bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: IL-2 Is Critically Required for the In Vitro Activation of CD4+CD25+ T Cell Suppressor Function
Authors: Thornton Angela M. , Donovan Erin E. , Piccirillo Ciriaco A. , Shevach Ethan M. 
Published: April 2014

Abstract
CD4+CD25+ T cells are potent immunoregulatory cells that suppress TCR-induced proliferation of CD4 and CD8 T cells in vitro by a cell contact-dependent mechanism. Addition of IL-2 or anti-CD28 abrogates CD4+CD25+-mediated suppression of proliferation and has been assumed to “break suppression.” We examined IL-2 mRNA by quantitative PCR in cocultures of mouse CD4+CD25+ and CD4+CD25− T cells. Although IL-2 gene transcription was inhibited in the presence or absence of exogenous IL-2, the addition of anti-CD28 stimulated endogenous IL-2 production. Surprisingly, transcription of IL-2 mRNA was also restored in the cocultures in the presence of anti-IL-2. These results are most compatible with a model in which CD4+CD25+ T cells do not suppress the initial activation of CD4+CD25− T cells, but mediate their suppressive effects following production of IL-2 by the responder cells resulting in both the expansion of the CD4+CD25+ T cells and the induction of their suppressor function.
Cutting Edge: Hemokinin Has Substance P-Like Function and Expression in Inflammation
Authors: Metwali Ahmed , Blum Arthur M. , Elliott David E. , Setiawan Tommy , Weinstock Joel V. 
Published: April 2014

Abstract
Substance P (SP) belongs to the tachykinin family of molecules. SP, cleaved from preprotachykinin A, is a neuropeptide and a proinflammatory leukocyte product. SP engages neurokinin 1 receptor (NK-1R) to stimulate cells. Hemokinin (HK) is another tachykinin that binds NK-1R. HK comes from preprotachykinin C, which is distinct from preprotachykinin A. We determined whether HK functions like SP at inflammatory sites. Preprotachykinin C mRNA was in murine schistosome granulomas and intestinal lamina propria mononuclear cells. Granuloma T cells and macrophages expressed preprotachykinin C mRNA. HK bound granuloma T cell NK-1R with high affinity. SP and HK stimulated IFN-γ production with equal potency. NK-1R antagonist blocked the effect of SP and HK on IFN-γ secretion. Thus, both HK and SP are expressed at sites of chronic inflammation and share cell origin, receptor, and immunoregulatory function. Two distinct but functionally overlapping tachykinins govern inflammation through NK-1R at sites of chronic inflammation.
Essential Role of Bystander Cytotoxic CD122+CD8+ T Cells for the Antitumor Immunity Induced in the Liver of Mice by α-Galactosylceramide
Authors: Nakagawa Ryusuke , Inui Takuo , Nagafune Ikuko , Tazunoki Yoshiko , Motoki Kazuhiro , Yamauchi Akira , Hirashima Mitsuomi , Habu Yoshiko , Nakashima Hiroyuki , Seki Shuhji 
Published: April 2014

