bluuebunny/crossref_metadata_2025_split huggingface dataset:
OX40 Gene Expression Is Up-Regulated by Chromatin Remodeling in Its Promoter Region Containing Sp1/Sp3, YY1, and NF-κB Binding Sites
Authors: Tone Yukiko , Kojima Yoshitsugu , Furuuchi Keiji , Brady Maya , Yashiro-Ohtani Yumi , Tykocinski Mark L. , Tone Masahide 
Published: April 2014

Abstract
OX40 is a member of the TNFR superfamily (CD134; TNFRSF4) that is expressed on activated T cells and regulates T cell-mediated immune responses. In this study, we have examined the regulation of OX40 gene expression in T cells. Low-level OX40 mRNA expression was detected in both resting T cells and the nonactivated EL4 T cell line, and was up-regulated in both types of T cells upon activation with anti-CD3 Ab. We have shown in this study that basal OX40 promoter activity is regulated by constitutively expressed Sp1/Sp3 and YY1 transcription factors. NF-κB (p50 and p65) also binds to the OX40 promoter region, but the level of direct enhancement of the OX40 promoter activity by this transcription factor is not sufficient to account for the observed up-regulation of OX40 mRNA expression associated with activation. We have detected by chromatin immunoprecipitation that histone H4 molecules in the OX40 promoter region are highly acetylated by activation and NF-κB binds to the OX40 promoter in vivo. These findings suggest that OX40 gene expression is regulated by chromatin remodeling, and that NF-κB might be involved in initiation of chromatin remodeling in the OX40 promoter region in activated T cells. CD4+CD25+ regulatory T (Treg) cells also express OX40 at high levels, and signaling through this receptor can neutralize suppressive activity of this Treg cell. In CD4+CD25+ Treg cells, histone H4 molecules in the OX40 promoter region are also highly acetylated, even in the absence of in vitro activation.
A Natural Hypomorphic Variant of the Apoptosis Regulator Gimap4/IAN1
Authors: Carter Christine , Dion Carine , Schnell Silke , Coadwell W. John , Graham Margaret , Hepburn Lucy , Morgan Geoffrey , Hutchings Amanda , Pascall John C. , Jacobs Heinz , Miller J. Ross , Butcher Geoffrey W. 
Published: April 2014

Abstract
The Gimap/IAN family of GTPases has been implicated in the regulation of cell survival, particularly in lymphomyeloid cells. Prosurvival and prodeath properties have been described for different family members. We generated novel serological reagents to study the expression in rats of the prodeath family member Gimap4 (IAN1), which is sharply up-regulated at or soon after the stage of T cell-positive selection in the thymus. During these investigations we were surprised to discover a severe deficiency of Gimap4 expression in the inbred Brown Norway (BN) rat. Genetic analysis linked this trait to the Gimap gene cluster on rat chromosome 4, the probable cause being an AT dinucleotide insertion in the BN Gimap4 allele (AT(+)). This allele encodes a truncated form of Gimap4 that is missing 21 carboxyl-terminal residues relative to wild type. The low protein expression associated with this allele appears to have a posttranscriptional cause, because mRNA expression was apparently normal. Spontaneous and induced apoptosis of BN and wild-type T cells was analyzed in vitro and compared with the recently described mouse Gimap4 knockout. This revealed a “delayed” apoptosis phenotype similar to but less marked than that of the knockout. The Gimap4 AT(+) allele found in BN was shown to be rare in inbred rat strains. Nevertheless, when wild rat DNA samples were studied the AT(+) allele was found at a high overall frequency (∼30%). This suggests an adaptive significance for this hypomorphic allele.
Early Innate Immune Responses to Sin Nombre Hantavirus Occur Independently of IFN Regulatory Factor 3, Characterized Pattern Recognition Receptors, and Viral Entry
Authors: Prescott Joseph B. , Hall Pamela R. , Bondu-Hawkins Virginie S. , Ye Chunyan , Hjelle Brian 
Published: April 2014

