bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sumoylation of Peroxisome Proliferator-Activated Receptor γ by Apoptotic Cells Prevents Lipopolysaccharide-Induced NCoR Removal from κB Binding Sites Mediating Transrepression of Proinflammatory Cytokines
Authors: Jennewein Carla , Kuhn Anne-Marie , Schmidt Martina Victoria , Meilladec-Jullig Virginie , von Knethen Andreas , Gonzalez Frank J. , Brüne Bernhard 
Published: April 2014

Abstract
Efficient clearance of apoptotic cells (AC) by professional phagocytes is crucial for tissue homeostasis and resolution of inflammation. Macrophages respond to AC with an increase in antiinflammatory cytokine production but a diminished release of proinflammatory mediators. Mechanisms to explain attenuated proinflammatory cytokine formation remain elusive. We provide evidence that peroxisome proliferator-activated receptor γ (PPARγ) coordinates antiinflammatory responses following its activation by AC. Exposing murine RAW264.7 macrophages to AC before LPS stimulation reduced NF-κB transactivation and lowered target gene expression of, that is, TNF-α and IL-6 compared with controls. In macrophages overexpressing a dominant negative mutant of PPARγ, NF-κB transactivation in response to LPS was restored, while macrophages from myeloid lineage-specific conditional PPARγ knockout mice proved that PPARγ transmitted an antiinflammatory response, which was delivered by AC. Expressing a PPARγ-Δaa32–250 deletion mutant, we observed no inhibition of NF-κB. Analyzing the PPARγ domain structures within aa 32–250, we anticipated PPARγ sumoylation in mediating the antiinflammatory effect in response to AC. Interfering with sumoylation of PPARγ by mutating the predicted sumoylation site (K77R), or knockdown of the small ubiquitin-like modifier (SUMO) E3 ligase PIAS1 (protein inhibitor of activated STAT1), eliminated the ability of AC to suppress NF-κB. Chromatin immunoprecipitation analysis demonstrated that AC prevented the LPS-induced removal of nuclear receptor corepressor (NCoR) from the κB site within the TNF-α promoter. We conclude that AC induce PPARγ sumoylation to attenuate the removal of NCoR, thereby blocking transactivation of NF-κB. This contributes to an antiinflammatory phenotype shift in macrophages responding to AC by lowering proinflammatory cytokine production.
Overproduction of IgE Induces Macrophage-Derived Chemokine (CCL22) Secretion from Basophils
Authors: Watanabe Maki , Satoh Takahiro , Yamamoto Yoshihiro , Kanai Yasumasa , Karasuyama Hajime , Yokozeki Hiroo 
Published: April 2014

Abstract
Macrophage-derived chemokine (MDC) CCL22 is a potent chemoattractant for Th2 cells and has been implicated in Th2-predominant allergic inflammation. In the present study, we demonstrated that basophils produce MDC in response to monomeric IgE. In trinitrophenyl (TNP)-IgE transgenic mice, serum levels of MDC were persistently higher than in wild-type mice. The i.v. administration of TNP-specific IgE to wild-type mice transiently induced an elevation in serum MDC, which appeared to be mediated by FcεRI, as no increase in serum MDC was observed after IgE administration in FcRγ (−/−) mice. However, the IgE-mediated increase in MDC was observed in mast cell-deficient mice. Freshly isolated bone marrow cells and bone marrow-derived basophils secreted MDC in response to TNP-IgE without Ag stimulation. Furthermore, MDC production was not observed in bone marrow-derived basophils isolated from FcRγ (−/−) mice. IgE activated Lyn and ERK 1/2 in bone marrow-derived basophils. Treatment of TNP-IgE transgenic mice with a basophil-depletion Ab (Ba103) resulted in decreased serum MDC levels. Thus, IgE appears to be capable of stimulating basophils to produce MDC in the absence of a specific Ag, which may contribute to IgE-mediated and/or Th2-predominant allergic inflammation.
Effect of CpG Oligonucleotides on Vaccine-Induced B Cell Memory
Authors: Tross Debra , Klinman Dennis M. 
Published: April 2014