AbstractWe recently reported that NK cells and CD8+ T cells contribute to the antimetastatic effect in the liver induced by α-galactosylceramide (α-GalCer). In the present study, we further investigated how CD8+ T cells contribute to the antimetastatic effect induced by α-GalCer. The injection of anti-CD8 Ab into mice 3 days before α-GalCer injection (2 days before intrasplenic injection of B16 tumors) did not inhibit IFN-γ production nor did it reduce the NK activity of liver mononuclear cells after α-GalCer stimulation. However, it did cause a reduction in the proliferation of liver mononuclear cells and mouse survival time. Furthermore, although the depletion of NK and NKT cells (by anti-NK1.1 Ab) 2 days after α-GalCer injection no longer decreased the survival rate of B16 tumor-injected mice, the depletion of CD8+ T cells did. CD122+CD8+ T cells in the liver increased after α-GalCer injection, and antitumor cytotoxicity of CD8+ T cells in the liver gradually increased until day 6. These CD8+ T cells exhibited an antitumor cytotoxicity toward not only B16 cells, but also EL-4 cells, and their cytotoxicity significantly decreased by the depletion of CD122+CD8+ T cells. The critical, but bystander role of CD122+CD8+ T cells was further confirmed by adoptive transfer experiments into CD8+ T cell-depleted mice. Furthermore, it took 14 days after the first intrasplenic B16/α-GalCer injection for the mice to generate CD8+ T cells that can reject s.c. rechallenged B16 cells. These findings suggest that α-GalCer activates bystander antitumor CD122+CD8+ T cells following NK cells and further induces an adaptive antitumor immunity due to tumor-specific memory CD8+ CTLs.
Fatal Acute Lymphoblastic Leukemia in Mice Transgenic for B Cell-Restricted bcl-xL and c-myc
Authors: Swanson Penelope J. , Kuslak Sheri L. , Fang Wei , Tze Lina , Gaffney Patrick , Selby Scott , Hippen Keli L. , Nunez Gabriel , Sidman Charles L. , Behrens Timothy W. 
Published: April 2014

Abstract
Expression of the c-myc gene is frequently dysregulated in malignant tumors and translocations of c-myc into the Ig H chain locus are associated with Burkitt’s-type lymphoma. There is indirect evidence that bcl-x, an anti-apoptotic member of the bcl-2 gene family, may also contribute to a variety of B lymphoid tumors. In this study, we show that mice transgenic for both B cell-restricted c-myc and bcl-xL developed aggressive, acute leukemias expressing early B lineage and stem cell surface markers. Of interest, the tumor cells proliferated and differentiated down the B cell developmental pathway following in vitro treatment with IL-7. Analysis of sorted leukemic cells from spleen indicated constitutive expression of sterile μ and κ transcripts in combination with evidence for D-JH DNA rearrangements. Several B cell-specific genes were either not expressed or were expressed at low levels in primary tumor cells and were induced following culture with IL-7. IL-7 also increased V-Jκ and V-DJH rearrangements. These data demonstrate oncogenic synergy between c-myc and bcl-xL in a new mouse model for acute lymphoblastic leukemia. Tumors in these animals target an early stage in B cell development characterized by the expression of both B lineage and stem cell genes.
Linker for Activation of B Cells: A Functional Equivalent of a Mutant Linker for Activation of T Cells Deficient in Phospholipase C-γ1 Binding
Authors: Janssen Erin , Zhu Minghua , Craven Brandon , Zhang Weiguo 
Published: April 2014

Abstract
Adaptor proteins have important functions in coupling stimulation through immunoreceptors with downstream events. The adaptor linker for activation of B cells (LAB)/non-T cell activation linker (NTAL) is expressed in various immune cell types and has a similar domain structure as linker for activation of T cells (LAT). In this study we generated a LAB transgenic mouse to compare the functional differences between LAB and LAT. A LAB transgene expressed in LAT-deficient T cells was able to restore T cell development. However, these mice developed severe organomegaly with disorganized lymphoid tissues. Lymphocytes from these transgenic mice were hyperactivated, and T cells produced large amounts of type II cytokines. In addition, these activities appeared to be uncoupled from the TCR. An examination of the signaling capabilities of these T cells revealed that LAB resembled a LAT molecule unable to bind phospholipase C-γ1.
Toll-Like Receptor 9 Signaling Activates NF-κB through IFN Regulatory Factor-8/IFN Consensus Sequence Binding Protein in Dendritic Cells
Authors: Tsujimura Hideki , Tamura Tomohiko , Kong Hee Jeong , Nishiyama Akira , Ishii Ken J. , Klinman Dennis M. , Ozato Keiko 
Published: April 2014