Abstract
Sin Nombre virus (SNV) is a highly pathogenic New World virus and etiologic agent of hantavirus cardiopulmonary syndrome. We have previously shown that replication-defective virus particles are able to induce a strong IFN-stimulated gene (ISG) response in human primary cells. RNA viruses often stimulate the innate immune response by interactions between viral nucleic acids, acting as a pathogen-associated molecular pattern, and cellular pattern-recognition receptors (PRRs). Ligand binding to PRRs activates transcription factors which regulate the expression of antiviral genes, and in all systems examined thus far, IFN regulatory factor 3 (IRF3) has been described as an essential intermediate for induction of ISG expression. However, we now describe a model in which IRF3 is dispensable for the induction of ISG transcription in response to viral particles. IRF3-independent ISG transcription in human hepatoma cell lines is initiated early after exposure to SNV virus particles in an entry- and replication-independent fashion. Furthermore, using gene knockdown, we discovered that this activation is independent of the best-characterized RNA- and protein-sensing PRRs including the cytoplasmic caspase recruitment domain-containing RNA helicases and the TLRs. SNV particles engage a heretofore unrecognized PRR, likely located at the cell surface, and engage a novel IRF3-independent pathway that activates the innate immune response.
Inhibition of Phagosome Maturation by Mycobacteria Does Not Interfere with Presentation of Mycobacterial Antigens by MHC Molecules
Authors: Majlessi Laleh , Combaluzier Benoit , Albrecht Imke , Garcia Jessica E. , Nouze Clémence , Pieters Jean , Leclerc Claude 
Published: April 2014

Abstract
Pathogenic mycobacteria escape host innate immune responses by surviving within phagosomes of host macrophages and blocking their delivery to lysosomes. Avoiding lysosomal delivery may also be involved in the capacity of living mycobacteria to modulate MHC class I- or II-dependent T cell responses, which may contribute to their pathogenicity in vivo. In this study, we show that the presentation of mycobacterial Ags is independent of the site of intracellular residence inside professional APCs. Infection of mouse macrophages or dendritic cells in vitro with mycobacterial mutants that are unable to escape lysosomal transfer resulted in an identical efficiency of Ag presentation compared with wild-type mycobacteria. Moreover, in vivo, such mutants induced CD4+ Th1 or CD8+ CTL responses in mice against various mycobacterial Ags that were comparable to those induced by their wild-type counterparts. These results suggest that the limiting factor for the generation of an adaptive immune response against mycobacteria is not the degree of lysosomal delivery. These findings are important in the rational design of improved vaccines to combat mycobacterial diseases.
Cutting Edge: The ST2 Ligand IL-33 Potently Activates and Drives Maturation of Human Mast Cells
Authors: Allakhverdi Zoulfia , Smith Dirk E. , Comeau Michael R. , Delespesse Guy 
Published: April 2014

AbstractIL-33, the natural ligand of the IL-1 receptor family member ST2L, is known to enhance experimental allergic-type inflammatory responses by costimulating the production of cytokines from activated Th2 lymphocytes. Although ST2L has long been known to be expressed by mast cells, its role in their biology has not been explored. In this study we report that IL-33 directly stimulates primary human mast cells (MCs) to produce several proinflammatory cytokines and chemokines and also exerts a permissive effect on the MCs response to thymic stromal lymphopoietin, a recently described potent MCs activator. IL-33 also acts both alone and in concert with thymic stromal lymphopoietin to accelerate the in vitro maturation of CD34+ MC precursors and induce the secretion of Th2 cytokines and Th2-attracting chemokines. Taken together, these results suggest that IL-33 may play an important role in mast cell-mediated inflammation and further emphasize the role of innate immunity in allergic diseases.
Generation of CD8 T Cell Memory Is Regulated by IL-12
Authors: Pearce Erika L. , Shen Hao 
Published: April 2014

