bluuebunny/crossref_metadata_2025_split huggingface dataset:
B6 Strain Ly49I Inhibitory Gene Expression on T Cells in FVB.Ly49IB6 Transgenic Mice Fails to Prevent Normal T Cell Functions
Authors: Morris Margaret A. , Liu Jingxuan , Arora Veera , George Thaddeus C. , Klem Jennifer , Schatzle John D. , Kumar Vinay , Bennett Michael 
Published: April 2014

AbstractInhibitory Ly49 receptors expressed on NK cells provide a mechanism for tolerance to normal self tissues. The immunoregulatory tyrosine-based inhibitory motifs present in some Ly49s are able to transmit an inhibitory signal upon ligation by MHC class I ligands. In our system, as well as others, mice transgenic for inhibitory Ly49 receptors express these receptors on both NK and T cells. FVB (H2q) mice transgenic for the B6 strain Ly49I (Ly49IB6) express the inhibitory Ly49 receptor on the surface of both T and NK cells. Although Ly49I functions to prevent NK-mediated rejection of H2b donor bone marrow cells in this transgenic mouse strain, the T cells do not appear to be affected by the expression of the Ly49I transgene. FVB.Ly49I T cells have normal proliferative capabilities both in vitro and in vivo in response to the Ly49I ligand, H2b. In vivo functional T cell assays were also done, showing that transgenic T cells were not functionally affected. T cells in these mice also appear to undergo normal T cell development and activation. Only upon stimulation with suboptimal doses of anti-CD3 in the presence of anti-Ly49I is T cell proliferation inhibited. These data are in contrast with findings in Ly49A, and Ly49G2 receptor transgenic models. Perhaps Ly49I-H2b interactions are weaker or of lower avidity than Ly49A-H-2Dd interactions, especially in T cells.
Inducible Costimulator Costimulates Cytotoxic Activity and IFN-γ Production in Activated Murine NK Cells
Authors: Ogasawara Kouetsu , Yoshinaga Steven K. , Lanier Lewis L. 
Published: April 2014

AbstractThe functions of NK cells are regulated by the balance of activating and inhibitory signals. The inhibitory NK cell receptors are well understood; however, less is known about the activating signaling pathways. To explore whether a costimulatory receptor, inducible costimulator (ICOS), is involved in NK cell function, we assessed the role of ICOS in NK cell-mediated cytotoxicity and cytokine production. In addition, to determine whether ICOS contributes to the elimination of tumors in vivo, we examined the tumor growth survival of mice injected with a tumor expressing the ICOS ligand, B7RP-1. We found that ICOS was up-regulated by cytokine stimulation in murine NK cells. Consistent with ICOS expression on activated NK cells, ICOS-dependent cytotoxicity and IFN-γ production were observed, and appeared to require signaling through the phosphoinositide 3-kinase pathway. Interestingly, ICOS-mediated stimulation allowed activated NK cells to kill more efficiently tumor cells expressing MHC class I. Furthermore, fewer metastases appeared in the liver and spleen of mice injected with the ICOS ligand-expressing tumor compared with mice bearing the parental tumor. These results indicate that NK cell functions are regulated by ICOS.
Altered IL-4 mRNA Stability Correlates with Th1 and Th2 Bias and Susceptibility to Hypersensitivity Pneumonitis in Two Inbred Strains of Mice
Authors: Butler Noah S. , Monick Martha M. , Yarovinsky Timur O. , Powers Linda S. , Hunninghake Gary W. 
Published: April 2014