Abstract
Adding synthetic oligodeoxynucleotides containing unmethylated CpG motifs to Anthrax vaccine adsorbed (AVA, the licensed human vaccine) increases the speed and magnitude of the resultant Ab response. Ab titers persist in the protective range for &gt;1 year, significantly longer than in animals vaccinated with AVA alone. Unexpectedly, a majority of mice immunized with CpG-adjuvanted AVA maintained resistance to anthrax infection even after their Ab titers had declined into the subprotective range. The survival of these animals was mediated by the de novo production of protective Abs by high affinity memory B cells re-stimulated immediately after challenge. Thus, a previously unrecognized benefit of CpG oligodeoxynucleotides adjuvants is their ability to expand the long-lived memory B cell population. Current findings demonstrate that CpG-adjuvanted AVA mediates protection both by stimulating a strong/persistent serum Ab response and by generating a high-affinity long-lived pool of memory B cells.
Macrophages as APC and the Dendritic Cell Myth
Authors: Hume David A. 
Published: April 2014

Abstract
Dendritic cells have been considered an immune cell type that is specialized for the presentation of Ag to naive T cells. Considerable effort has been applied to separate their lineage, pathways of differentiation, and effectiveness in Ag presentation from those of macrophages. This review summarizes evidence that dendritic cells are a part of the mononuclear phagocyte system and are derived from a common precursor, responsive to the same growth factors (including CSF-1), express the same surface markers (including CD11c), and have no unique adaptation for Ag presentation that is not shared by other macrophages.
Jakmip1 Is Expressed upon T Cell Differentiation and Has an Inhibitory Function in Cytotoxic T Lymphocytes
Authors: Libri Valentina , Schulte Dörte , van Stijn Amber , Ragimbeau Josiane , Rogge Lars , Pellegrini Sandra 
Published: April 2014

Abstract
Jakmip1 belongs to a family of three related genes encoding proteins rich in coiled-coils. Jakmip1 is expressed predominantly in neuronal and lymphoid cells and colocalizes with microtubules. We have studied the expression of Jakmip1 mRNA and protein in distinct subsets of human primary lymphocytes. Jakmip1 is absent in naive CD8+ and CD4+ T lymphocytes from peripheral blood but is highly expressed in Ag-experienced T cells. In cord blood T lymphocytes, induction of Jakmip1 occurs upon TCR/CD28 stimulation and parallels induction of effector proteins, such as granzyme B and perforin. Further analysis of CD8+ and CD4+ T cell subsets showed a higher expression of Jakmip1 in the effector CCR7− and CD27− T cell subpopulations. In a gene expression follow-up of the development of CMV-specific CD8+ response, Jakmip1 emerged as one of the most highly up-regulated genes from primary infection to latent stage. To investigate the relationship between Jakmip1 and effector function, we monitored cytotoxicity of primary CD8+ T cells silenced for Jakmip1 or transduced with the full-length protein or the N-terminal region. Our findings point to Jakmip1 being a novel effector memory gene restraining T cell-mediated cytotoxicity.
A Complex Interplay among Virus, Dendritic Cells, T Cells, and Cytokines in Dengue Virus Infections
Authors: Dejnirattisai Wanwisa , Duangchinda Thaneeya , Lin Chen-Lung Steve , Vasanawathana Sirijitt , Jones Meleri , Jacobs Michael , Malasit Prida , Xu Xiao-ning , Screaton Gavin , Mongkolsapaya Juthathip 
Published: April 2014

Abstract
Severe dengue virus (DV) infections can cause the life-threatening condition dengue hemorrhagic fever, which is characterized by a severe plasma leak, thrombocytopenia, hemorrhage, and, in severe cases, circulatory collapse and death. There is now much evidence that pre-existing immunity to DV can enhance disease when an individual becomes infected on a second or sequential occasion. It has been shown that in contrast to infected dendritic cells (DC), noninfected bystander DC underwent maturation in dengue infection. In this study, we show that TNF-α and type I IFN contribute to the maturation of bystander DC, whereas the inhibition of DV-infected DC maturation can be overcome by activated T cells. Furthermore, IFN-γ-inducible chemokines, CXCL9, 10, and 11 produced by infected DC are greatly amplified in the presence of DV-specific T cells. The chemokine secretion is also enhanced in coculture of HUVEC with either DV-infected DC or activated T cells. Finally, we found a close correlation between the serum level of these three chemokines and disease severity.
E47 Controls the Developmental Integrity and Cell Cycle Quiescence of Multipotential Hematopoietic Progenitors
Authors: Yang Qi , Kardava Lela , St. Leger Anthony , Martincic Kathleen , Varnum-Finney Barbara , Bernstein Irwin D. , Milcarek Christine , Borghesi Lisa 
Published: April 2014