Abstract
Various signals during infection influence CD8 T cell memory generation, but these factors have yet to be fully defined. IL-12 is a proinflammatory cytokine that has been shown to enhance IFN-γ-producing T cell responses and has been widely tested as a vaccine adjuvant. In this study, we show that IL-12-deficient mice generate a weaker primary CD8 T cell response and are more susceptible to Listeria monocytogenes infection, but have substantially more memory CD8 T cells and greater protective immunity against reinfection. Kinetic analyses show that in the absence of IL-12 there is a reduced contraction of Ag-specific CD8 T cells and a gradual increase in memory CD8 T cells as a result of increased homeostatic renewal. By signaling directly through its receptor on CD8 T cells, IL-12 influences their differentiation to favor the generation of fully activated effectors, but hinders the formation of CD8 T cell memory precursors and differentiation of long-term CD8 T cell memory. These results have implications for understanding memory T cell development and enhancing vaccine efficacy, and offer new insight into the role of IL-12 in coordinating the innate and adaptive immune response.
NK Cell Lysis of HIV-1-Infected Autologous CD4 Primary T Cells: Requirement for IFN-Mediated NK Activation by Plasmacytoid Dendritic Cells
Authors: Tomescu Costin , Chehimi Jihed , Maino Vernon C. , Montaner Luis J. 
Published: April 2014

Abstract
In vivo, several mechanisms have been postulated to protect HIV-1-infected cells from NK surveillance. In vitro, previous research indicates HIV-1-infected autologous CD4+ primary T cells are resistant to NK lysis. We hypothesized that NK lysis of HIV-1-infected target cells would be augmented by the presence of accessory cells and/or accessory cell factors. In this study, we show that stimulation of plasmacytoid dendritic cells (PDC) with the TLR9 agonist, CpG ODN 2216, triggered NK lysis of HIV-1-infected autologous CD4+ primary T cells. PDC-stimulated NK lysis was dependent upon MHC class I (MHC-I) down-regulation on infected cells, and primary HIV-1 isolates that exhibited enhanced MHC-I down-regulation were more susceptible to NK-mediated lysis. PDC-stimulated NK lysis of HIV-1-infected autologous CD4+ primary T cells was blocked by neutralizing Abs to type 1 IFN and was perforin/granzyme dependent. Overall, our data suggest that HIV-infected cells are not innately resistant to NK lysis, and that exogenous NK stimulation derived from PDC can trigger NK cytotoxicity against HIV-1-infected autologous CD4+ primary T cells.
Antigen, in the Presence of TGF-β, Induces Up-Regulation ofFoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses
Authors: Kapp Judith A. , Honjo Kazuhito , Kapp Linda M. , Goldsmith Kelly , Bucy R. Pat 
Published: April 2014

AbstractCD4+CD25+ regulatory T cells (Tregs) inhibit immune responses to a variety of Ags, but their specificity and mechanism of suppression are controversial. This controversy is largely because many studies focused on natural Tregs with undefined specificities and suppression has frequently been measured on polyclonal T cell responses. To address the issue of specificity further, we have bred Kd-specific, CD4+ TCR (TCR75) transgenic mice to Foxp3gfp knockin reporter mice to permit sorting of Tregs with a known specificity. Foxp3gfp.TCR75 mice did not express significant numbers of natural FoxP3+ Tregs expressing the TCR75 transgenes, but FoxP3 expression was induced by stimulating with Kd plus TGF-β. The resulting GFP+ TCR75 cells were anergic, whereas the GFP− TCR75 cells proliferated upon restimulation with Kd peptide. Yet both exhibited severely reduced expression of intracellular IFN-γ and TNF-α upon restimulation. GFP+, but not GFP−, TCR75 T cells suppressed responses by naive TCR75 T cells and by nontransgenic spleen cells stimulated with anti-CD3. GFP+ TCR75 cells also inhibited polyclonal C57BL/6 anti-Kd CTL responses if the APC expressed Kd and both MHC class I and class II, and responses by OT1 T cells to B6.Kd.OVA but not B6.Kd plus OVA expressing APC, demonstrating linked-suppression of CD8 responses. Thus, Tregs exhibit a greater degree of specificity in vitro than previously appreciated. The observation that Tregs and responder T cells must recognize the same APC provides a mechanistic explanation for the observation that Tregs must be in direct contact with effector T cells to suppress their responses.
Role of Direct Effects of IFN-γ on T Cells in the Regulation of CD8 T Cell Homeostasis
Authors: Tewari Kavita , Nakayama Yumi , Suresh M. 
Published: April 2014