Abstract
Previously, we have shown in a model of hypersensitivity pneumonitis that Th1-biased C57BL/6 mice are susceptible and Th2-biased DBA/2 mice are resistant to disease. We also showed that this was explained in part by differential regulation of IL-12 by IL-4. For these reasons, we postulated that C57BL/6 and DBA/2 mice differentially express IL-4. In this study, we show that C57BL/6 immune cells express Th2 but not Th1 cytokines at lower levels than DBA/2 cells. We also found that C57BL/6 splenocytes exhibit decreased mRNA stability of Th2 cytokines, relative to DBA/2 splenocytes. Stability of IL-2 and IFN-γ were similar in the two strains of mice. Differences in Th2 cytokine mRNA stability between C57BL/6 and DBA/2 cells were not due to sequence polymorphism at specific regions of the IL-4/IL-13 locus. Furthermore, expression of Th1- and Th2-specific transcription factors T-bet and GATA-3, as well as the nuclear factor of activated T cells transcription factor, NFATc, was not significantly different between the two mice. Our data suggest that decreased mRNA stability of Th2 cytokines in C57BL/6 splenocytes may underlie the differential susceptibility to hypersensitivity pneumonitis between C57BL/6 and DBA/2 mice. Moreover, our results indicate that regulation of mRNA stability may serve as an important mechanism underlying Th1/Th2 immune polarization.
A Novel Costimulation Pathway Via the 4C8 Antigen for the Induction of CD4+ Regulatory T Cells
Authors: Masuyama Jun-ichi , Kaga Shuji , Kano Shogo , Minota Seiji 
Published: April 2014

AbstractCD4+CD25+ regulatory T (Treg) cells naturally occur in mice and humans, and similar Treg cells can be induced in vivo and in vitro. However, the molecular mechanisms that mediate the generation of these Treg cell populations remain unknown. We previously described anti-4C8 mAbs that inhibit the postadhesive transendothelial migration of T cells through human endothelial cell monolayers. We demonstrate in this work that Treg cells are induced by costimulation of CD4+ T cells with anti-CD3 plus anti-4C8. The costimulation induced full activation of CD4+ T cells with high levels of IL-2 production and cellular expansion that were comparable to those obtained on costimulation by CD28. However, upon restimulation, 4C8-costimulated cells produced high levels of IL-10 but no IL-2 or IL-4, and maintained high expression levels of CD25 and intracellular CD152, as compared to CD28-costimulated cells. The former cells showed hyporesponsiveness to anti-CD3 stimulation and suppressed the activation of bystander T cells depending on cell contact but not IL-10 or TGF-β. The suppressor cells developed from CD4+CD25−CD45RO+ cells. The results suggest that 4C8 costimulation induces the generation of Treg cells that share phenotypic and functional features with CD4+CD25+ T cells, and that CD25− memory T cells may differentiate into certain Treg cell subsets in the periphery.
T Cell Receptor-γ Allele-Specific Selection of Vγ1/Vδ4 Cells in the Intestinal Epithelium
Authors: Grigoriadou Kalliopi , Boucontet Laurent , Pereira Pablo 
Published: April 2014

AbstractPrevious genetic analyses have shown that the relative representation of subsets of γδ intestinal intraepithelial lymphocytes (i-IELs) is influenced by genes linked to the TCRγ, TCRδ, and MHC loci. Here, we have analyzed V-gene use in γδ i-IELs from C57BL/6 (B6) and C57BL/10 (B10) mice and from their F1 and F2 progenies with a larger panel of Vγ- and Vδ-specific mAbs and have shown that the influence of TCRγ-linked genes operates at two levels: one influencing the representation of Vγ1 (or Vγ7) i-IELs and other acting specifically on the Vγ1/Vδ4 i-IEL subset, which represents 3% and 15% of the γδ i-IELs in B6 and B10 mice, respectively. Analysis of mice transgenic for a rearranged Vγ1Jγ4Cγ4 chain of B6 origin demonstrated that the TCRγ-linked genes influencing the representation of the Vγ1/Vδ4 i-IEL subset are the structural genes of TCRγ chains. This influence is allele specific and cell autonomous, as evidenced by the different behavior of Vγ1/Vδ4 cells bearing either parental allele in F1 mice. The representation of Vγ1/Vδ4 cells among γδ thymocytes is similar in B6 and B10 mice, demonstrating that the Vδ4 chain can pair well with both alleles of the Vγ1Jγ4Cγ4 chain and strongly suggesting that a cellular selection mechanism is responsible for the observed differences. The Vγ1-Jγ4 junctional amino acid sequences of B6 Vγ1/Vδ4 i-IELs are diverse but display less variation in length than those found in similar cells from B10 mice, indicating that B6 Vγ1/Vδ4 cells are the target of this cellular selection event.
c-Cbl Is Involved in Met Signaling in B Cells and Mediates Hepatocyte Growth Factor-Induced Receptor Ubiquitination
Authors: Taher Taher E. I. , Tjin Esther P. M. , Beuling Esther A. , Borst Jannie , Spaargaren Marcel , Pals Steven T. 
Published: April 2014

