bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoglobulin M Efficacy AgainstCryptococcus neoformans: Mechanism, Dose Dependence, and Prozone-Like Effects in Passive Protection Experiments
Authors: Taborda Carlos P. , Casadevall Arturo 
Published: April 2014

AbstractThe IgM mAbs 12A1 and 13F1 are protective and nonprotective, respectively, against lethal Cryptococcus neoformans infection in mice. To better understand the variables that contribute to IgM efficacy against C. neoformans, we studied the effects of inoculum size, route of infection, and Ab dose for each of these mAbs. mAb 13F1 did not prolong survival under any condition studied. mAb 12A1 prolonged survival after the administration of certain Ab doses after i.p. infection with defined inocula and promoted phagocytosis, agglutination, and the formation of inflammatory cell rings around yeast cells in vivo. Large Ab doses of mAb 12A1 resulted in either no protection or enhanced infection, consistent with a prozone-like effect. Investigation of this phenomenon revealed that the fungal cell was protected against microbicidal nitrogen-derived oxidants when large amounts of Ab were bound to the C. neoformans capsule. mAb 12A1 was opsonic in vitro for peritoneal, but not splenic or alveolar macrophages. In summary, our results indicate that IgM efficacy against C. neoformans is a function of the route of infection, inoculum, and Ab dose and is associated with its ability to promote opsonization, agglutination, and phagocytic ring formation in vivo. The occurrence of the prozone-like phenomenon implies that high Ab titers are not necessarily beneficial in assuring protection against certain pathogens and that caution should be exercised in using high Ab titer as a measure for vaccine efficacy.
Amelioration of Experimental Autoimmune Encephalomyelitis with Anti-OX40 Ligand Monoclonal Antibody: A Critical Role for OX40 Ligand in Migration, But Not Development, of Pathogenic T Cells
Authors: Nohara Chiyoko , Akiba Hisaya , Nakajima Atsuo , Inoue Atsushi , Koh Chang-Sung , Ohshima Hideo , Yagita Hideo , Mizuno Yoshikuni , Okumura Ko 
Published: April 2014

Abstract
OX40 (CD134) and its ligand (OX40L) have been implicated in T cell activation and migration. In this study, we examined the contribution of these molecules to the pathogenesis of experimental autoimmune encephalomyelitis (EAE) by administering a neutralizing mAb against murine OX40L (RM134L) to proteolipid protein (139–151) peptide-induced EAE in SJL mice. Administration of RM134L effectively ameliorated the disease in both actively induced and adoptively transferred EAE models. Histological examination showed that the RM134L treatment greatly reduced mononuclear cell infiltration into the spinal cord. The RM134L treatment did not inhibit the development of pathogenic T cells, given that proliferative response and IFN-γ production by draining lymph node cells were not reduced or rather enhanced upon restimulation with proteolipid protein (139–151) in vitro, and these cells effectively transferred EAE to naive SJL mice. Flow cytometric analyses showed that the RM134L treatment inhibited the accumulation of OX40-expressing CD4+ T cells and the migration of adoptively transferred CD4+ T cells in the spinal cord. Immunohistochemical staining showed that OX40L was most prominently expressed on endothelial cells in the inflamed spinal cord. These results suggest that the OX40/OX40L interaction plays a critical role for the migration of pathogenic T cells into the CNS in the pathogenesis of EAE.
Antigen-Specific Mediated Suppression of β Cell Autoimmunity by Plasmid DNA Vaccination
Authors: Tisch Roland , Wang Bo , Weaver Donald J. , Liu Bo , Bui Thi , Arthos James , Serreze David V. 
Published: April 2014