Abstract
Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-κB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN consensus sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8−/− mice were unresponsive to CpG and failed to induce TNF-α and IL-6, targets of NF-κB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8−/− DCs in response to LPS that signals through TLR4. IRF-8−/− DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-κB in −/− cells. This was due to the selective inability of −/− DCs to activate I-κB kinase αβ, the kinases required for NF-κB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-κB and cytokine induction in −/− DCs. Together, TLR signals that activate NF-κB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
Infection-Induced Expansion of a MHC Class Ib-Dependent Intestinal Intraepithelial γδ T Cell Subset
Authors: Davies Adrian , Lopez-Briones Sergio , Ong Helena , O’Neil-Marshall Cynthia , Lemonnier François A. , Nagaraju Kanneboyina , Metcalf Eleanor S. , Soloski Mark J. 
Published: April 2014

AbstractSalmonella species invade the host via the intestinal epithelium. Hence, intestinal intraepithelial lymphocytes (iIELs) are potentially the first element of the immune system to encounter Salmonella during infection. In this study, we demonstrate, in a mouse model, the expansion of a CD8αβ+CD94−TCRγδ+ T cell subset within the iIEL population in response to oral infection with virulent or avirulent Salmonella. This population can be detected 3 days following infection, represents up to 15% of the TCRγδ+ iIELs, and is dependent on the MHC class Ib molecule T23 (Qa-1). Qa-1 is expressed by intestinal epithelial cells and thus accessible for iIEL recognition. Such cells may play a role in the early immune response to Salmonella.
TNF Influences Chemokine Expression of Macrophages In Vitro and That of CD11b+ Cells In Vivo during Mycobacterium tuberculosis Infection
Authors: Algood Holly M. Scott , Lin Philana Ling , Yankura David , Jones Alvin , Chan John , Flynn JoAnne L. 
Published: April 2014

Abstract
Granulomas, focal accumulations of immune cells, form in the lung during Mycobacterium tuberculosis infection. Chemokines, chemotactic cytokines, are logical candidates for inducing migration of T lymphocytes and monocytes to and within the lung. TNF influences chemokine expression in some models. TNF-deficient mice infected with M. tuberculosis are highly susceptible to disease, and granuloma formation is inhibited. Through in vitro assays, we demonstrate that neutralization of TNF in M. tuberculosis-infected macrophages led to a reduction in many inflammatory chemokines, such as C-C chemokine ligand 5, CXC ligand 9 (CXCL9), and CXCL10. In TNF-deficient mice, immune cells migrated to the lungs early after infection, but did not organize to form granulomas within the lung. Although chemokine expression, as measured in whole lung tissue, was not different, the expression of chemokines in the CD11b+ subset of cells isolated ex vivo from the lungs of TNF-deficient mice had reduced expression of C-C chemokine ligand 5, CXCL9, and CXCL10 at early time points after TNF neutralization. Local expression of CXCR3-binding chemokines within the lungs, as determined by in situ hybridization, was also affected by TNF. Therefore, TNF affects the expression of chemokines by macrophages in vitro and CD11b+ cells in vivo, which probably influences the local chemokine gradients and granuloma formation.
Bacterial Ghosts Are an Efficient Delivery System for DNA Vaccines
Authors: Ebensen Thomas , Paukner Susanne , Link Claudia , Kudela Pavol , de Domenico Carola , Lubitz Werner , Guzmán Carlos A. 
Published: April 2014