Abstract
Hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase Met are key regulators of epithelial motility and morphogenesis. Recent studies indicate that the HGF/Met pathway also plays a role in B cell differentiation, whereas uncontrolled Met signaling may lead to B cell neoplasia. These observations prompted us to explore HGF/Met signaling in B cells. In this study, we demonstrate that HGF induces strong tyrosine phosphorylation of the proto-oncogene product c-Cbl in B cells and increases Cbl association with the Src family tyrosine kinases Fyn and Lyn, as well as with phosphatidylinositol-3 kinase and CrkL. In addition, we demonstrate that c-Cbl mediates HGF-induced ubiquitination of Met. This requires the juxtamembrane tyrosine Y1001 (Y2) of Met, but not the multifunctional docking site (Y14/15) or any additional C-terminal tyrosine residues (Y13–16). In contrast to wild-type c-Cbl, the transforming mutants v-Cbl and 70Z/3 Cbl, which lack the ubiquitin ligase RING finger domain, suppress Met ubiquitination. Our findings identify c-Cbl as a negative regulator of HGF/Met signaling in B cells, mediating ubiquitination and, consequently, proteosomal degradation of Met, and suggest a role for Cbl in Met-mediated tumorigenesis.
Bcl-2 Rescues the Germinal Center Response But Does Not Alter the V Gene Somatic Hypermutation Spectrum in MSH2-Deficient Mice
Authors: Alabyev Boris , Manser Tim 
Published: April 2014

Abstract
Ab V genes in mice deficient for the postreplication mismatch repair factor MutS homolog (MSH2) have been reported to display an abnormal bias for hypermutations at G and C nucleotides and hotspots. We previously showed that the germinal center (GC) response is severely attenuated in MSH2-deficient mice. This suggested that premature death of GC B cells might preclude multiple rounds of hypermutation necessary to generate a normal spectrum of base changes. To test this hypothesis, we created MSH2-deficient mice in which Bcl-2 expression was driven in B cells from a transgene. In such mice, the elevated levels of intra-GC apoptosis and untimely GC dissolution characteristic of MSH2-deficient mice are suppressed. However, the spectrum of hypermutation is unchanged. These data indicate that the effects of MSH2 deficiency on GC B cell viability and the hypermutation process are distinct.
Mac-1 (CD11b/CD18) as Accessory Molecule for FcαR (CD89) Binding of IgA
Authors: van Spriel Annemiek B. , Leusen Jeanette H. W. , Vilé Henriëtte , van de Winkel Jan G. J. 
Published: April 2014

AbstractIgA, the principal ligand for FcαRI, exists in serum as monomeric IgA and at mucosal sites as secretory IgA (SIgA). SIgA consists of dimeric IgA linked by joining chain and secretory components. Human polymorphonuclear leukocytes (PMN) and mouse PMN transgenic for human FcαRI exhibited spreading and elicited respiratory burst activity upon interaction with either serum or SIgA. However, PMN devoid of the β2 integrin Mac-1 (Mac-1−/−) were unable to bind SIgA, despite expression of FcαRI. Consistent with this, serum IgA stimulated Mac-1−/− PMN oxygen radical production, in contrast to SIgA. Binding studies showed the secretory component, by itself, to interact with Mac-1-expressing PMN, but not with Mac-1−/− PMN. These data demonstrate an essential role for Mac-1 in establishing SIgA-FcαRI interactions.
DNA-Encoded Fetal Liver Tyrosine Kinase 3 Ligand and Granulocyte Macrophage-Colony-Stimulating Factor Increase Dendritic Cell Recruitment to the Inoculation Site and Enhance Antigen-Specific CD4+ T Cell Responses Induced by DNA Vaccination of Outbred Animals
Authors: Mwangi Waithaka , Brown Wendy C. , Lewin Harris A. , Howard Chris J. , Hope Jayne C. , Baszler Timothy V. , Caplazi Patrick , Abbott Jeffrey , Palmer Guy H. 
Published: April 2014