Abstract
Little is known about the transcriptional regulators that control the proliferation of multipotent bone marrow progenitors. Understanding the mechanisms that restrict proliferation is of significant interest since the loss of cell cycle integrity can be associated with hematopoietic exhaustion, bone marrow failure, or even oncogenic transformation. Herein, we show that multipotent LSKs (lineage−Scahighc-kit+) from E47-deficient mice exhibit a striking hyperproliferation associated with a loss of cell cycle quiescence and increased susceptibility to in vivo challenge with a mitotoxic drug. Total LSKs contain long-term self-renewing hematopoietic stem cells and downstream multipotential progenitors (MPPs) that possess very limited or no self-renewal ability. Within total LSKs, we found specific developmental and functional deficits in the MPP subset. E47 knockout mice have grossly normal numbers of self-renewing hematopoietic stem cells but a 50–70% reduction in nonrenewing MPPs and downstream lineage-restricted populations. The residual MPPs in E47 knockout mice fail to fully up-regulate flk2 or initiate V(D)J recombination, hallmarks of normal lymphoid lineage progression. Consistent with the loss of normal cell cycle restraints, we show that E47-deficient LSKs have a 50% decrease in p21, a cell cycle inhibitor and known regulator of LSK proliferation. Moreover, enforced expression studies identify p21 as an E47 target gene in primary bone marrow LSKs. Thus, E47 appears to regulate the developmental and functional integrity of early hematopoietic subsets in part through effects on p21-mediated cell cycle quiescence.
A Quantitative Trait Locus on Chromosome 4 Affects Cycling of Hematopoietic Stem and Progenitor Cells through Regulation of TGF-β2 Responsiveness
Authors: Avagyan Serine , Glouchkova Ludmila , Choi Juhyun , Snoeck Hans-Willem 
Published: April 2014

Abstract
The hematopoietic stem and progenitor cell (HSPC) compartment is subject to extensive quantitative genetic variation. We have previously shown that TGF-β2 at low concentrations enhances flt3 ligand-induced growth of HSPCs, while it is potently antiproliferative at higher concentrations. This in vitro enhancing effect was subject to quantitative genetic variation, for which a quantitative trait locus (QTL) was tentatively mapped to chromosome 4 (chr.4). Tgfb2+/− mice have a smaller and more slowly cycling HSPC compartment, which has a decreased serial repopulation capacity, and are less susceptible to the lethal effect of high doses of 5-fluorouracil. To unequivocally demonstrate that these phenotypes can be attributed to the enhancing effect of TGF-β2 on HSPC proliferation observed in vitro and are therefore subject to mouse strain-dependent variation as well, we generated congenic mice where the telomeric region of chr.4 was introgressed from DBA/2 into C57BL/6 mice. In these mice, the enhancing effect of TGF-β2 on flt3 signaling, but not the generic antiproliferative effect of high concentrations of TGF-β2, was abrogated, confirming the location of this QTL, which we named tb2r1, on chr.4. These mice shared a smaller and more slowly cycling HSPC compartment and increased 5-fluorouracil resistance but not a decreased serial repopulation capacity with Tgfb2+/− mice. The concordance of phenotypes between Tgfb2+/− and congenic mice indicates that HSPC frequency and cycling are regulated by tb2r1, while an additional QTL in the telomeric region of chr.4 may regulate the serial repopulation capacity of hematopoietic stem cells.
Fas Expression on Antigen-Specific T Cells Has Costimulatory, Helper, and Down-Regulatory Functions In Vivo for Cytotoxic T Cell Responses but Not for T Cell-Dependent B Cell Responses
Authors: Puliaeva Irina , Puliaev Roman , Shustov Andrei , Haas Mark , Via Charles S. 
Published: April 2014