Abstract
In this study, we have investigated the use of plasmid DNA (pDNA) vaccination to elicit Th2 effector cell function in an Ag-specific manner and in turn prevent insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. pDNA recombinants were engineered encoding a secreted fusion protein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) linked to IgGFc, and IL-4. Intramuscular injection of pDNA encoding GAD65-IgGFc and IL-4 effectively prevented diabetes in NOD mice treated at early or late preclinical stages of IDDM. This protection was GAD65-specific since NOD mice immunized with pDNA encoding hen egg lysozyme-IgGFc and IL-4 continued to develop diabetes. Furthermore, disease prevention correlated with suppression of insulitis and induction of GAD65-specific regulatory Th2 cells. Importantly, GAD65-specific immune deviation was dependent on pDNA-encoded IL-4. In fact, GAD65-specific Th1 cell reactivity was significantly enhanced in animals immunized with pDNA encoding only GAD65-IgGFc. Finally, NOD.IL4null mice treated with pDNA encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating that endogenous IL-4 was also required for disease prevention. These results demonstrate that pDNA vaccination is an effective strategy to elicit β cell-specific Th2 regulatory cell function for the purpose of preventing IDDM even at a late stage of disease development.
The Growth of the Very Large CD8+ T Cell Clones in Older Mice Is Controlled by Cytokines
Authors: Ku Chia-Chi , Kappler John , Marrack Philippa 
Published: April 2014

AbstractOlder humans and mice frequently contain very large clones of CD8+ T cells. In mice these cells are phenotypically very similar to memory CD8+ T cells. Like memory CD8+ T cells, most members of the clones are in continuous slow division, apparently independently of Ag stimulation. Proliferation of the CD8+ clonal T cells is inhibited in mice treated with Ab to the IL-2R β-chain that blocks signaling by either IL-2 or IL-15. However, inhibition of IL-2 increases the numbers of dividing clonal cells. Therefore, like normal memory CD8+ T cells, expansion of the clones is driven by IL-15 and inhibited by IL-2 and is probably limited by the amounts of IL-15 and IL-2 present in the host. Control by these two cytokines may account for the fact that, although the clones can be very large, they do not overwhelm or kill their hosts. Nevertheless the clonal cells compete successfully with normal memory CD8+ T cells for growth. Perhaps the clonal cells use IL-15 more effectively or are more resistant to the inhibitory effects of IL-2. Thus they might affect the immune response of their hosts by competing for factors that stimulate and inhibit normal CD8+ memory T cells.
Human Thymic Epithelial Cells Inhibit IL-15- and IL-2-Driven Differentiation of NK Cells from the Early Human Thymic Progenitors
Authors: Le Phong T. , Adams Kimberly L. , Zaya Ninef , Mathews Herbert L. , Storkus Walter J. , Ellis Thomas M. 
Published: April 2014

Abstract
T/NK progenitors are present in the thymus; however, the thymus predominantly promotes T cell development. In this study, we demonstrated that human thymic epithelial cells (TEC) inhibit NK cell development. Most ex vivo human thymocytes express CD1a, indicating that thymic progenitors are predominantly committed to the T cell lineage. In contrast, the CD1a−CD3−CD56+ NK population comprises only 0.2% (n = 7) of thymocytes. However, we observed increases in the percentage (20- to 25-fold) and absolute number (13- to 71-fold) of NK cells when thymocytes were cultured with mixtures of either IL-2, IL-7, and stem cell factor or IL-15, IL-7, and stem cell factor. TEC, when present in the cultures, inhibited the increases in the percentage (3- to 10-fold) and absolute number (3- to 25-fold) of NK cells. Furthermore, we show that TEC-derived soluble factors inhibit generation of NK-CFU and inhibit IL15- or IL2-driven NK cell differentiation from thymic CD34+ triple-negative thymocytes. The inhibitory activity was found to be associated with a 8,000- to 30,000 Da fraction. Thus, our data demonstrate that TEC inhibit NK cell development from T/NK CD34+ triple negative progenitors via soluble factor(s), suggesting that the human thymic microenvironment not only actively promotes T cell maturation but also controls the development of non-T lineage cells such as the NK lineage.
Activated p56lck Directs Maturation of Both CD4 and CD8 Single-Positive Thymocytes
Authors: Sohn Sue J. , Forbush Katherine A. , Pan Xiao Cun , Perlmutter Roger M. 
Published: April 2014