AbstractDNA-based immunization is a contemporary strategy for developing vaccines to prevent infectious diseases in animals and humans. Translating the efficacy of DNA immunization demonstrated in murine models to the animal species that represent the actual populations to be protected remains a significant challenge. We tested two hypotheses directed at enhancing DNA vaccine efficacy in outbred animals. The first hypothesis, that DNA-encoding fetal liver tyrosine kinase 3 ligand (Flt3L) and GM-CSF increases dendritic cell (DC) recruitment to the immunization site, was tested by intradermal inoculation of calves with plasmid DNA encoding Flt3L and GM-CSF followed by quantitation of CD1+ DC. Peak DC recruitment was detected at 10–15 days postinoculation and was significantly greater (p &lt; 0.05) in calves in the treatment group as compared with control calves inoculated identically, but without Flt3L and GM-CSF. The second hypothesis, that DNA encoding Flt3L and GM-CSF enhances immunity to a DNA vector-expressed Ag, was tested by analyzing the CD4+ T lymphocyte response to Anaplasma marginale major surface protein 1a (MSP1a). Calves immunized with DNA-expressing MSP1a developed strong CD4+ T cell responses against A. marginale, MSP1a, and specific MHC class II DR-restricted MSP1a epitopes. Administration of DNA-encoding Flt3L and GM-CSF before MSP1a DNA vaccination significantly increased the population of Ag-specific effector/memory cells in PBMC and significantly enhanced MSP1a-specific CD4+ T cell proliferation and IFN-γ secretion as compared with MHC class II DR-matched calves vaccinated identically but without Flt3L and GM-CSF. These results support use of these growth factors in DNA vaccination and specifically indicate their applicability for vaccine testing in outbred animals.
The β-Glucan Receptor, Dectin-1, Is Predominantly Expressed on the Surface of Cells of the Monocyte/Macrophage and Neutrophil Lineages
Authors: Taylor Philip R. , Brown Gordon D. , Reid Delyth M. , Willment Janet A. , Martinez-Pomares Luisa , Gordon Siamon , Wong Simon Y. C. 
Published: April 2014

AbstractWe recently identified dectin-1 (βGR) as a major β-glucan receptor on leukocytes and demonstrated that it played a significant role in the non-opsonic recognition of soluble and particulate β-glucans. Using a novel mAb (2A11) raised against βGR, we show here that the receptor is not dendritic cell-restricted as first reported, but is broadly expressed, with highest surface expression on populations of myeloid cells (monocyte/macrophage (Mφ) and neutrophil lineages). Dendritic cells and a subpopulation of T cells also expressed the βGR, but at lower levels. Alveolar Mφ, like inflammatory Mφ, exhibited the highest surface expression of βGR, indicative of a role for this receptor in immune surveillance. In contrast, resident peritoneal Mφ expressed much lower levels of βGR on the cell surface. Characterization of the nonopsonic recognition of zymosan by resident peritoneal Mφ suggested the existence of an additional β-glucan-independent mechanism of zymosan binding that was not observed on elicited or bone marrow-derived Mφ. Although this recognition could be inhibited by mannan, we were able to exclude involvement of the Mφ mannose receptor and complement receptor 3 in this process. These observations imply the existence of an additional mannan-dependent receptor involved in the recognition of zymosan by resident peritoneal Mφ.
IL-1 Receptor-Associated Kinase and Low Molecular Weight GTPase RhoA Signal Molecules Are Required for Bacterial Lipopolysaccharide-Induced Cytokine Gene Transcription
Authors: Chen Ling-Yu , Zuraw Bruce L. , Liu Fu-Tong , Huang Shuang , Pan Zhixing K. 
Published: April 2014

