bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stromal-Derived Factor 1 Expression in the Human Thymus
Authors: Zaitseva Marina , Kawamura Tatsuyoshi , Loomis Rebecca , Goldstein Harris , Blauvelt Andrew , Golding Hana 
Published: April 2014

AbstractStromal-derived factor-1 (SDF-1), the only known ligand for the chemokine receptor CXCR4, is broadly expressed in cells of both the immune and central nervous systems, and it can induce the migration of resting leukocytes and hemopoietic progenitors. SDF-1 mRNA was previously detected in human thymus-derived stromal cells, but its role in thymopoiesis was unknown. Here we show that SDF-1 is expressed in medullar epithelial cells forming Hassall’s corpuscles (HC). In search of the cell type that may be attracted by SDF-1+ cells in the medulla, we determined that dendritic cells (DC) could be found in situ in close proximity to SDF-1+ epithelial cells in HC. In HIV-1-infected SCID-hu thymuses, DC contained apoptotic cells and were located within enlarged HC. It was further demonstrated that uptake of apoptotic thymocytes by immature DC induced an increase in CXCR4 expression and SDF-1-mediated chemotaxis. Our data suggest a role for SDF-1 in the elimination of apoptotic thymocytes.
Homeostatic Regulation of Intestinal Villous Epithelia by B Lymphocytes
Authors: Nishiyama Yasuhiro , Hamada Hiromasa , Nonaka Satoshi , Yamamoto Hiroshi , Nanno Masanobu , Katayama Yasuo , Takahashi Hidemi , Ishikawa Hiromichi 
Published: April 2014

AbstractThe epithelial cell of the small intestine is one of the most rapidly regenerating cells in the body. However, the cellular mechanism and biological significance underlying this rapid regeneration remain elusive. In this study we examined the intestinal epithelia of mutant mice that lack B and/or T cells and those of normal littermates. The absence of B cells in Ig μ-chain mutant mice or B and T cells in recombination-activating gene (RAG)-2−/− as well as SCID mutant mice was associated with a marked acceleration of epithelial cell turnover and an up-regulation of the expression of MHC class II molecules. No such effects were observed in T cell-deficient TCR-δ and -β double-mutant mice. As far as the goblet cells of villous epithelium are concerned, absolute numbers of them remained the same among these mutant mice that have no B and/or T cells. Alymphoplasia (aly/aly) mutant mice that lacked Peyer’s patches and Ig-producing cells in the lamina propria, but harbored a large number of intestinal mucosal T cells, also displayed a significant acceleration of epithelial cell turnover and, to some extent, up-regulated expression of MHC class II molecules. Notably, the accelerated epithelial cell turnover was not observed and returned to normalcy in the Ig μ-chain mutant mice that had been given antibiotic-containing water. These findings indicate that B cells down-regulate the generation and differentiation of intestinal epithelial cells in the normal wild-type condition and suggest that enteric microorganisms are implicated in the accelerated generation of epithelial cells in mice that have no B cells.
DC-SIGN (CD209) Expression Is IL-4 Dependent and Is Negatively Regulated by IFN, TGF-β, and Anti-Inflammatory Agents
Authors: Relloso Miguel , Puig-Kröger Amaya , Pello Oscar Muñiz , Rodríguez-Fernández José Luis , de la Rosa Gonzalo , Longo Natividad , Navarro Joaquín , Muñoz-Fernández Mari Angeles , Sánchez-Mateos Paloma , Corbí Angel L. 
Published: April 2014

AbstractDendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) is a monocyte-derived dendritic cell (MDDC)-specific lectin which participates in dendritic cell (DC) migration and DC-T lymphocyte interactions at the initiation of immune responses and enhances trans-infection of T cells through its HIV gp120-binding ability. The generation of a DC-SIGN-specific mAb has allowed us to determine that the acquisition of DC-SIGN expression during the monocyte-DC differentiation pathway is primarily induced by IL-4, and that GM-CSF cooperates with IL-4 to generate a high level of DC-SIGN mRNA and cell surface expression on immature MDDC. IL-4 was capable of inducing DC-SIGN expression on monocytes without affecting the expression of other MDDC differentiation markers. By contrast, IFN-α, IFN-γ, and TGF-β were identified as negative regulators of DC-SIGN expression, as they prevented the IL-4-dependent induction of DC-SIGN mRNA on monocytes, and a similar inhibitory effect was exerted by dexamethasone, an inhibitor of the monocyte-MDDC differentiation pathway. The relevance of the inhibitory action of dexamethasone, IFN, and TGF-β on DC-SIGN expression was emphasized by their ability to inhibit the DC-SIGN-dependent HIV-1 binding to differentiating MDDC. These results demonstrate that DC-SIGN, considered as a MDDC differentiation marker, is a molecule specifically expressed on IL-4-treated monocytes, and whose expression is subjected to a tight regulation by numerous cytokines and growth factors. This feature might help in the development of strategies to modulate the DC-SIGN-dependent cell surface attachment of HIV for therapeutic purposes.
Thalidomide Suppresses NF-κB Activation Induced by TNF and H2O2, But Not That Activated by Ceramide, Lipopolysaccharides, or Phorbol Ester
Authors: Majumdar Sekhar , Lamothe Betty , Aggarwal Bharat B. 
Published: April 2014