Abstract
p56lck is a protein tyrosine kinase expressed throughout T cell development. It associates noncovalently with the cytoplasmic domains of the CD4 and CD8 coreceptor molecules and has been implicated in TCR signaling in mature T cells. Its role in early thymocyte differentiation has been demonstrated in vivo, both by targeted gene disruption and by transgene expression. Previously, we showed that expression of a dominant-negative form of p56lck in double-positive thymocytes inhibits positive selection. We now demonstrate that expression of constitutively activated p56lck (p56lckF505) accelerates the transition from the double-positive to the single-positive stage. Importantly, p56lckF505 drives survival and lineage commitment of thymocytes in the absence of TCR engagement by appropriate MHC molecules. These results indicate that activation of p56lck constitutes an early step in conveying maturational signals after TCR ligation by a positively selecting ligand. Our study provides direct in vivo evidence for the role of p56lck in regulating TCR signaling.
NF-κB/Rel Participation in the Lymphokine-Dependent Proliferation of T Lymphoid Cells
Authors: Mora Ana L. , Youn Jeehee , Keegan Achsah D. , Boothby Mark 
Published: April 2014

Abstract
Proliferative responses of lymphoid cells to IL-2 and IL-4 depend on activation of the cells, but the mechanism(s) by which activation enhances cellular competence to respond to cytokines is not fully understood. The NF-κB/Rel family represents one signal transduction pathway induced during such activation. We show in this study that inhibition of NF-κB through the expression of an IκBα (inhibitory protein that dissociates from NF-κB) mutant refractory to signal-induced degradation (IκBα(ΔN)) interfered with the acquisition of competence to proliferate in response to IL-4 as well as IL-2. Thymocytes and T cells from IκBα(ΔN) transgenic mice expressed normal levels of IL-2R subunits. However, transgenic cells exhibited a dramatic defect in Stat5A activation treatment with IL-2, and a similar defect was observed for IL-4-induced Stat5. In contrast, T lymphoid cells with inhibition of NF-κB showed normal insulin receptor substrate-2 phosphorylation and only a modest decrease in Stat6 activation and insulin receptor substrate-1 phosphorylation after IL-4 stimulation. These results indicate that the NF-κB/Rel/IκBα system can regulate cytokine receptor capacitation through effects on the induction of downstream signaling by the Stat transcription factor family.
IFN-γ Regulation of Class II Transactivator Promoter IV in Macrophages and Microglia: Involvement of the Suppressors of Cytokine Signaling-1 Protein
Authors: O’Keefe George M. , Nguyen Vince T. , Ping Tang Li , Benveniste Etty N. 
Published: April 2014

AbstractThe discovery of the class II transactivator (CIITA) transcription factor, and its IFN-γ-activated promoter (promoter IV), have provided new opportunities to understand the molecular mechanisms of IFN-γ-induced class II MHC expression. Here, we investigated the molecular regulation of IFN-γ-induced murine CIITA promoter IV activity in microglia/macrophages. In the macrophage cell line RAW264.7, IFN-γ inducibility of CIITA promoter IV is dependent on an IFN-γ activation sequence (GAS) element and adjacent E-Box, and an IFN response factor (IRF) element, all within 196 bp of the transcription start site. In both RAW cells and the microglia cell line EOC20, two IFN-γ-activated transcription factors, STAT-1α and IRF-1, bind the GAS and IRF elements, respectively. The E-Box binds upstream stimulating factor-1 (USF-1), a constitutively expressed transcription factor. Functionally, the GAS, E-Box, and IRF elements are each essential for IFN-γ-induced CIITA promoter IV activity. The effects of the suppressors of cytokine signaling-1 (SOCS-1) protein on IFN-γ-induced CIITA and class II MHC expression were examined. Ectopic expression of SOCS-1 inhibits IFN-γ-induced activation of CIITA promoter IV and subsequent class II MHC protein expression. Interestingly, SOCS-1 inhibits the constitutive expression of STAT-1α and its IFN-γ-induced tyrosine phosphorylation and binding to the GAS element in CIITA promoter IV. As well, IFN-γ-induced expression of IRF-1 and its binding to the IRF element is inhibited. These results indicate that SOCS-1 may be responsible for attenuating IFN-γ-induced CIITA and class II MHC expression in macrophages.
Distinct CpG DNA and Polyinosinic-Polycytidylic Acid Double-Stranded RNA, Respectively, Stimulate CD11c− Type 2 Dendritic Cell Precursors and CD11c+ Dendritic Cells to Produce Type I IFN
Authors: Kadowaki Norimitsu , Antonenko Svetlana , Liu Yong-Jun 
Published: April 2014

