem cell (HSC) numbers are tightly regulated and maintained in postnatal hematopoiesis. Extensive studies have supported a role of the cytokine tyrosine kinase receptor Kit in sustaining cycling HSCs when competing with wild-type HSCs posttransplantation, but not in maintenance of quiescent HSCs in steady state adult bone marrow. In this study, we investigated HSC regulation in White Spotting 41 (KitW41/W41) mice, with a partial loss of function of Kit. Although the extensive fetal HSC expansion was Kit-independent, adult KitW41/W41 mice had an almost 2-fold reduction in long-term HSCs, reflecting a loss of roughly 10,000 Lin−Sca-1+Kithigh (LSK)CD34−Flt3− long-term HSCs by 12 wk of age, whereas LSKCD34+Flt3− short-term HSCs and LSKCD34+Flt3+ multipotent progenitors were less affected. Whereas homing and initial reconstitution of KitW41/W41 bone marrow cells in myeloablated recipients were close to normal, self-renewing KitW41/W41 HSCs were progressively depleted in not only competitive but also noncompetitive transplantation assays. Overexpression of the anti-apoptotic regulator BCL-2 partially rescued the posttransplantation KitW41/W41 HSC deficiency, suggesting that Kit might at least in the posttransplantation setting in part sustain HSC numbers by promoting HSC survival. Most notably, accelerated in vivo BrdU incorporation and cell cycle kinetics implicated a previously unrecognized role of Kit in maintaining quiescent HSCs in steady state adult hematopoiesis.
Selective Regulation of CD8 Effector T Cell Migration by the p110γ Isoform of Phosphatidylinositol 3-Kinase
Authors: Martin Amanda L. , Schwartz Matthew D. , Jameson Stephen C. , Shimizu Yoji 
Published: April 2014

Abstract
Chemokine-mediated T cell migration is essential to an optimal immune response. The p110γ isoform of PI3K is activated by G protein-coupled receptors and regulates neutrophil and macrophage chemotaxis. We used p110γ-deficient mice to examine the role of p110γ in CD8 T cell migration and activation in response to viral challenge. Naive CD8 T cell migration in response to CCL21 in vitro and trafficking into secondary lymphoid organs in vivo was unaffected by the loss of p110γ. Furthermore, loss of p110γ did not affect CD8 T cell proliferation and effector cell differentiation in vitro in response to anti-CD3 stimulation or in vivo in response to vaccinia virus (VV) challenge. However, there was reduced migration of p110γ knockout (p110γ−/−) CD8 effector T cells into the peritoneum following i.p. challenge with VV. The role of p110γ in CD8 effector T cell migration was intrinsic to T cells, as p110γ−/− CD8 effector T cells exhibited impaired migration into the inflamed peritoneum following secondary transfer into wild-type recipients. In addition, p110γ−/− CD8 effector T cells exhibited impaired migration in vitro in response to inflammatory chemoattractants. Although wild-type mice efficiently cleared VV at high viral doses, infection of p110γ knockout mice resulted in visible illness and death less than a week after infection. Thus, p110γ is dispensable for constitutive migration of naive CD8 T cells and subsequent activation and differentiation into effector CD8 T cells, but plays a central role in the migration of effector CD8 T cells into inflammatory sites.
STAT1 Signaling in CD8 T Cells Is Required for Their Clonal Expansion and Memory Formation Following Viral Infection In Vivo
Authors: Quigley Michael , Huang Xiaopei , Yang Yiping 
Published: April 2014

Abstract
Recent advances have shown that direct type I IFN signaling on T cells is required for their efficient expansion in response to viral infections in vivo. It is not clear which intracellular signaling molecule is responsible for this effect. Although STAT1 has been shown to mediate many of the type I IFN-dependent biological effects, its role in T cells remains uncertain in vivo. In this study, we demonstrated that STAT1 signaling in CD8 T cells was required for their efficient expansion by promoting the survival of activated CD8 T cells upon vaccinia viral infection in vivo, suggesting that the direct effect of type I IFNs on CD8 T cells is mediated by STAT1. Furthermore, effector CD8 T cells that lack STAT1 signaling did not survive the contraction phase to differentiate into long-lived memory cells. These results identify a critical role for type I IFN-STAT1 signaling in multiple stages of CD8 T cell response in vivo and suggest that strategies to activate type I IFN-STAT1 signaling pathway may enhance vaccine potency.
Leukemia Inhibitory Factor Deficiency Modulates the Immune Response and Limits Autoimmune Demyelination: A New Role for Neurotrophic Cytokines in Neuroinflammation
Authors: Linker Ralf A. , Kruse Niels , Israel Stephanie , Wei Tao , Seubert Silvia , Hombach Anja , Holtmann Bettina , Luhder Fred , Ransohoff Richard M. , Sendtner Michael , Gold Ralf 
Published: April 2014