AbstractThalidomide ([+]-α-phthalimidoglutarimide), a psychoactive drug that readily crosses the blood-brain barrier, has been shown to exhibit anti-inflammatory, antiangiogenic, and immunosuppressive properties through a mechanism that is not fully established. Due to the central role of NF-κB in these responses, we postulated that thalidomide mediates its effects through suppression of NF-κB activation. We investigated the effects of thalidomide on NF-κB activation induced by various inflammatory agents in Jurkat cells. The treatment of these cells with thalidomide suppressed TNF-induced NF-κB activation, with optimum effect occurring at 50 μg/ml thalidomide. These effects were not restricted to T cells, as other hematopoietic and epithelial cell types were also inhibited. Thalidomide suppressed H2O2-induced NF-κB activation but had no effect on NF-κB activation induced by PMA, LPS, okadaic acid, or ceramide, suggesting selectivity in suppression of NF-κB. The suppression of TNF-induced NF-κB activation by thalidomide correlated with partial inhibition of TNF-induced degradation of an inhibitory subunit of NF-κB (IκBα), abrogation of IκBα kinase activation, and inhibition of NF-κB-dependent reporter gene expression. Thalidomide abolished the NF-κB-dependent reporter gene expression activated by overexpression of TNFR1, TNFR-associated factor-2, and NF-κB-inducing kinase, but not that activated by the p65 subunit of NF-κB. Overall, our results clearly demonstrate that thalidomide suppresses NF-κB activation specifically induced by TNF and H2O2 and that this may contribute to its role in suppression of proliferation, inflammation, angiogenesis, and the immune system.
Efficient and Qualitatively Distinct MHC Class I-Restricted Presentation of Antigen Targeted to the Endoplasmic Reticulum
Authors: Golovina Tatiana N. , Wherry E. John , Bullock Timothy N. J. , Eisenlohr Laurence C. 
Published: April 2014

AbstractFor most nascent glycoprotein Ags, the MHC class I-restricted processing pathway begins in the endoplasmic reticulum (ER). From this location, they are translocated to the cytosol for degradation by the proteasome. A reasonable assumption is that processing of exocytic Ags is less efficient than that of cytosolic Ags, due to the requirement for additional handling, but that the processing pathways for the two types of proteins are otherwise similar. To test this, we compared the presentation of three epitopes within influenza nucleoprotein (NP) when this Ag is targeted to the cytosol or the ER. Surprisingly, under conditions of limited Ag expression, presentation of two proteasome-dependent epitopes is comparable when NP is targeted to the ER while presentation of a third is negatively impacted. Furthermore, presentation of the third epitope is unaffected by the addition of proteasome inhibitor when cytosolic NP is expressed but is significantly enhanced when exocytic NP is expressed. These results indicate that delivery of Ag to the ER need not preclude efficient presentation and that processing of cytosolic and ER-targeted Ag is qualitatively distinct.
Recognition of Nonclassical HLA Class I Antigens by γδ T Cells During Pregnancy
Authors: Barakonyi Aliz , Kovacs Katalin T. , Miko Eva , Szereday Laszlo , Varga Peter , Szekeres-Bartho Julia 
Published: April 2014