Abstract
Fas-mediated apoptosis is an important contributor to contraction of Ag-driven T cell responses acting only on activated Ag-specific T cells. The effects of targeted Fas deletion on selected cell populations are well described however little is known regarding the consequences of Fas deletion on only activated Ag-specific T cells. We addressed this question using the parent-into-F1 (P→F1) model of acute or chronic (lupus-like) graft-vs-host disease (GVHD) as a model of either a CTL-mediated or T-dependent B cell-mediated response, respectively. By transferring Fas-deficient lpr donor T cells into Fas-intact F1 hosts, the in vivo role of Ag-specific T cell Fas can be determined. Our results demonstrate a novel dichotomy of Ag-specific T cell Fas function in that: 1) Fas expression on Ag-activated T cells has costimulatory, helper, and down-regulatory roles in vivo and 2) these roles were observed only in a CTL response (acute GVHD) and not in a T-dependent B cell response (chronic GVHD). Specifically, CD4 T cell Fas expression is important for optimal CD4 initial expansion and absolutely required for help for CD8 effector CTL. Donor CD8 T cell Fas expression played an important but not exclusive role in apoptosis and down-regulation. By contrast, CD4 Fas expression played no detectable role in modulating chronic GVHD induction or disease expression. These results demonstrate a novel role for Ag-specific T cell Fas expression in in vivo CTL responses and support a review of the paradigm by which Fas deficiency accelerates lupus in MRL/lpr lupus-prone mice.
Experimental Extracorporeal Photopheresis Inhibits the Sensitization and Effector Phases of Contact Hypersensitivity via Two Mechanisms: Generation of IL-10 and Induction of Regulatory T Cells
Authors: Maeda Akira , Schwarz Agatha , Bullinger Ann , Morita Akimichi , Peritt David , Schwarz Thomas 
Published: April 2014

Abstract
Extracorporeal photopheresis (ECP) is used to treat immune-mediated diseases including transplant rejection and graft-vs-host-disease. An experimental murine model of ECP utilizing contact hypersensitivity (CHS) revealed that ECP inhibits the sensitization of CHS and induces regulatory T cells (Treg). In this study, we find that ECP inhibits not only the sensitization but also the effector phase of CHS, although Treg only inhibited sensitization. IL-10 was determined to be a critical component of the effector phase inhibition and also a driving force in developing Treg. Thus, we propose that the inhibition of the effector phase of CHS by ECP is a process that does not require Treg but may be mediated via enhanced IL-10 as suggested by the use of IL-10-deficient mice. This suggests that ECP has at least two mechanisms of action, one inhibiting the effector phase of CHS and one generating Treg, which in turn can inhibit CHS sensitization and is responsible for the transferable protection. Together, this may help explain the clinical benefits of ECP in prophylactic, acute, and therapeutic settings.
IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression
Authors: Sainz-Perez Alexander , Gary-Gouy Hélène , Gaudin Françoise , Maarof Ghyath , Marfaing-Koka Anne , de Revel Thierry , Dalloul Ali 
Published: April 2014

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G0/G1 phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G2/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin-α and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.
Selective Regulation of TCR Signaling Pathways by the CD45 Protein Tyrosine Phosphatase during Thymocyte Development
Authors: Falahati Rustom , Leitenberg David 
Published: April 2014

AbstractIn CD45-deficient animals, there is a severe defect in thymocyte-positive selection, resulting in an absence of mature T cells and the accumulation of thymocytes at the DP stage of development. However, the signaling defect(s) responsible for the block in development of mature single-positive T cells is not well characterized. Previous studies have found that early signal transduction events in CD45-deficient cell lines and thymocytes are markedly diminished following stimulation with anti-CD3. Nevertheless, there are also situations in which T cell activation and TCR signaling events can be induced in the absence of CD45. For example, CD45-independent TCR signaling can be recovered upon simultaneous Ab cross-linking of CD3 and CD4 compared with cross-linking of CD3 alone. These data suggest that CD45 may differentially regulate TCR signaling events depending on the nature of the signal and/or on the differentiation state of the cell. In the current study, we have assessed the role of CD45 in regulating primary thymocyte activation following physiologic stimulation with peptide. Unlike CD3-mediated stimulation, peptide stimulation of CD45-deficient thymocytes induces diminished, but readily detectable TCR-mediated signaling events, such as phosphorylation of TCR-associated ζ, ZAP70, linker for activation of T cells, and Akt, and increased intracellular calcium concentration. In contrast, phosphorylation of ERK, which is essential for positive selection, is more severely affected in the absence of CD45. These data suggest that CD45 has a selective role in regulating different aspects of T cell activation.
Human NK Cells Kill Resting but Not Activated Microglia via NKG2D- and NKp46-Mediated Recognition
Authors: Lünemann Anna , Lünemann Jan D. , Roberts Susanne , Messmer Brady , da Silva Rosa Barreira , Raine Cedric S. , Münz Christian 
Published: April 2014