Abstract
Two classes of nucleic acids, bacterial DNA containing unmethylated CpG motifs and dsRNA in viruses, induce the production of type I IFN that contributes to the immunostimulatory effects of these microbial molecules. Thus, it is important to determine which cells produce type I IFN in response to CpG DNA and dsRNA. CD4+CD11c− type 2 dendritic cell precursors (pre-DC2) were identified as the main producers of type I IFN in human blood in response to viruses. Here we asked whether pre-DC2 also produce type I IFN in response to CpG DNA and dsRNA. Oligodeoxynucleotides containing particular palindromic CpG motifs induced pre-DC2, but not CD11c+ blood DC or monocytes, to produce IFN-α. In contrast, a synthetic dsRNA, polyinosinic polycytidylic-acid, induced CD11c+ DC, but not pre-DC2 or monocytes, to produce IFN-αβ. These data indicate that CpG DNA and polyinosinic-polycytidylic acid stimulate different types of cells to produce type I IFN and that it is important to select oligodeoxynucleotides containing particular CpG motifs to induce pre-DC2 to produce type I IFN, which may play a key role in the strong adjuvant effects of CpG DNA.
Peripheral Deletion After Bone Marrow Transplantation with Costimulatory Blockade Has Features of Both Activation-Induced Cell Death and Passive Cell Death
Authors: Wekerle Thomas , Kurtz Josef , Sayegh Mohamed H. , Ito Hiroshi , Wells Andrew D. , Bensinger Steven , Shaffer Juanita , Turka Laurence A. , Sykes Megan 
Published: April 2014

AbstractTwo major pathways of death of previously activated T cells have been described: activation-induced cell death can be triggered by restimulating activated T cells with high concentrations of Ag, is Fas-dependent, is not influenced by proteins of the Bcl family, and is blocked by cyclosporin A; in contrast, passive cell death is induced by the withdrawal of growth factors and activation stimuli, is Fas-independent, and is blocked by Bcl family proteins. We examined the role of these two forms of cell death in the peripheral deletion of donor-reactive host T cells after allogeneic bone marrow transplantation and costimulatory blockade with anti-CD154 plus CTLA4Ig in two murine models. The substantial decline in donor-reactive CD4 cells seen in wild-type recipients 1 wk after bone marrow transplantation with costimulatory blockade was largely inhibited in Fas-deficient recipients and in Bcl-xL-transgenic recipients. We observed these effects both in a model involving low-dose total body irradiation and a conventional dose of bone marrow, and in a radiation-free regimen using high-dose bone marrow transplantation. Furthermore, cyclosporin A did not completely block the deletion of donor-reactive CD4+ T cells in recipients of bone marrow transplantation with costimulatory blockade. Thus, the deletion of donor-reactive T cells occurring early after bone marrow transplantation with costimulatory blockade has features of both activation-induced cell death and passive cell death. Furthermore, these in vivo data demonstrate for the first time the significance of in vitro results indicating that proteins of the Bcl family can prevent Fas-mediated apoptosis under certain circumstances.
Lysophosphatidic Acid Receptor-Selective Effects on Jurkat T Cell Migration Through a Matrigel Model Basement Membrane
Authors: Zheng Yuhua , Kong Yvonne , Goetzl Edward J. 
Published: April 2014