AbstractThe healthy trophoblast does not express classical HLA-A and HLA-B products; therefore, an MHC-restricted recognition of trophoblast-presented Ags is unlikely. In the decidua and also in peripheral blood of healthy pregnant women, γδ T cells significantly increase in number. We investigated the possible role of γδ T cells in recognition of trophoblast-presented Ags. PBL and isolated γδ T cells from healthy pregnant women as well as from those at risk for premature pregnancy termination were conjugated to choriocarcinoma cells (JAR) transfected with nonclassical HLA Ags (HLA-E, HLA-G). To investigate the involvement of killer-inhibitory/killer-activatory receptors in trophoblast recognition, we tested the effect of CD94 block on cytotoxic activity of Vδ2+ enriched γδ T cells to HLA-E- and/or HLA-G-transfected targets. Lymphocytes from healthy pregnant women preferentially recognized HLA− choriocarcinoma cells, whereas those from pathologically pregnant patients did not discriminate between HLA+ and HLA− cells. Normal pregnancy Vδ2+ T cells conjugated at a significantly increased rate to HLA-E transfectants, whereas Vδ2+ lymphocytes from pathologically pregnant women did not show a difference between those and HLA− cells. Blocking of the CD94 molecule of Vδ2+ lymphocytes from healthy pregnant women resulted in an increased cytotoxic activity to HLA-E-transfected target cells. These data indicate that Vδ2+ lymphocytes of healthy pregnant women recognize HLA-E on the trophoblast, whereas Vδ1 cells react with other than HLA Ags. In contrast to Vδ2+ lymphocytes from healthy pregnant women, those from women with pathological pregnancies do not recognize HLA-E via their killer-inhibitory receptors and this might account for their high cytotoxic activity.
CD28 Costimulation Mediates Down-Regulation of p27kip1and Cell Cycle Progression by Activation of the PI3K/PKB Signaling Pathway in Primary Human T Cells
Authors: Appleman Leonard J. , van Puijenbroek Andre A. F. L. , Shu Kirstin M. , Nadler Lee M. , Boussiotis Vassiliki A. 
Published: April 2014

AbstractCD28 provides a costimulatory signal that cooperates with the TCR/CD3 complex to induce T cell activation, cytokine production, and clonal expansion. We have recently shown that CD28 directly regulates progression of T lymphocytes through the cell cycle. Although a number of signaling pathways have been linked to the TCR/CD3 and to CD28, it is not known how these two receptors cooperate to induce cell cycle progression. Here, using cell-permeable pharmacologic inhibitors of phosphatidylinositol 3-hydroxykinase (PI3K) and mitogen-activated protein kinase kinase (MEK1/2), we show that cell cycle progression of primary T lymphocytes requires simultaneous activation of PI3K- and MEK1/2-dependent pathways. Decreased abundance of cyclin-dependent kinase inhibitor p27kip1, which requires simultaneous TCR/CD3 and CD28 ligation, was dependent upon both MEK and PI3K activity. Ligation of TCR/CD3, but not CD28 alone, resulted in activation of MEK targets extracellular signal-related kinase 1/2, whereas ligation of CD28 alone was sufficient for activation of PI3K target protein kinase B (PKB; c-Akt). CD28 ligation alone was also sufficient to mediate inactivating phosphorylation of PKB target glycogen synthase kinase-3 (GSK-3). Moreover, direct inactivation of GSK-3 by LiCl in the presence of anti-CD3, but not in the presence of anti-CD28, resulted in down-regulation of p27kip1, hyperphosphorylation of retinoblastoma tumor suppressor gene product, and cellular proliferation. Thus, inactivation of the PI3K-PKB target GSK-3 could substitute for CD28 but not for CD3 signals. These results show that the PI3K-PKB pathway links CD28 to cell cycle progression and suggest that p27kip1 integrates mitogenic MEK- and PI3K-dependent signals from TCR and CD28 in primary T lymphocytes.
Focal Localization of Placental Protein 14 Toward Sites of TCR Engagement
Authors: Rachmilewitz Jacob , Borovsky Zipora , Mishan-Eisenberg Galit , Yaniv Einat , Riely Gregory J. , Tykocinski Mark L. 
Published: April 2014

Abstract
TCR signal transduction is amplified by the dynamic accumulation of accessory molecules at APC-T cell contact sites, along with the simultaneous exclusion from these sites of negative regulators, such as certain tyrosine phosphatases and large glycosylated proteins. However, given the general nature of the cytoskeleton-driven clustering mechanism underlying molecular segregation events at the APC-T cell interaction site, the possibility exists that negative regulators might similarly be segregated at these sites. Using fluorescence microscopy, we have demonstrated that placental protein 14 (PP14), a direct T cell inhibitor, focuses toward APC-T cell contact sites in conjunction with conjugate formation. We have further established that the function of PP14 is dependent upon its localization to the sites of TCR triggering, where it negatively regulates T cell activation. Thus, PP14 provides an example of a soluble negative T cell regulator whose inhibitory activity is linked to modulation of the APC-T cell contact site, thereby hindering early events triggered by the TCR.
Essential Role for CD40 Ligand Interactions in T Lymphocyte-Mediated Modulation of the Murine Immune Response to Pneumococcal Capsular Polysaccharides
Authors: Jeurissen Axel , Wuyts Margreet , Kasran Ahmad , Ramdien-Murli Sheema , Boon Louis , Ceuppens Jan L. , Bossuyt Xavier 
Published: April 2014