Abstract
Microglia are resident macrophage-like APCs of the CNS. To avoid escalation of inflammatory processes and bystander damage within the CNS, microglia-driven inflammatory responses need to be tightly regulated and both spatially and temporally restricted. Following traumatic, infectious, and autoimmune-mediated brain injury, NK cells have been found in the CNS, but the functional significance of NK cell recruitment and their mechanisms of action during brain inflammation are not well understood. In this study, we investigated whether and by which mechanisms human NK cells might edit resting and activated human microglial cells via killing in vitro. IL-2-activated NK cells efficiently killed both resting allogeneic and autologous microglia in a cell-contact-dependent manner. Activated NK cells rapidly formed synapses with human microglial cells in which perforin had been polarized to the cellular interface. Ab-mediated NKG2D and NKp46 blockade completely prevented the killing of human microglia by activated NK cells. Up-regulation of MHC class I surface expression by TLR4 stimulation protected microglia from NK cell-mediated killing, whereas MHC class I blockade enhanced cytotoxic NK cell activity. These data suggest that brain-infiltrating NK cells might restrict innate and adaptive immune responses within the human CNS via elimination of resting microglia.
Mycobacterium bovisBacille Calmette-Guérin Infection in the CNS Suppresses Experimental Autoimmune Encephalomyelitis and Th17 Responses in an IFN-γ-Independent Manner
Authors: Lee JangEun , Reinke Emily K. , Zozulya Alla L. , Sandor Matyas , Fabry Zsuzsanna 
Published: April 2014

AbstractMultiple sclerosis and an animal model resembling multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), are inflammatory demyelinating diseases of the CNS that are suppressed by systemic mycobacterial infection in mice and BCG vaccination in humans. Host defense responses against Mycobacterium in mice are influenced by T lymphocytes and their cytokine products, particularly IFN-γ, which plays a protective regulatory role in EAE. To analyze the counter-regulatory role of mycobacterial infection-induced IFN-γ in the CNS on the function of the pathological Th17 cells and the clinical outcome of EAE, we induced EAE in mice that were intracerebrally infected with Mycobacterium bovis bacille Calmette-Guerin (BCG). In this study, we demonstrate that intracerebral (i.c.) BCG infection prevented inflammatory cell recruitment to the spinal cord and suppressed the development of EAE. Concomitantly, there was a significant decrease in the frequency of myelin oligodendrocyte glycoprotein-specific IFN-γ-producing CD4+ T cells in the CNS. IL-17+CD4+ T cell responses were significantly suppressed in i.c. BCG-infected mice following EAE induction regardless of T cell specificity. The frequency of Foxp3+CD4+ T cells in these mice was equivalent to that of control mice. Intracerebral BCG infection-induced protection of EAE and suppression of myelin oligodendrocyte glycoprotein-specific IL-17+CD4+ T cell responses were similar in both wild-type and IFN-γ-deficient mice. These data show that live BCG infection in the brain suppresses CNS autoimmunity. These findings also reveal that the regulation of Th17-mediated autoimmunity in the CNS can be independent of IFN-γ-mediated mechanisms.
Transcription Factor Gfi1 Restricts B Cell-Mediated Autoimmunity
Authors: Rathinam Chozhavendan , Lassmann Hans , Mengel Michael , Klein Christoph 
Published: April 2014

Abstract
The zinc finger transcription factor Gfi1 (growth factor-independent-1) has been involved in various cellular differentiation processes. Gfi1 acts as a transcriptional repressor and splicing control factor upon binding to cognate binding sites in regulatory elements of its target genes. In this study, we report that Gfi1-deficient mice develop autoimmunity. Gfi1-deficient peripheral B cells show a hyperproliferative phenotype leading to expansion of plasma cells, increased levels of nuclear autoantibodies, and Ig deposition in brain and kidneys. Dysregulation of multiple transcription factors and cell cycle control elements may contribute to B cell-dependent autoimmunity. Gfi1 thus emerges as a novel master regulator restricting autoimmunity.