Abstract
It is well recognized that IFN-γ plays a critical role in the control of CD8 T cell expansion and contraction during immune responses to several intracellular pathogens. However, our understanding of the mechanisms underlying the regulation of T cell fate by IFN-γ is sorely incomplete. Specifically, it is unclear whether regulation of CD8 T cell homeostasis occurs by a T cell intrinsic IFN-γ pathway. In this study, we have determined the role of the direct effects of IFN-γ on T cells in regulating the expansion, contraction, and memory phases of the polyclonal CD8 T cell response to an acute viral infection. Using two complementary approaches we demonstrate that the direct effects of IFN-γ suppress IL-7R expression on Ag-specific effector CD8 T cells, but clonal expansion or deletion of activated CD8 T cells in vivo can occur in the apparent absence of IFN-γR signaling in T cells. These findings have clarified fundamental features of control of T cell homeostasis by IFN-γ in the context of CD8 T cell memory and protective immunity.
Induction of FoxP3+CD4+25+ Regulatory T Cells Following Hemopoietic Stem Cell Transplantation: Role of Bone Marrow-Derived Facilitating Cells
Authors: Taylor Kendra N. , Shinde-Patil Vivek R. , Cohick Evan , Colson Yolonda L. 
Published: April 2014

Abstract
The establishment of donor cell lineages following allogeneic bone marrow transplantation is frequently associated with the development of graft-vs-host disease (GVHD). The identification of cell populations that are capable of supporting allogeneic stem cell (SC) engraftment and the induction of tolerance without inducing GVHD could expand the use of this therapy. CD8+TCR− facilitating cells (FC) have been shown to promote allogeneic SC engraftment with resulting transplantation tolerance across complete MHC barriers without inducing GVHD. Although donor reconstitution in SC plus FC recipients is associated with the induction of regulatory T cell-associated factors, it is not known whether an induction of regulatory T cells and subsequent tolerance is a direct effect of the FC. The current study demonstrates that 1) SC plus FC transplantation results in the induction of donor CD4+25+ regulatory T cells and that FC are present in the spleen of recipients before the induction of these cells, 2) activation of FC with CpG-oligodeoxynucleotide promotes CD4+25− T cell differentiation into CD4+25+ regulatory T cells in vitro, as demonstrated by cytokine and forkhead/winged helix transcription factor (FoxP3) gene and protein expression, and 3) direct contact between FC and CD4+25− T cells is required for FoxP3+CD4+25+ regulatory T cell induction and is dependent on CD86 expression on FC. This is the first report to demonstrate a mechanism for FC in the induction of regulatory T cells following allogeneic SC plus FC transplantation. The transplantation of donor FC may provide an alternative approach to permit clinical SC engraftment and induction of transplantation tolerance in the future.
Selective Expansion of Foxp3-Positive Regulatory T Cells and Immunosuppression by Suppressors of Cytokine Signaling 3-Deficient Dendritic Cells
Authors: Matsumura Yumiko , Kobayashi Takashi , Ichiyama Kenji , Yoshida Ryoko , Hashimoto Masayuki , Takimoto Tomohito , Tanaka Kentaro , Chinen Takatoshi , Shichita Takashi , Wyss-Coray Tony , Sato Katsuaki , Yoshimura Akihiko 
Published: April 2014