AbstractProtection against infection with pneumococci is provided by anti-capsular polysaccharide (caps-PS) Abs. We investigated whether CD40 ligand (CD40L) plays a role in T lymphocyte-mediated regulation of the immune response to caps-PS, which are considered thymus-independent Ags. Administration of MR1, an antagonist mAb against murine CD40L, in BALB/c mice immunized with Pneumovax resulted in an inhibition of the IgM and IgG Ab response for various caps-PS serotypes. Evidence for the involvement of CD4+ T lymphocytes in the Ab response to caps-PS was obtained in SCID/SCID mice that, when reconstituted with B lymphocytes and CD4+ T lymphocytes, mounted a higher specific IgM response compared with SCID/SCID mice reconstituted with only B lymphocytes. This helper effect of CD4+ T lymphocytes was abrogated by MR1. Blocking CD40L in vitro decreased the IgM response to caps-PS and abolished the helper effect of CD4+ T lymphocytes. CD8+ T lymphocyte-depleted murine spleen cells mounted a higher in vivo immune response than total murine spleen cells, which provided evidence for a suppressive role of CD8+ T lymphocytes on the anti-caps-PS immune response. CD4+ T lymphocyte-depleted murine spleen cells, leaving a B and CD8+ T lymphocyte fraction, elicited only a weak in vivo and in vitro Ab response, which was enhanced after MR1 administration. In summary, our data provide evidence that T lymphocytes contribute to the regulation of the anti-caps-PS immune response in a CD40L-dependent manner.
A Novel Murine Model of Graves’ Hyperthyroidism with Intramuscular Injection of Adenovirus Expressing the Thyrotropin Receptor
Authors: Nagayama Yuji , Kita-Furuyama Masako , Ando Takao , Nakao Kazuhiko , Mizuguchi Hiroyuki , Hayakawa Takao , Eguchi Katsumi , Niwa Masami 
Published: April 2014

AbstractIn this work we report a novel method to efficiently induce a murine model of Graves’ hyperthyroidism. Inbred mice of different strains were immunized by i.m. injection with adenovirus expressing thyrotropin receptor (TSHR) or β-galactosidase (1 × 1011 particles/mouse, three times at 3-wk intervals) and followed up to 8 wk after the third immunization. Fifty-five percent of female and 33% of male BALB/c (H-2d) and 25% of female C57BL/6 (H-2b) mice developed Graves’-like hyperthyroidism with elevated serum thyroxine (T4) levels and positive anti-TSHR autoantibodies with thyroid-stimulating Ig (TSI) and TSH-binding inhibiting Ig (TBII) activities. In contrast, none of female CBA/J (H-2k), DBA/1J (H-2q), or SJL/J (H-2s) mice developed Graves’ hyperthyroidism or anti-TSHR autoantibodies except SJL/J, which showed strong TBII activities. There was a significant positive correlation between TSI values and T4 levels, but the correlations between T4 and TBII and between TSI and TBII were very weak. TSI activities in sera from hyperthyroid mice measured with some chimeric TSH/lutropin receptors suggested that their epitope(s) on TSHR appeared similar to those in patients with Graves’ disease. The thyroid glands from hyperthyroid mice displayed diffuse enlargement with hypertrophy and hypercellularity of follicular epithelia with occasional protrusion into the follicular lumen, characteristics of Graves’ hyperthyroidism. Decreased amounts of colloid were also observed. However, there was no inflammatory cell infiltration. Furthermore, extraocular muscles from hyperthyroid mice were normal. Thus, the highly efficient means that we now report to induce Graves’ hyperthyroidism in mice will be very useful for studying the pathogenesis of autoimmunity in Graves’ disease.
Regulation of Cytokine Expression by Ligands of Peroxisome Proliferator Activated Receptors
Authors: Cunard Robyn , Ricote Mercedes , DiCampli Dennis , Archer D. Clay , Kahn Daniel A. , Glass Christopher K. , Kelly Carolyn J. 
Published: April 2014