Abstract
Mass implementation of DNA vaccines is hindered by the requirement of high plasmid dosages and poor immunogenicity. We evaluated the capacity of Mannheimia haemolytica ghosts as delivery system for DNA vaccines. In vitro studies showed that bacterial ghosts loaded with a plasmid carrying the green fluorescent protein-encoding gene (pEGFP-N1) are efficiently taken up by APC, thereby leading to high transfection rates (52–60%). Vaccination studies demonstrated that ghost-mediated delivery by intradermal or i.m. route of a eukaryotic expression plasmid containing the gene coding for β-galactosidase under the control of the CMV immediate early gene promoter (pCMVβ) stimulates more efficient Ag-specific humoral and cellular (CD4+ and CD8+) immune responses than naked DNA in BALB/c mice. The use of ghosts also allows modulating the major Th response from a mixed Th1/Th2 to a more dominant Th2 pattern. Intravenous immunization with dendritic cells loaded ex vivo with pCMVβ-containing ghosts also resulted in the elicitation of β-galactosidase-specific responses. This suggests that dendritic cells play an important role in the stimulation of immune responses when bacterial ghosts are used as a DNA delivery system. Bacterial ghosts not only target the DNA vaccine construct to APC, but also provide a strong danger signal, acting as natural adjuvants, thereby promoting efficient maturation and activation of dendritic cells. Thus, bacterial ghosts constitute a promising technology platform for the development of more efficient DNA vaccines.
Murine Cytomegalovirus Interference with Antigen Presentation Has Little Effect on the Size or the Effector Memory Phenotype of the CD8 T Cell Response
Authors: Gold Marielle C. , Munks Michael W. , Wagner Markus , McMahon Christopher W. , Kelly Ann , Kavanagh Daniel G. , Slifka Mark K. , Koszinowski Ulrich H. , Raulet David H. , Hill Ann B. 
Published: April 2014

Abstract
As with most herpesviruses, CMVs encode viral genes that inhibit Ag presentation to CD8 T cells (VIPRs). VIPR function has been assumed to be essential for CMV to establish its characteristic lifetime infection of its host. We compared infection of C57BL/6 mice with wild-type murine CMV (MCMV) and a virus lacking each of MCMV’s three known VIPRs: m4, m6, and m152. During acute infection, there was very little difference between the two viruses with respect to the kinetics of viral replication and clearance, or in the size and kinetics of the virus-specific CD8 T cell response. During chronic infection, a large, effector memory, virus-specific CD8 T cell population (CD8lowCD62L−CD11c+NKG2A+) was maintained in both infections; the size and phenotype of the CD8 T cell response to both viruses was remarkably similar. The characteristic effector memory phenotype of the CD8 T cells suggested that both wild-type and Δm4+m6+m152 virus continued to present Ag to CD8 T cells during the chronic phase of infection. During the chronic phase of infection, MCMV cannot be isolated from immunocompetent mice. However, upon immunosuppression, both Δm4+m6+m152 and wild-type virus could be reactivated from mice infected for 6 wk. Thus, restoring the ability of CD8 T cells to detect MCMV had little apparent effect on the course of MCMV infection and on the CD8 T cell response to it. These results challenge the notion that VIPR function is necessary for CMV persistence in the host.
C3a Enhances Nerve Growth Factor-Induced NFAT Activation and Chemokine Production in a Human Mast Cell Line, HMC-1
Authors: Ahamed Jasimuddin , Venkatesha Rampura T. , Thangam E. Berla , Ali Hydar 
Published: April 2014

Abstract
Activation of cell surface G protein-coupled receptors leads to transphosphorylation and activation of a number of receptor tyrosine kinases. Human mast cells express G protein-coupled receptors for the complement component C3a (C3aR) and high affinity nerve growth factor (NGF) receptor tyrosine kinase, TrkA. To determine whether C3a cross-regulates TrkA signaling and biological responses, we used a human mast cell-line, HMC-1, that natively expresses both receptors. We found that NGF caused tyrosine phosphorylation of TrkA, resulting in a sustained Ca2+ mobilization, NFAT activation, extracellular-signal regulated kinase (ERK) phosphorylation, and chemokine, macrophage inflammatory protein-1β (MIP-1β) production. In contrast, C3a induced a transient Ca2+ mobilization and ERK phosphorylation but failed to stimulate TrkA phosphorylation, NFAT activation, or MIP-1β production. Surprisingly, C3a significantly enhanced NGF-induced NFAT activation, ERK phosphorylation, and MIP-1β production. Pertussis toxin, a Gi/o inhibitor, selectively blocked priming by C3a but had no effect on NGF-induced responses. Mitogen-activated protein/ERK kinase inhibitor U0126 caused ∼30% inhibition of NGF-induced MIP-1β production but had no effect on priming by C3a. However, cyclosporin A, an inhibitor of calcineurin-mediated NFAT activation, caused substantial inhibition of NGF-induced MIP-1β production both in the absence and presence of C3a. These data demonstrate that NGF caused tyrosine phosphorylation of TrkA to induce chemokine production in HMC-1 cells via a pathway that mainly depends on sustained Ca2+ mobilization and NFAT activation. Furthermore, C3a enhances NGF-induced transcription factor activation and chemokine production via a G protein-mediated pathway that does not involve TrkA phosphorylation.
Volume-Sensitive Chloride Channels Do Not Mediate Activation-Induced Chloride Efflux in Human Neutrophils
Authors: Perez-Cornejo Patricia , Arreola Jorge , Law Foon-Yee , Schultz Joanne B. , Knauf Philip A. 
Published: April 2014