Abstract
Dendritic cells (DCs) induce immunity and immunological tolerance as APCs. It has been shown that DCs secreting IL-10 induce IL-10+ Tr1-type regulatory T (Treg) cells, whereas Foxp3-positive Treg cells are expanded from naive CD4+ T cells by coculturing with mature DCs. However, the regulatory mechanism of expansion of Foxp3+ Treg cells by DCs has not been clarified. In this study, we demonstrated that suppressors of cytokine signaling (SOCS)-3-deficient DCs have a strong potential as Foxp3+ T cell-inducing tolerogenic DCs. SOCS3−/− DCs expressed lower levels of class II MHC, CD40, CD86, and IL-12 than wild-type (WT)-DCs both in vitro and in vivo, and showed constitutive activation of STAT3. Foxp3− effector T cells were predominantly expanded by the priming with WT-DCs, whereas Foxp3+ Treg cells were selectively expanded by SOCS3−/− DCs. Adoptive transfer of SOCS3−/− DCs reduced the severity of experimental autoimmune encephalomyelitis. Foxp3+ T cell expansion was blocked by anti-TGF-β Ab, and SOCS3−/− DCs produced higher levels of TGF-β than WT-DCs, suggesting that TGF-β plays an essential role in the expansion of Foxp3+ Treg cells. These results indicate an important role of SOCS3 in determining on immunity or tolerance by DCs.
Acute Rejection of Allografted CTL-Susceptible Leukemia Cells from Perforin/Fas Ligand Double-Deficient Mice
Authors: Nomi Hayahito , Tashiro-Yamaji Junko , Yamamoto Yumiko , Miura-Takeda Sayako , Miyoshi-Higashino Masako , Takahashi Takeshi , Azuma Haruhito , Ueda Haruhiko , Katsuoka Yoji , Kubota Takahiro , Yoshida Ryotaro 
Published: April 2014

AbstractThe generation of knockout mice demonstrated that CD4+, but not CD8+, T cells were essential for the rejection of allografted skin or heart, presumably because these targets were CTL resistant. In the case of CTL-susceptible targets (e.g., P815 mastocytoma cells and EL-4 or RLmale1 T lymphoma cells), however, it is assumed that the CTL is the effector cell responsible for allograft rejection and that perforin and Fas ligand (FasL) pathways are the killing mechanisms. In the present study, we examined the role of these cytotoxic molecules in the rejection of i.p. allografted CTL-susceptible leukemia cells. Unexpectedly, the allografted leukemia cells were acutely rejected from gld (a mutation of FasL), perforin−/−, or double-deficient mice. The peritoneal exudate cells from gld or normal mice showed T cell-, TCRαβ-, and perforin-dependent cytotoxic activity against the allograft, whereas the exudate cells from perforin−/− mice exhibited almost full cytotoxic activity in the presence of Fas-Fc. Furthermore, the infiltrates from double-deficient mice showed a high cytotoxic activity against the allografted cells even in the presence of anti-TCRαβ Ab or in the absence of T cells. The cytotoxic cells appeared to be macrophages, because they were Mac-1+ mononuclear cells with a kidney- or horseshoe-shaped nucleus and because the cytotoxic activity was completely suppressed by the addition of NG-monomethyl-l-arginine, an inhibitor of inducible NO synthase. These results indicate that macrophages are ready and available to kill CTL-susceptible allografts when CTLs lack both perforin and FasL molecules.
Phospholipase Cβ Is Critical for T Cell Chemotaxis
Authors: Bach Tami L. , Chen Qing-Min , Kerr Wesley T. , Wang Yanfeng , Lian Lurong , Choi John K. , Wu Dianqing , Kazanietz Marcelo G. , Koretzky Gary A. , Zigmond Sally , Abrams Charles S. 
Published: April 2014

