bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-9 Is a Susceptibility Factor in Leishmania major Infection by Promoting Detrimental Th2/Type 2 Responses
Authors: Arendse Berenice , Van Snick Jacques , Brombacher Frank 
Published: April 2014

Abstract
IL-9 is a cytokine produced by Th2 cells, induced during Leishmania major infection. Because the role of IL-9 in leishmaniasis is currently unknown, IL-9-deficient mice were generated by immunization with mouse IL-9 coupled to OVA. This produced strong and long-lasting neutralizing anti-IL-9 Abs in vivo. Anti-IL-9 vaccination showed protective effects, because it enabled L. major-infected nonhealer BALB/c mice to better resist to leishmaniasis with doubling the time span until pathological disease progression occurred. Increased resistance was also demonstrated by moderate footpad swelling and histopathology due to reduced parasite burden compared with sham-immunized BALB/c mice. Mechanistically, IL-9 neutralization in BALB/c mice resulted in a reduction of detrimental Th2/type 2 responses with an observed shift toward protective Th1 immune responses. This led to an alteration from alternative to classical macrophage activation with subsequent enhanced killing effector functions, as demonstrated by increased NO production but reduced arginase 1-mediated macrophage responses. Conclusively, the data show that IL-9 is a susceptible factor in leishmaniasis. They further suggest that IL-9 is able to influence Th dichotomy in leishmaniasis by promoting detrimental Th2/type 2 responses in BALB/c mice. The results extend efforts made to generate autoantibodies capable of regulating biological processes, with IL-9 a potential drug target against leishmaniasis.
Modulation of Macrophage Phenotype by Soluble Product(s) Released from Neutrophils
Authors: Daley Jean M. , Reichner Jonathan S. , Mahoney Eric J. , Manfield Laura , Henry William L. , Mastrofrancesco Balduino , Albina Jorge E. 
Published: April 2014

Abstract
The regulation of macrophage phenotype by neutrophils was studied in the s.c. polyvinyl alcohol sponge wound model in mice made neutropenic by anti-Gr-1 Ab, as well as in cell culture. Wounds in neutropenic mice contained 100-fold fewer neutrophils than those in nonneutropenic controls 1 day after sponge implantation. Wound fluids from neutropenic mice contained 68% more TNF-α, 168% more IL-6, and 61% less TGF-β1 than those from controls. Wound fluid IL-10 was not different between the two groups, and IL-4 was not detected. Intracellular TNF-α staining was greater in cells isolated from neutropenic wounds than in those from control wounds. The hypothesis that wound neutrophil products modulate macrophage phenotype was tested in Transwell cocultures of LPS-stimulated J774A.1 macrophages and day 1 wound cells (84% neutrophils/15% macrophages). Overnight cocultures accumulated 60% less TNF-α and IL-6 than cultures of J774A.1 alone. The suppression of cytokine release was mediated by a soluble factor(s), because culture supernatants from wound cells inhibited TNF-α and IL-6 release from LPS-stimulated J774A.1 cells. Culture supernatants from purified wound neutrophils equally suppressed TNF-α release from LPS-stimulated J774A.1 cells. Wound cell supernatants also suppressed TNF-α and superoxide release from murine peritoneal macrophages. The TNF-α inhibitory factor has a molecular mass &lt;3000 Da and is neither PGE2 nor adenosine. The present findings confirm a role for neutrophils in the regulation of innate immune responses through modulation of macrophage phenotype.
CpG RNA: Identification of Novel Single-Stranded RNA That Stimulates Human CD14+CD11c+ Monocytes
Authors: Sugiyama Takahiro , Gursel Mayda , Takeshita Fumihiko , Coban Cevayir , Conover Jacqueline , Kaisho Tsuneyasu , Akira Shizuo , Klinman Dennis M. , Ishii Ken J. 
Published: April 2014