Abstract
Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors with diverse actions including adipocyte differentiation and lipid metabolism. Recent studies have revealed anti-inflammatory activities, but the majority of these studies have been performed in monocyte/macrophages. In these studies, we investigate the effects of PPAR ligands in murine mitogen-activated splenocytes. Ciglitazone, a PPARγ ligand, consistently decreased IFN-γ and IL-2 production by mitogen-activated splenocytes and had modest effects on splenocyte proliferation. The effects of WY14,643, a representative of the fibrate class of PPARα ligands, on splenocyte proliferation and IL-2 levels are less marked than those observed with the PPARγ ligand. In addition, treatment with WY14,643 and other fibrates led to marked increases in supernatant concentrations of IL-4. However, treatment with a potent and specific PPARα ligand (GW7,647) did not augment IL-4. Also, WY14,643 induced IL-4 expression in splenocytes from PPARα knockout mice, suggesting that the fibrate effect on IL-4 was largely through a PPARα-independent mechanism. This increase in IL-4 was associated with and causatively related to augmented expression of CD23 by CD45R/B220+ cells. We also demonstrate that PPARγ gene expression is up-regulated in T cells by mitogen activation, that it is positively regulated by IL-4 and WY14,643, and that it is blocked by anti-IL-4. Finally, we demonstrate that WY14,643 can modestly augment IL-4 promoter activity in a PPARα-independent manner. In concert, these findings support the roles of PPAR ligands in modulating inflammatory responses involving lymphocytes but also establish potent effects of the fibrate class of PPARα ligands on IL-4 expression that are receptor independent.
CD66a Interactions Between Human Melanoma and NK Cells: A Novel Class I MHC-Independent Inhibitory Mechanism of Cytotoxicity
Authors: Markel Gal , Lieberman Niva , Katz Gil , Arnon Tal I. , Lotem Michal , Drize Olga , Blumberg Richard S. , Bar-Haim Erez , Mader Reuven , Eisenbach Lea , Mandelboim Ofer 
Published: April 2014

Abstract
NK cells are able to kill virus-infected and tumor cells via a panel of lysis receptors. Cells expressing class I MHC proteins are protected from lysis primarily due to the interactions of several families of NK receptors with both classical and nonclassical class I MHC proteins. In this study we show that a class I MHC-deficient melanoma cell line (1106mel) is stained with several Ig-fused lysis receptors, suggesting the expression of the appropriate lysis ligands. Surprisingly, however, this melanoma line was not killed by CD16-negative NK clones. The lack of killing is shown to be the result of homotypic CD66a interactions between the melanoma line and the NK cells. Furthermore, 721.221 cells expressing the CD66a protein were protected from lysis by YTS cells and by NK cells expressing the CD66a protein. Redirected lysis experiments demonstrated that the strength of the inhibitory effect is correlated with the levels of CD66a expression. Finally, the expression of CD66a protein was observed on NK cells derived from patients with malignant melanoma. These findings suggest the existence of a novel class I MHC-independent inhibitory mechanism of human NK cell cytotoxicity. This may be a mechanism that is used by some of the class I MHC-negative melanoma cells to evade attack by CD66a-positive NK cells.
Differential Patterns of Methylation of the IFN-γ Promoter at CpG and Non-CpG Sites Underlie Differences in IFN-γ Gene Expression Between Human Neonatal and Adult CD45RO− T Cells
Authors: White Gregory P. , Watt Paul M. , Holt Barbara J. , Holt Patrick G. 
Published: April 2014

AbstractIFN-γ is a potent pleiotropic Th1 cytokine, the production of which is tightly regulated during fetal development. Negative control of fetal/neonatal IFN-γ production is generally attributed to the Th1-antagonistic effect of mediators produced by the placenta, but evidence exists of additional and more direct transcriptional regulation. We report that neonatal (cord blood) CD3+/CD45RO− T cells, in particular the CD4+/CD45RO− subset, are hypermethylated at CpG and non-CpG (CpA and CpT) sites within and adjacent to the IFN-γ promoter. In contrast, CpG methylation patterns in cord blood IFN-γ-producing CD8+/CD45RO− T cells and CD56+/CD16+/CD3− NK cells did not differ significantly from those in their adult counterparts. Consistent with this finding, IFN-γ production by stimulated naive cord blood CD4+ T cells is reduced 5- to 10-fold relative to adult CD4+ T cells, whereas production levels in neonatal and adult CD8+ T cells are of a similar order. Evidence of significant CpA and CpT methylation was not discovered in promoter sequence from other cytokines (IL-4, TNF-α, or IFN-γR α-chain). We additionally demonstrate that overexpression of DNA methyltransferase 3a in embryonic kidney carcinoma cells is accompanied by CpA methylation of the IFN-γ promoter.