Abstract
Chemokines acting through G protein-coupled receptors play an essential role in the immune response. PI3K and phospholipase C (PLC) are distinct signaling molecules that have been proposed in the regulation of chemokine-mediated cell migration. Studies with knockout mice have demonstrated a critical role for PI3K in Gαi protein-coupled receptor-mediated neutrophil and lymphocyte chemotaxis. Although PLCβ is not essential for the chemotactic response of neutrophils, its role in lymphocyte migration has not been clearly defined. We compared the chemotactic response of peripheral T cells derived from wild-type mice with mice containing loss-of-function mutations in both of the two predominant lymphocyte PLCβ isoforms (PLCβ2 and PLCβ3), and demonstrate that loss of PLCβ2 and PLCβ3 significantly impaired T cell migration. Because second messengers generated by PLCβ lead to a rise in intracellular calcium and activation of PKC, we analyzed which of these responses was critical for the PLCβ-mediated chemotaxis. Intracellular calcium chelation decreased the chemotactic response of wild-type lymphocytes, but pharmacologic inhibition of several PKC isoforms had no effect. Furthermore, calcium efflux induced by stromal cell-derived factor-1α was undetectable in PLCβ2β3-null lymphocytes, suggesting that the migration defect is due to the impaired ability to increase intracellular calcium. This study demonstrates that, in contrast to neutrophils, phospholipid second messengers generated by PLCβ play a critical role in T lymphocyte chemotaxis.
Effective Treatment of Inflammatory Disease Models with Exosomes Derived from Dendritic Cells Genetically Modified to Express IL-4
Authors: Kim Seon Hee , Bianco Nicole R. , Shufesky William J. , Morelli Adrian E. , Robbins Paul D. 
Published: April 2014

Abstract
In this study, we demonstrate that genetically modified bone marrow-derived dendritic cells (DC) and exosomes derived from the DC, expressing either secreted IL-4 or membrane-bound IL-4, can reduce the severity and the incidence of established collagen-induced arthritis and inhibit inflammation of delayed-type hypersensitivity (DTH) in mice. The ability of the DC and DC-derived exosomes to suppress the DTH response was MHC class II and, in part, Fas ligand/Fas dependent. The DC-derived exosomes were internalized by CD11c+ DC in the dermis at the site of injection and in the draining lymph node as well as by CD11c+ DC and F4/80+ macrophages in the spleen. Moreover, adoptive transfer of CD11c+ or CD3+ splenic cells from mice treated with exosomes showed significant reduction of footpad swelling in the DTH model. These results demonstrate that administration of DC/IL-4 or exosomes derived from DC/IL-4 are able to modulate the activity of APC and T cells in vivo through a MHC class II and partly Fas ligand/Fas-dependent mechanism, resulting in effective treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. Thus, APC-derived exosomes could be used therapeutically for the treatment of autoimmune disease and inflammatory disorders.
Class IA Phosphoinositide 3-Kinase Modulates Basal Lymphocyte Motility in the Lymph Node
Authors: Matheu Melanie P. , Deane Jonathan A. , Parker Ian , Fruman David A. , Cahalan Michael D. 
Published: April 2014

Abstract
Recruitment of PI3K to the cell membrane is an indispensable step in normal lymphocyte proliferation and activation. In this study we identify PI3K as an important signaling molecule for maintaining basal T and B lymphocyte motility and homing in the intact lymph node. Pharmacological inhibition of PI3K catalytic isoforms exerted broad effects on basal lymphocyte motility, including changes in homing kinetics, localization of B cells within the lymph node, and reduced cell velocities. Lymphocytes deficient in either or both of the class IA PI3K regulatory subunits p85α and p85β also exhibited reduced velocities, with the magnitude of reduction depending upon both cell type and isoform specificity. B cells deficient in p85α exhibited gross morphological abnormalities that were not evident in cells treated with a PI3K inhibitor. Our results show, for the first time, that class IA PI3Ks play an important role in regulating basal lymphocyte motility and that p85α regulatory subunit expression is required to maintain B cell morphology in a manner independent of PI3K catalytic function. Moreover, we demonstrate distinct roles for catalytic domain function and class IA PI3K regulatory domain activity in lymphocyte motility, homing, and homeostatic localization of mature resting B cells.