Abstract
The neurotrophic cytokines ciliary neurotrophic factor and leukemia inhibitory factor (LIF) play a key role in neuronal and oligodendrocyte survival and as protective factors in neuroinflammation. To further elucidate the potential of endogenous LIF in modulating neuroinflammation, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LIF knockout mice (LIF−/− mice). In the late phase of active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, LIF−/− mice exhibited a markedly milder disease course. The inflammatory infiltrate in LIF−/− mice was characterized by an increase in neutrophilic granulocytes early and fewer infiltrating macrophages associated with less demyelination later in the disease. In good correlation with an effect of endogenous LIF on the immune response, we found an Ag-specific T cell-priming defect with impaired IFN-γ production in LIF−/− mice. On the molecular level, the altered recruitment of inflammatory cells is associated with distinct patterns of chemokine production in LIF−/− mice with an increase of CXCL1 early and a decrease of CCL2, CCL3, and CXCL10 later in the disease. These data reveal that endogenous LIF is an immunologically active molecule in neuroinflammation. This establishes a link between LIF and the immune system which was not observed in the ciliary neurotrophic factor knockout mouse.
Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock
Authors: Falasca Laura , Farrace Maria Grazia , Rinaldi Alessandra , Tuosto Loretta , Melino Gennard , Piacentini Mauro 
Published: April 2014

Abstract
The pathogenesis of sepsis is characterized by the inability of the host to regulate the inflammatory response, and as a consequence, dysregulated inflammatory processes induce organ dysfunctions and death. Altered transglutaminase type II (TG2) expression is associated with the development of many inflammatory diseases. Therefore, in this study, we questioned whether TG2 could also contribute to the pathological inflammatory dysregulation occurring in septic shock in vivo. To this aim, we used as an experimental model the TG2 knockout mice, in which the process of septic shock was elicited by treatment with LPS. Interestingly, our results demonstrated that TG2 ablation leads to partial resistance to experimental sepsis. The increased survival of TG2−/− mice was reflected in a drastic reduction of organ injury, highlighted by a limited infiltration of neutrophils in kidney and peritoneum and by a better homeostasis of the proinflammatory mediators as well as mitochondrial function. We also showed that in wild-type mice, the TG2 expression is increased during endotoxemia and, being directly involved in the mechanisms of NF-κB activation, it may cause a continuous activation cycle in the inflammatory process, thus contributing to development of sepsis pathogenesis. We propose that the inhibition of TG2 could represent a novel approach in the treatment of inflammatory processes associated with sepsis.
Cutting Edge: Vasoactive Intestinal Peptide (VIP) Induces Differentiation of Th17 Cells with a Distinctive Cytokine Profile
Authors: Yadav Mahesh , Rosenbaum Jennifer , Goetzl Edward J. 
Published: April 2014

Abstract
Immune cellular effects of vasoactive intestinal peptide (VIP) are transduced by VIP G protein-coupled receptors type 1 (VPAC1) and type 2 (VPAC2). We now show that VIP with TGFβ stimulates the transformation of CD4 T cells to a distinctive type of Th17 cell that generates IL-17 but not IL-6 or IL-21. VIP induction of Th17 cells was higher in VPAC2 knockout mice than wild-type mice, suggesting that VPAC1 is the principal transducer. Compared with Th17 cells elicited by IL-6, those evoked by VIP were similar in the secretion of IL-17 and IL-22, but lacked IL-21 secretion. Suppression of VIP induction of Th17 cells by protein kinase A inhibitors and enhancement by pharmacologically increased cAMP supports a role for this signal. The ability of VIP-VPAC1 axis signals to evoke development of a novel type of Th17 cells demonstrates the unique specificity of neuroregulatory mechanisms in the immunological environment.
Heparan Sulfate and Heparin Enhance ERK Phosphorylation and Mediate preBCR-Dependent Events during B Lymphopoiesis
Authors: Milne Craig D. , Corfe Steven A. , Paige Christopher J. 
Published: April 2014