Abstract
Synthetic immunostimulatory nucleic acids such as CpG DNA are being harnessed therapeutically as vaccine adjuvants, anticancer or antiallergic agents. Efforts to identify nucleic acid-based agents capable of more specifically modulating the immune system are being developed. The current study identifies a novel class of single-stranded oligoribonucleotides (ORN) containing unmethylated CpG motifs and a poly(G) run at the 3′ end (CpG ORN) that directly stimulate human CD14+CD11c+ monocytes but not dendritic cells or B cells. CpG ORN activate NF-κB and p38 MAPK, resulting in IL-6 and IL-12 production and costimulatory molecule up-regulation but not IFNα. Methylation of cytosine at the 5′ portion in core CpG motif abrogates such activation. TLR3, 7, 8, or 9 alone did not confer response to CpG ORN, in contrast to previously reported respective nucleic acid ligands. These data suggest that CpG ORN represent a novel class of synthetic immunostimulatory nucleic acids with distinct target cells, receptors, and functions from that of previously known immunomodulatory nucleic acids.
In Vitro and In Vivo Induction of Heme Oxygenase 1 in Mouse Macrophages following Melanocortin Receptor Activation
Authors: Lam Connie W. , Getting Stephen J. , Perretti Mauro 
Published: April 2014

Abstract
RAW264.7 cell incubation with adrenocorticotrophin (ACTH) led to a time-dependent (4–24 h) and concentration-related (1–100 ng/ml) induction of heme oxygenase (HO)-1, and this was a specific effect, because the pattern of expression of other cellular proteins (HO-2, heat shock proteins 70 and 90) was not modified by ACTH. Combined RT-PCR and Western blot analyses revealed expression of the melanocortin receptor (MC-R) types 1 and 3, but not 4, in these cells. However, use of more selective agonists (including melanotan (MTII)) indicated a predominant role for MC3-R in the induction of HO-1 expression and activity. Relevantly, ACTH and MTII incubation with primary peritoneal macrophages (Mφ) also induced HO-1 expression. The potential link between MC3-R dependent cAMP formation and HO-1 induction was ascertained by the following: 1) ACTH and MTII produced a concentration-dependent accumulation of cAMP in RAW264.7 cells, and 2) whereas a selective inhibitor of cAMP-dependent protein kinase A abrogated ACTH- and MTII-induced HO-1 expression, a soluble cAMP derivative promoted HO-1 induction both in RAW264.7 cells and primary Mφ. HO-1 induction in peritoneal Mφ was also detected following in vivo administration of MTII, and appeared to be functionally related to the antimigratory effect of this melanocortin, as determined with a specific inhibitor (zinc protoporphyrin IX). In conclusion, this study highlights a biochemical link between MC-R activation and HO-1 induction in the Mφ, and proposes that this may be of functional relevance in determining MC-R-dependent control of the host inflammatory response.
Preferential Recognition of Undisruptable Dimers of Inducible Nitric Oxide Synthase by a Monoclonal Antibody Directed against an N-Terminal Epitope
Authors: Mazumdar Tuhina , Eissa N. Tony 
Published: April 2014

Abstract
Overproduction of NO by inducible NO synthase (iNOS) has been implicated in the pathogenesis of many diseases. iNOS is active only as a homodimer in which the subunits align in a head-to-head manner, with the N-terminal oxygenase domains forming the dimer interface and a zinc metal center stabilizing the dimer. Thus, dimerization represents a critical locus for therapeutic interventions for regulation of NO synthesis. We have recently shown that intracellular iNOS forms dimers that are “undisruptable (UD)” by heat, SDS, strong denaturants, and/or reducing agents. Our data further suggest that the zinc metal center plays a role in forming and/or stabilizing iNOS undisruptable dimers (UD-dimers). In this study, we show that a mAb directed against a unique epitope at the oxygenase domain of human iNOS preferentially recognizes UD-dimers. This observation has implications for the mechanism of formation and regulation of dimer formation of iNOS. Our data suggest that UD-dimers of iNOS, in spite of SDS-PAGE denaturation, still maintain features of the quaternary structure of iNOS particularly at its N-terminal end and including head-to-head contact of the oxygenase domains.
L-Selectin, α4β1, and α4β7 Integrins Participate in CD4+ T Cell Recruitment to Chronically Inflamed Small Intestine
Authors: Rivera-Nieves Jesús , Olson Timothy , Bamias Giorgos , Bruce Anthony , Solga Michael , Knight Robert F. , Hoang Sharon , Cominelli Fabio , Ley Klaus 
Published: April 2014