Abstract
Proinflammatory cytokines such as IL-1, TNF, IL-6, and IL-8 are produced by leukocytes in response to bacteria or bacterial components. A great deal has been learned during the past few years about the synthesis and release of proinflammatory cytokines by leukocytes; however, relatively little is known about the intracellular events that lead to leukocyte proinflammatory cytokine gene transcription. This study examined the signal transduction pathway of IL-8 induction by bacterial LPS. Stimulation of monocytes with LPS rapidly activated RhoA, and pretreatment of monocytes with a RhoA inhibitor, C3 transferase exoenzyme, effectively blocked LPS-induced IL-8 gene expression. Overexpression of dominant negative RhoA (T19N) or IL-1R-associated kinase completely inhibited LPS-stimulated reporter gene expression. Induction of IL-8 was also inhibited by dominant negative IκB kinase and myeloid differentiation protein (MyD88). These results indicate that RhoA and IL-1R-associated kinase are novel signal transducers for LPS-induced Toll-like receptor 4-mediated proinflammatory cytokine synthesis in human monocytes.
NF-κB Regulation in Human Neutrophils by Nuclear IκBα: Correlation to Apoptosis
Authors: Castro-Alcaraz Susana , Miskolci Veronika , Kalasapudi Bharati , Davidson Dennis , Vancurova Ivana 
Published: April 2014

Abstract
Neutrophils are among the first circulating leukocytes involved in acute inflammatory processes. Transcription factor NF-κB plays a key role in the inflammatory response, regulating the expression of proinflammatory and anti-apoptotic genes. Recently we have shown that human neutrophils contain a significant amount of NF-κB inhibitor, IκBα, in the nucleus of unstimulated cells. The present objective was to examine the mechanisms controlling the nuclear content of IκBα in human neutrophils and to determine whether increased accumulation of IκBα in the nucleus is associated with increased neutrophil apoptosis. We show for the first time that neutrophil stimulation with pro-inflammatory signals results in degradation of IκBα that occurs in both cytoplasm and nucleus. Prolonged (2-h) stimulation with TNF and LPS induces resynthesis of IκBα that is again translocated to the nucleus in human neutrophils, but not in monocytic cells. Leptomycin B, a specific inhibitor of nuclear export, increases nuclear accumulation of IκBα in stimulated neutrophils by blocking the IκBα nuclear export, and this is associated with inhibition of NF-κB activity, induction of caspase-3 activation, and apoptosis. Based on our data we present a new model of NF-κB regulation in human neutrophils by nuclear IκBα. Our results demonstrate that the NF-κB activity in human neutrophils is regulated by mechanisms clearly different from those in monocytes and other human cells and suggest that the increased nuclear content of IκBα in human neutrophils might represent one of the underlying mechanisms for the increased apoptosis in these cells.
Cellular Activation, Phagocytosis, and Bactericidal Activity Against Group B Streptococcus Involve Parallel Myeloid Differentiation Factor 88-Dependent and Independent Signaling Pathways
Authors: Henneke Philipp , Takeuchi Osamu , Malley Richard , Lien Egil , Ingalls Robin R. , Freeman Mason W. , Mayadas Tanya , Nizet Victor , Akira Shizuo , Kasper Dennis L. , Golenbock Douglas T. 
Published: April 2014