Abstract
As B lineage cells develop, they interact with cells, proteins, and extracellular matrix components of the surrounding microenvironment. In vitro, one critical checkpoint for developing cells occurs as they lose responsiveness to IL-7. These cells require contact with either stromal cells or other B lineage cells to mature. Our results demonstrate that heparan sulfate and heparin are able to promote this transition when added exogenously to the culture system or when heparan sulfate-bearing cell lines are cocultured with primary B cell progenitors. Addition of heparan sulfate or heparin to LPS-stimulated cultures of primary B cell progenitors resulted in more IgM secreted compared with untreated cultures. Heparan sulfate has been reported to be a ligand for the pre-B cell receptor (preBCR). Extending this observation, we found that treatment of preBCR+ cells with heparan sulfate before anti-μ stimulation leads to increased phosphorylation of ERK1/2. Consequently, preBCR+ cells proliferate more in the presence of IL-7 and heparan sulfate, whereas preBCR− cells are unaffected, suggesting that in these experiments, heparan sulfate is not directly affecting IL-7 activity. Heparin treatment of cultures induces many of the same biological effects as treatment with heparan sulfate, including elevated pERK levels in preBCR+ cells. However, heparin reduces the proliferation of cells expressing only the preBCR (opposed to both the preBCR and BCR) possibly due to internalization of the preBCR. Heparan sulfates are present on stromal cells and B lineage cells present in hemopoietic tissues and may provide stimulation to preB cells testing the signaling capacity of the preBCR.
The Tumor Suppressor Death-Associated Protein Kinase Targets to TCR-Stimulated NF-κB Activation
Authors: Chuang Ya-Ting , Fang Li-Wen , Lin-Feng Ming-Hsien , Chen Ruey-Hwa , Lai Ming-Zong 
Published: April 2014

Abstract
Death-associated protein kinase (DAPK) is a unique multidomain kinase acting both as a tumor suppressor and an apoptosis inducer. The molecular mechanism underlying the effector function of DAPK is not fully understood, while the role of DAPK in T lymphocyte activation is mostly unknown. DAPK was activated after TCR stimulation. Through the expression of a dominant-negative and a constitutively active form of DAPK in T cells, we found that DAPK negatively regulated T cell activation. DAPK markedly affected T cell proliferation and IL-2 production. We identified TCR-induced NF-κB activation as a target of DAPK. In contrast, IL-1β- and TNF-α-triggered NF-κB activation was not affected by DAPK. We further found that DAPK selectively modulated the TCR-induced translocation of protein kinase Cθ, Bcl-10, and IκB kinase into membrane rafts. Notably, the effect of DAPK on the raft entry was specific for the NF-κB pathway, as other raft-associated molecules, such as linker for activation of T cells, were not affected. Our results clearly demonstrate that DAPK is a novel regulator targeted to TCR-activated NF-κB and T cell activation.
Immunodominance of the VH1–46 Antibody Gene Segment in the Primary Repertoire of Human Rotavirus-Specific B Cells Is Reduced in the Memory Compartment through Somatic Mutation of Nondominant Clones
Authors: Tian Cuixia , Luskin Grace K. , Dischert Kevin M. , Higginbotham James N. , Shepherd Bryan E. , Crowe James E. 
Published: April 2014

Abstract
Detailed characterization of Ag-specific naive and memory B cell Ab repertoires elucidates the molecular basis for the generation of Ab diversity and the optimization of Ab structures that bind microbial Ags. In this study, we analyzed the immunophenotype and VH gene repertoire of rotavirus (RV) VP6-specific B cells in three circulating naive or memory B cell subsets (CD19+IgD+CD27−, CD19+IgD+CD27+, or CD19+IgD−CD27+) at the single-cell level. We aimed to investigate the influence of antigenic exposure on the molecular features of the two RV-specific memory B cell subsets. We found an increased frequency of CD19+IgD+CD27+ unclass-switched memory B cells and a low frequency of somatic mutations in CD19+IgD−CD27+ class-switched memory B cells in RV-specific memory B cells, suggesting a reduced frequency of isotype switching and somatic mutation in RV VP6-specific memory B cells compared with other memory B cells. Furthermore, we found that dominance of the VH1–46 gene segment was a prominent feature in the VH gene repertoire of RV VP6-specific naive B cells, but this dominance was reduced in memory B cells. Increased diversity in the VH gene repertoire of the two memory B cell groups derived from broader usage of VH gene segments, increased junctional diversity that was introduced by differential TdT activities, and somatic hypermutation.
Vra4 Congenic Rats with Allelic Differences in the Class II Transactivator Gene Display Altered Susceptibility to Experimental Autoimmune Encephalomyelitis
Authors: Harnesk Karin , Swanberg Maria , Öckinger Johan , Diez Margarita , Lidman Olle , Wallström Erik , Lobell Anna , Olsson Tomas , Piehl Fredrik 
Published: April 2014