Abstract
Many agents that activate neutrophils, enabling them to adhere to venular walls at sites of inflammation, cause a rapid Cl− efflux. This Cl− efflux and the increase in the number and affinity of β2 integrin surface adhesion molecules (up-regulation) are all inhibited by ethacrynic acid and certain aminomethyl phenols. The effectiveness of the latter compounds correlates with their inhibition of swelling-activated Cl− channels (IClvol), suggesting that IClvol mediates the activator-induced Cl− efflux. To test this hypothesis, we used whole-cell patch clamp in hypotonic media to examine the effects of inhibitors of up-regulation on IClvol in neutrophils and promyelocytic leukemic HL-60 cells. Both the channel blocker 5-nitro-2-(3-phenylpropylamino)benzoic acid and [3-methyl-1-p-sulfophenyl-5-pyrazolone-(4)]-[1,3-dibutylbarbituric acid]-pentamethine oxonol (WW781), a nonpenetrating oxonol, inhibited IClvol at concentrations similar to those that inhibit β2 integrin up-regulation. However, ethacrynic acid, at the same concentration that inhibits activator-induced Cl− efflux and up-regulation, had no effect on IClvol and swelling-activated Cl− efflux, providing evidence against the involvement of IClvol in the activator-induced Cl− efflux.
Role of Calcium in Pancreatic Islet Cell Death by IFN-γ/TNF-α
Authors: Chang Inik , Cho Namjoo , Kim Sunshin , Kim Ja Young , Kim Eunshil , Woo Ji-Eun , Nam Joo Hyun , Kim Sung Joon , Lee Myung-Shik 
Published: April 2014

Abstract
We studied the intracellular events associated with pancreatic β cell apoptosis by IFN-γ/TNF-α synergism. IFN-γ/TNF-α treatment of MIN6N8 insulinoma cells increased the amplitude of high voltage-activated Ca2+ currents, while treatment with IFN-γ or TNF-α alone did not. Cytosolic Ca2+ concentration ([Ca2+]c) was also increased by IFN-γ/TNF-α treatment. Blockade of L-type Ca2+ channel by nifedipine abrogated death of insulinoma cells by IFN-γ/TNF-α. Diazoxide that attenuates voltage-activated Ca2+ currents inhibited MIN6N8 cell death by IFN-γ/TNF-α, while glibenclamide that accentuates voltage-activated Ca2+ currents augmented insulinoma cell death. A protein kinase C inhibitor attenuated MIN6N8 cell death and the increase in [Ca2+]c by IFN-γ/TNF-α. Following the increase in [Ca2+]c, calpain was activated, and calpain inhibitors decreased insulinoma cell death by IFN-γ/TNF-α. As a downstream of calpain, calcineurin was activated and the inhibition of calcineurin activation by FK506 diminished insulinoma cell death by IFN-γ/TNF-α. BAD phosphorylation was decreased by IFN-γ/TNF-α because of the increased calcineurin activity, which was reversed by FK506. IFN-γ/TNF-α induced cytochrome c translocation from mitochondria to cytoplasm and activation of caspase-9. Effector caspases such as caspase-3 or -7 were also activated by IFN-γ/TNF-α treatment. These results indicate that IFN-γ/TNF-α synergism induces pancreatic β cell apoptosis by Ca2+ channel activation followed by downstream intracellular events such as mitochondrial events and caspase activation and also suggest the therapeutic potential of Ca2+ modulation in type 1 diabetes.
Distinct Transcriptional Programs Activated by Interleukin-10 with or without Lipopolysaccharide in Dendritic Cells: Induction of the B Cell-Activating Chemokine, CXC Chemokine Ligand 13
Authors: Perrier Patrick , Martinez Fernando O. , Locati Massimo , Bianchi Giancarlo , Nebuloni Manuela , Vago Gianluca , Bazzoni Flavia , Sozzani Silvano , Allavena Paola , Mantovani Alberto 
Published: April 2014