Abstract
CD4+ T cells are essential for development and perpetuation of Crohn’s disease, a chronic immune-mediated condition that affects primarily the small intestine. Using novel models of Crohn’s disease-like ileitis (i.e., SAMP1/YitFc and CD4+ T cell transfer models), we have begun to understand the adhesive pathways that mediate lymphocyte trafficking to the chronically inflamed small bowel. Expansion of the CD4/β7+ population and increased mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression were observed within the intestinal lamina propria with disease progression. However, Ab blockade of the β7 integrin, the α4β7 heterodimer, MAdCAM-1, or L-selectin did not attenuate inflammation. Blockade of two pathways (L-selectin and MAdCAM-1 or α4 integrins) was required to improve ileitis. Further analyses showed that 55 ± 7% of the mesenteric lymph node α4β7+CD4 expressed L-selectin. These L-selectin+ T cells were the main producers of TNF-α and the predominant ileitis-inducing subpopulation. Mechanistically, combined blockade of L-selectin and MAdCAM-1 depleted the intestinal lamina propria of CD4+ T cells that aberrantly coexpressed α4β7 and α4β1 integrins, markedly decreasing local production of TNF-α and IFN-γ. Thus, pathogenic CD4+ T cells not only use the physiologic α4β7/MAdCAM-1 pathway, but alternatively engage α4β1 and L-selectin to recirculate to the chronically inflamed small intestine.
Cellular Basis of the Role of Diesel Exhaust Particles in Inducing Th2-Dominant Response
Authors: Ohtani Tomoyuki , Nakagawa Satoshi , Kurosawa Masahiro , Mizuashi Masato , Ozawa Maki , Aiba Setsuya 
Published: April 2014

Abstract
There is growing evidence that diesel exhaust particles (DEP) can induce allergic diseases with increased IgE production and preferential activation of Th2 cells. To clarify the cellular basis of the role of DEP in the induction of Th2-dominant responses, we examined the effects of DEP on the cytokine production by T cells stimulated with anti-CD3/CD28 Ab and on that by monocyte-derived dendritic cells (MoDCs) stimulated with CD40L and/or IFN-γ. We examined IFN-γ, IL-4, IL-5, IL-8, and IL-10 produced by T cells and TNF-α, IL-1β, IL-10, and IL-12 produced by MoDCs using real-time PCR analysis or by ELISA. To highlight the effects of DEP, we compared the effects of DEP with those of dexamethasone (DEX) and cyclosporin A (CyA). DEP significantly suppressed IFN-γ mRNA expression and protein production, while it did not affect IL-4 or IL-5 mRNA expression or protein production. The suppressive effect on IFN-γ mRNA expression was more potent than that of DEX and comparable at 30 μg/ml with 10−7 M CyA. The suppressive effect on IFN-γ production was also more potent than that of either DEX or CyA. DEP suppressed IL-12p40 and IL-12p35 mRNA expression and IL-12p40 and IL-12p70 production by MoDCs, while it augmented IL-1β mRNA expression. Finally, by using a thiol antioxidant, N-acetyl cysteine, we found that the suppression of IFN-γ production by DEP-treated T cells was mediated by oxidative stress. These data revealed a unique characteristic of DEP, namely that they induce a Th2 cytokine milieu in both T cells and dendritic cells.
Targeted Disruption of the Artemis Murine Counterpart Results in SCID and Defective V(D)J Recombination That Is Partially Corrected with Bone Marrow Transplantation
Authors: Li Lanying , Salido Eduardo , Zhou Yungui , Bhattacharyya Swati , Yannone Steven M. , Dunn Elizabeth , Meneses Juanito , Feeney Ann J. , Cowan Morton J. 
Published: April 2014