Abstract
Presentation of Ag bound to MHC class II (MHC II) molecules to CD4+ T cells is a key event in adaptive immune responses. Genetic differences in MHC II expression in the rat CNS were recently positioned to allelic variability in the CIITA gene (Mhc2ta), located within the Vra4 locus on rat chromosome 10. In this study, we have examined reciprocal Vra4-congenic strains on the DA and PVGav1 backgrounds, respectively. After experimental nerve injury the strain-specific MHC II expression on microglia was reversed in the congenic strains. Similar findings were obtained after intraparenchymal injection of IFN-γ in the brain. Expression of MHC class II was also lower on B cells and dendritic cells from the DA.PVGav1-Vra4- congenic strain compared with DA rats after in vitro stimulation with IFN-γ. We next explored whether Vra4 may affect the outcome of experimental autoimmune disease. In experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein, DA.PVGav1-Vra4 rats displayed a lower disease incidence and milder disease course compared with DA, whereas both PVGav1 and PVGav1.DA-Vra4 rats were completely protected. These results demonstrate that naturally occurring allelic differences in Mhc2ta have profound effects on the quantity of MHC II expression in the CNS and on immune cells and that this genetic variability also modulates susceptibility to autoimmune neuroinflammation.
Significant Virus Replication in Langerhans Cells following Application of HIV to Abraded Skin: Relevance to Occupational Transmission of HIV
Authors: Kawamura Tatsuyoshi , Koyanagi Yoshio , Nakamura Yuumi , Ogawa Youichi , Yamashita Atsuya , Iwamoto Taku , Ito Masahiko , Blauvelt Andrew , Shimada Shinji 
Published: April 2014

Abstract
The cellular events that occur following occupational percutaneous exposure to HIV have not been defined. In this study, we studied relevant host cellular and molecular targets used for acquisition of HIV infection using split-thickness human skin explants. Blockade of CD4 or CCR5 before R5 HIV application to the epithelial surface of skin explants completely blocked subsequent HIV transmission from skin emigrants to allogeneic T cells, whereas preincubation with C-type lectin receptor inhibitors did not. Immunomagnetic bead depletion studies demonstrated that epithelial Langerhans cells (LC) accounted for &gt;95% of HIV dissemination. When skin explants were exposed to HIV variants engineered to express GFP during productive infection, GFP+ T cells were found adjacent to GFP+ LC. In three distinct dendritic cell (DC) subsets identified among skin emigrants (CD1a+langerin+DC-specific intercellular adhesion molecule grabbing non-integrin (SIGN)− LC, CD1a+langerin−DC-SIGN− dermal DC, and CD1a−langerin−DC-SIGN+ dermal macrophages), HIV infection was detected only in LC. These results suggest that productive HIV infection of LC plays a critical role in virus dissemination from epithelium to cells located within subepithelial tissue. Thus, initiation of antiretroviral drugs soon after percutaneous HIV exposure may not prevent infection of LC, which is likely to occur rapidly, but may prevent or limit subsequent LC-mediated infection of T cells.
Airway Epithelial versus Immune Cell Stat1 Function for Innate Defense against Respiratory Viral Infection
Authors: Shornick Laurie P. , Wells Audrey G. , Zhang Yong , Patel Anand C. , Huang Guangming , Takami Kazutaka , Sosa Moises , Shukla Nikhil A. , Agapov Eugene , Holtzman Michael J. 
Published: April 2014