Abstract
Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) from platelets and mononuclear phagocytes mediate T cell functions through endothelial differentiation gene-encoded G protein-coupled receptors (Edg Rs) specific for LPA (Edg-2, -4, and -7) or S1P (Edg-1, -3, -5, -6, and -8). Jurkat leukemic T cells with the SV40 virus large T Ag (Jurkat-T cells) express Edg-3&gt;-2&gt;-4 Rs, as assessed by RT-semiquantitative PCR and Western blots with anti-Edg R mAbs. Jurkat-T cells expressing predominantly Edg-2 R (Jurkat-T-2 cells) and Edg-4 R (Jurkat-T-4 cells) were developed by cotransfection with the respective sense plasmids and a mixture of antisense plasmids for the other Edg Rs, and hygromycin selection. Migration of Jurkat-T-4 cells, but not Jurkat-T-2 cells, through a layer of Matrigel on a 5-um pore polycarbonate filter was stimulated up to 5-fold by 10−9 to 10−6 M LPA and by 30–300 ng/ml of anti-Edg-4 R Ab, but not anti-Edg-2 R Ab. LPA and anti-Edg-4 R Ab also enhanced by up to 4-fold the expression of matrix metalloproteinase by Jurkat-T-4 cells, but not Jurkat-T-2 cells, as assessed by cleavage of [3H]-type IV human collagen in the Matrigel. Enhancement of matrix metalloproteinase-dependent trans-Matrigel migration of Jurkat-T cells by the chemokine RANTES was suppressed by anti-Edg-2 R Abs, but was stimulated by anti-Edg-4 R Abs. The opposite effects of Edg-2 and Edg-4 LPA receptors on trans-Matrigel migration and some other T cell functions provide receptor-selective mechanisms for regulation of T cell recruitment and immune contributions.
Ly-49W, an Activating Receptor of Nonobese Diabetic Mice With Close Homology to the Inhibitory Receptor Ly-49G, Recognizes H-2Dk and H-2Dd
Authors: Silver Elizabeth T. , Gong Dong-Er , Hazes Bart , Kane Kevin P. 
Published: April 2014

AbstractThe diversity and ligand specificity of activating Ly-49 receptors expressed by murine NK cells are largely unknown. We cloned a new Ly-49-activating receptor, expressed by NK cells of the nonobese diabetic mouse strain, which we have designated Ly-49W. Ly-49W is highly related to the known inhibitory receptor Ly-49G in its carbohydrate recognition domain, exhibiting 97.6% amino acid identity in this region. We demonstrate that the 4D11 and Cwy-3 Abs, thought to be Ly-49G specific, also recognize Ly-49W. Rat RNK-16 cells transfected with Ly-49W mediated reverse Ab-dependent cellular cytotoxicity of FcR-positive target cells, indicating that Ly-49W can activate NK-mediated lysis. We further show that Ly-49W is allo-MHC specific: Ly-49W transfectants of RNK-16 only lysed Con A blasts expressing H-2k or H-2d haplotypes, and Ab-blocking experiments indicated that H-2Dk and Dd are ligands for Ly-49W. Ly-49W is the first activating Ly-49 receptor demonstrated to recognize an H-2k class I product. Ly-49G and Ly-49W represent a new pair of NK receptors with very similar ligand-binding domains, but opposite signaling functions.
Transactivation of C-Reactive Protein by IL-6 Requires Synergistic Interaction of CCAAT/Enhancer Binding Protein β (C/EBPβ) and Rel p50
Authors: Agrawal Alok , Cha-Molstad Hyunjoo , Samols David , Kushner Irving 
Published: April 2014