AbstractGroup B streptococci (GBS) vigorously activate inflammatory responses. We reported previously that a secreted GBS “factor” activates phagocytes via Toll-like receptor (TLR)2 and TLR6, but that GBS cell walls activate cells independently of these receptors. We hypothesized that the phagocytic immune functions in response to GBS, such as inflammation, uptake, and elimination of bacteria, occur through a coordinated engagement of TLRs, along with the coreceptors CD14 and CD11b/CD18. Using various knockout mice we show that GBS-induced activation of p38 and NF-κB depends upon the expression of the cytoplasmic TLR adapter protein, myeloid differentiation factor 88 (MyD88), but not TLR2 and/or TLR4. Macrophages with deletions of CD14 and complement receptor 3 had a normal cytokine response to whole bacteria, although the response to GBS factor was abrogated in CD14-null cells. The intracellular formation of bactericidal oxygen species proved to be MyD88 dependent; however, uptake of GBS, a prerequisite for intracellular killing by O2 radicals, occurred independently of MyD88. While deletion of complement receptor 3 greatly diminished the uptake of opsonized GBS, it did not affect the formation of bactericidal O2 radicals or inflammatory signaling intermediates. We conclude that the inflammatory, bactericidal, and phagocytic responses to GBS occur via parallel but independent processes.
Accelerated Onset and Increased Severity of Acute Graft-Versus-Host Disease Following Adoptive Transfer of DR6-Deficient T Cells
Authors: Liu Jinqi , Heuer Josef G. , Na Songqing , Galbreath Elizabeth , Zhang Tonghai , Yang Derek D. , Glasebrook Andrew , Song Ho Yeong 
Published: April 2014

AbstractDR6 is a recently identified member of the TNFR family. In a previous study, we have shown that DR6 KO mice have enhanced CD4+ T cell proliferation and Th2 cytokine production. Acute graft-vs-host disease (GVHD) results from the activation and expansion of alloreactive donor T cells following bone marrow transplantation. In this article, we demonstrate that the transfer of donor T cells from DR6 KO mice into allogeneic recipient mice in a parent into an F1 model of acute GVHD results in a more rapid onset of GVHD with increased severity. Recipients of DR6 KO T cells exhibit earlier systemic symptoms of GVHD, more rapid weight loss, earlier histopathological organ damage in the thymus, spleen, and intestines, and earlier mortality. The rapid onset of GVHD in these mice may be attributable to the enhanced activation and expansion of DR6 KO CD4+ and CD8+ T cells. Our findings support the hypothesis that DR6 serves as an important regulatory molecule in T cell immune responses. The identification and use of DR6 ligands and/or agonistic Abs to DR6 may represent useful therapeutics in the treatment of T cell-mediated diseases such as GVHD.
Dual Roles for IFN-γ, But Not for IL-4, in Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice
Authors: Yu Shiguang , Sharp Gordon C. , Braley-Mullen Helen 
Published: April 2014

AbstractSpontaneous autoimmune thyroiditis (SAT) is an organ-specific autoimmune disease characterized by chronic inflammation of the thyroid by T and B lymphocytes. To investigate the roles of Th1 and Th2 cytokines in the pathogenesis of SAT, IFN-γ−/− and IL-4−/− NOD.H-2h4 mice were generated. IL-4−/− mice developed lymphocytic SAT (L-SAT) comparable to that of wild-type (WT) mice. They produced little anti-mouse thyroglobulin (MTg) IgG1, but had levels of anti-MTg IgG2b comparable to WT mice. Compared with WT mice, IFN-γ−/− mice produced significantly less anti-MTg IgG1 and IgG2b. Absence of IFN-γ resulted in abnormal proliferation of thyroid epithelial cells with minimal lymphocyte infiltration. Thyroids of IFN-γ−/− mice had markedly reduced B lymphocyte chemoattractant expression, B cell and plasma cell infiltration, and decreased MHC class II expression on thyrocytes compared with WT mice. Adoptive transfer of WT splenocytes to IFN-γ−/− mice restored the capacity to develop typical L-SAT, enhanced anti-MTg IgG1 and IgG2b production, up-regulated MHC class II expression on thyrocytes and decreased thyrocyte proliferation. These results suggest that IFN-γ plays a dual role in the development of SAT. IFN-γ is required for development of L-SAT, and it also functions to inhibit thyroid epithelial cell proliferation.