Abstract
The epithelial surface is often proposed to actively participate in host defense, but evidence that this is the case remains circumstantial. Similarly, respiratory paramyxoviral infections are a leading cause of serious respiratory disease, but the basis for host defense against severe illness is uncertain. Here we use a common mouse paramyxovirus (Sendai virus) to show that a prominent early event in respiratory paramyxoviral infection is activation of the IFN-signaling protein Stat1 in airway epithelial cells. Furthermore, Stat1−/− mice developed illness that resembled severe paramyxoviral respiratory infection in humans and was characterized by increased viral replication and neutrophilic inflammation in concert with overproduction of TNF-α and neutrophil chemokine CXCL2. Poor control of viral replication as well as TNF-α and CXCL2 overproduction were both mimicked by infection of Stat1−/− airway epithelial cells in culture. TNF-α drives the CXCL2 response, because it can be reversed by TNF-α blockade in vitro and in vivo. These findings pointed to an epithelial defect in Stat1−/− mice. Indeed, we next demonstrated that Stat1−/− mice that were reconstituted with wild-type bone marrow were still susceptible to infection with Sendai virus, whereas wild-type mice that received Stat1−/− bone marrow retained resistance to infection. The susceptible epithelial Stat1−/− chimeric mice also exhibited increased viral replication as well as excessive neutrophils, CXCL2, and TNF-α in the airspace. These findings provide some of the most definitive evidence to date for the critical role of barrier epithelial cells in innate immunity to common pathogens, particularly in controlling viral replication.
MHC Class II-Associated Invariant Chain Linkage of Antigen Dramatically Improves Cell-Mediated Immunity Induced by Adenovirus Vaccines
Authors: Holst Peter Johannes , Sorensen Maria Rathmann , Mandrup Jensen Camilla Maria , Orskov Cathrine , Thomsen Allan Randrup , Christensen Jan Pravsgaard 
Published: April 2014

Abstract
The ideal vaccine induces a potent protective immune response, which should be rapidly induced, long-standing, and of broad specificity. Recombinant adenoviral vectors induce potent Ab and CD8+ T cell responses against transgenic Ags within weeks of administration, and they are among the most potent and versatile Ag delivery vehicles available. However, the impact of chronic infections like HIV and hepatitis C virus underscore the need for further improvements. In this study, we show that the protective immune response to an adenovirus-encoded vaccine Ag can be accelerated, enhanced, broadened, and prolonged by tethering of the rAg to the MHC class II-associated invariant chain (Ii). Thus, adenovirus-vectored vaccines expressing lymphocytic choriomeningitis virus (LCMV)-derived glycoprotein linked to Ii increased the CD4+ and CD8+ T cell stimulatory capacity in vitro and in vivo. Furthermore, mice vaccinated with a single dose of adenovirus-expressing LCMV-derived glycoprotein linked to Ii were protected against lethal virus-induced choriomeningitis, lethal challenge with strains mutated in immunodominant T cell epitopes, and systemic infection with a highly invasive strain. In therapeutic tumor vaccination, the vaccine was as efficient as live LCMV. In comparison, animals vaccinated with a conventional adenovirus vaccine expressing unmodified glycoprotein were protected against systemic infection, but only temporarily against lethal choriomeningitis, and this vaccine was less efficient in tumor therapy.
Blockade of Antimicrobial Proteins S100A8 and S100A9 Inhibits Phagocyte Migration to the Alveoli in Streptococcal Pneumonia
Authors: Raquil Marie-Astrid , Anceriz Nadia , Rouleau Pascal , Tessier Philippe A. 
Published: April 2014

AbstractWe investigated the roles of the potent, chemotactic antimicrobial proteins S100A8, S100A9, and S100A8/A9 in leukocyte migration in a model of streptococcal pneumonia. We first observed differential secretion of S100A8, S100A9, and S100A8/A9 that preceded neutrophil recruitment. This is partially explained by the expression of S100A8 and S100A9 proteins by pneumocytes in the early phase of Streptococcus pneumoniae infection. Pretreatment of mice with anti-S100A8 and anti-S100A9 Abs, alone or in combination had no effect on bacterial load or mice survival, but caused neutrophil and macrophage recruitment to the alveoli to diminish by 70 and 80%, respectively, without modifying leukocyte blood count, transendothelial migration or neutrophil sequestration in the lung vasculature. These decreases were also associated with a 68% increase of phagocyte accumulation in lung tissue and increased expression of the chemokines CXCL1, CXCL2, and CCL2 in lung tissues and bronchoalveolar lavages. These results show that S100A8 and S100A9 play an important role in leukocyte migration and strongly suggest their involvement in the transepithelial migration of macrophages and neutrophils. They also indicate the importance of antimicrobial proteins, as opposed to classical chemotactic factors such as chemokines, in regulating innate immune responses in the lung.