Abstract
We have previously found that overexpression of the Rel protein p50 stimulated C-reactive protein (CRP) expression in Hep 3B cells and that p50 could bind to a nonconsensus κB site overlapping the CCAAT/enhancer binding protein (C/EBP) binding site centered at position −53 on the CRP promoter. Accordingly, we employed EMSA to investigate possible cooperation between p50 and C/EBP proteins using an oligonucleotide probe (−63/−41) derived from the CRP promoter and containing both C/EBP and p50 binding sites. Abs to p50, but not to p65, decreased formation of C/EBPβ-containing complexes in nuclei of IL-6-treated cells, indicating that ternary complexes containing C/EBPβ and p50 are formed on the CRP promoter. Depletion of free Rel proteins by pretreatment of nuclear extracts with a κB consensus oligonucleotide markedly decreased formation of C/EBP complexes, indicating that Rel proteins are required for formation of such complexes. Overexpression of p50 in transient cotransfection studies using the proximal CRP promoter (−125/+9) linked to a luciferase reporter caused a 3-fold increase of luciferase activity, while C/EBPβ overexpression caused an 18-fold increase; simultaneous overexpression of both transcription factors increased luciferase activity ∼600-fold. Mutation of either the C/EBP binding site or the p50 binding site drastically reduced the effects of overexpressed transcription factors. Taken together, our findings indicate that binding of Rel p50 to the nonconsensus κB site enhances and stabilizes binding of C/EBPβ to the CRP promoter and that binding of both C/EBPβ and p50 to their overlapping cognate sites is required for induction of CRP expression by IL-6.
A Critical Role for CD2 in Both Thymic Selection Events and Mature T Cell Function
Authors: Sasada Tetsuro , Reinherz Ellis L. 
Published: April 2014

Abstract
To examine the function of CD2 in vivo, N15 TCR transgenic (tg) RAG-2−/− H-2b mice bearing a single TCR specific for the vesicular stomatitis virus octapeptide bound to the H-2Kb molecule were compared on a wild-type or CD2−/− background. In N15tg RAG-2−/− CD2−/− mice, thymic dysfunction is evident by 6 wk with a pre-TCR block in the CD4−CD8− double-negative thymocytes at the CD25+CD44− stage. Moreover, mature N15tg RAG-2−/− CD2−/− T cells are ∼100-fold less responsive to vesicular stomatitis virus octapeptide and unresponsive to weak peptide agonists, as judged by IFN-γ production. Repertoire analysis shows substantial differences in Vα usage between non-tg C57BL/6 (B6) and B6 CD2−/− mice. Collectively, these findings show that CD2 plays a role in pre-TCR function in double-negative thymocytes, TCR selection events during thymocyte development, and TCR-stimulated cytokine production in mature T cells.
Thrombospondin-1 Inhibits TCR-Mediated T Lymphocyte Early Activation
Authors: Li Zhuqing , He Liusheng , Wilson Katherine E. , Roberts David D. 
Published: April 2014

AbstractBiological activities of the matrix glycoprotein thrombospondin-1 (TSP1) are cell type specific and depend on the relative expression or activation of several TSP1 receptors. Although engaging individual TSP1 receptors in T lymphocytes can elicit costimulating signals, in this study we show that intact TSP1 inhibits TCR-mediated T cell activation, assessed globally using cDNA microarrays. TSP1 signaling suppressed expression of several genes induced in Jurkat T cells, including the T cell activation markers CD69, early growth response gene-1 (Egr-1), and phosphatase of activated cells (PAC-1). TCR-stimulated and CD47-costimulated IL-2 secretion and cell surface CD69 expression were also inhibited by TSP1. The specific inhibitory effect of TSP1 was verified in freshly isolated human PBMCs. TSP1 inhibited TCR-mediated but not protein kinase C-mediated T cell activation. Using CD69 expression as a marker, we demonstrated that the inhibitory activity of TSP1 depended on two TSP1 receptors, CD47 and integrin-associated protein heparan sulfate proteoglycans. Signals from these receptors inhibited TCR signaling downstream of ZAP70, but upstream of NF-AT. Therefore, the expression of TSP1 induced during wound repair and in tumor stroma may limit T cell activation at these sites.