Abstract
To understand the modulation of dendritic cell (DC) function by IL-10, gene expression profiling was performed by using Affymetrix technology (Santa Clara, CA) in human monocyte-derived DC treated with IL-10, alone or in combination with LPS. The modulation of selected genes was validated by real-time PCR, Northern blot, and protein production. IL-10 regulated in DC the expression of a limited number of genes, including IL-7, the receptors for transferrin and vitamin D3, structural matrix proteins, and signal transduction elements. The combined treatment with LPS plus IL-10 modulated a number of genes comparable to LPS alone, but the expression profiles were distinct. As expected, IL-10 suppressed the expression of several LPS-inducible proinflammatory molecules. Among genes uniquely modulated by the concomitant treatment with LPS plus IL-10, phosphatidylinositol 3-kinase γ was down-regulated while the suppressor of cytokine signaling 3, signaling lymphocytic activation molecule, regulator of G protein signaling 16, and the chemokine, CXC chemokine ligand (CXCL) 13, were up-regulated. Overall, four distinct transcriptional programs were identified, related to: 1) control of immunity and inflammation; 2) tuning of cytokine receptor and G protein-coupled receptor signaling; 3) remodeling of extracellular matrix; and 4) B cell function and lymphoid tissue neogenesis. Among the latter genes, we further demonstrate that IL-10 synergizes with TLR ligands for the production of functionally active B cell-attracting chemokine, CXCL13, in both myeloid and plasmacytoid DC. This novel finding reveals that IL-10 sustains humoral immunity by inducing the production in APCs of the chemokine, CXCL13, which amplifies B cell recruitment and promotes lymphoid tissue neogenesis.
Type 2 Monocyte and Microglia Differentiation Mediated by Glatiramer Acetate Therapy in Patients with Multiple Sclerosis
Authors: Kim Ho Jin , Ifergan Igal , Antel Jack P. , Seguin Rosanne , Duddy Martin , Lapierre Yves , Jalili Farzaneh , Bar-Or Amit 
Published: April 2014

Abstract
Glatiramer acetate (GA) therapy of patients with multiple sclerosis (MS) represents a unique setting in which in vivo Th2 deviation of T cells is consistently observed and associated with clinical benefit in a human autoimmune disease. We postulated that APCs are important targets of GA therapy and demonstrate that treatment of MS patients with GA reciprocally regulates the IL-10/IL-12 cytokine network of monocytes in vivo. We further show that Th1- or Th2-polarized GA-reactive T cells isolated from untreated or treated MS patients mediate type 1 and 2 APC differentiation of human monocytes, based on their ability to efficiently induce subsequent Th1 and Th2 deviation of naive T cells, respectively. These observations are extended to human microglia, providing the first demonstration of type 2 differentiation of CNS-derived APCs. Finally, we confirm that the fundamental capacity of polarized T cells to reciprocally modulate APC function is not restricted to GA-reactive T cells, thereby defining a novel and dynamic positive feedback loop between human T cell and APC responses. In the context of MS, we propose that GA therapy results in the generation of type 2 APCs, contributing to Th2 deviation both in the periphery and in the CNS of MS patients. In addition to extending insights into the therapeutic mode of action of GA, our findings revisit the concept of bystander suppression and underscore the potential of APCs as attractive targets for therapeutic immune modulation.