Abstract
Artemis is a mammalian protein, the absence of which results in SCID in Athabascan-speaking Native Americans (SCIDA). This novel protein has been implicated in DNA double-strand break repair and V(D)J recombination. We have cloned the Artemis murine counterpart, mArt, and generated a mouse with a targeted disruption of mArt. Artemis-deficient mice show a similar T−B− NK+ immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. mArt−/− embryonic fibroblasts show increased sensitivity to ionizing radiation. Hemopoietic stem cell (HSC) transplantation using 500-5000 enriched congenic, but not allogeneic mismatched HSC corrected the T cell and partially corrected the B cell defect. Large numbers (40,000) of allogeneic mismatched HSC or pretreatment with 300 cGy of radiation overcame graft resistance, resulting in limited B cell engraftment. Our results suggest that the V(D)J and DNA repair defects seen in this mArt−/− mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID.
Cutting Edge: NKG2D Is a Costimulatory Receptor for Human Naive CD8+ T Cells
Authors: Maasho Kerima , Opoku-Anane Jessica , Marusina Alina I. , Coligan John E. , Borrego Francisco 
Published: April 2014

Abstract
In humans, all αβ CD8+ T cells express NKG2D, but in mouse, it is only expressed by activated and memory CD8+ T cells. We purified human naive CD8+ T cells to show that NKG2D serves as a costimulatory receptor for TCR induced Ca2+ mobilization and proliferation. The resulting effector cells are skewed toward a type 1 phenotype and produce high levels of IFN-γ and TNF-α. NKG2D ligands, MHC class I chain-related (MIC)A, MICB, and UL16-binding proteins are expressed on the proliferating cells and NKG2D is down-regulated. The addition of the homeostatic cytokines IL-7 and IL-15 to the culture medium not only enhances proliferation but also counteracts the down-regulation of NKG2D, more so than the addition of IL-2. These results indicate that NKG2D can regulate the priming of human naive CD8+ T cells, which may provide an alternative mechanism for potentiating and channeling the immune response.
Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival
Authors: Lee Boris P.-L. , Mansfield Elaine , Hsieh Szu-Chuan , Hernandez-Boussard Tina , Chen Wenhao , Thomson Christopher W. , Ford Megan S. , Bosinger Steven E. , Der Sandy , Zhang Zhu-xu , Zhang Meixia , Kelvin David J. , Sarwal Minnie M. , Zhang Li 
Published: April 2014

AbstractRecent studies have demonstrated that both mouse and human αβTCR+CD3+NK1.1−CD4−CD8− double-negative regulatory T (DN Treg) cells can suppress Ag-specific immune responses mediated by CD8+ and CD4+ T cells. To identify molecules involved in DN Treg cell function, we generated a panel of murine DN Treg clones, which specifically kill activated syngeneic CD8+ T cells. Through serial cultivation of DN Treg clones, mutant clones arose that lost regulatory capacity in vitro and in vivo. Although all allogeneic cardiac grafts in animals preinfused with tolerant CD4/CD8 negative 12 DN Treg clones survived over 100 days, allograft survival is unchanged following infusion of mutant clones (19.5 ± 11.1 days) compared with untreated controls (22.8 ± 10.5 days; p &lt; 0.001). Global gene expression differences between functional DN Treg cells and nonfunctional mutants were compared. We found 1099 differentially expressed genes (q &lt; 0.025%), suggesting increased cell proliferation and survival, immune regulation, and chemotaxis, together with decreased expression of genes for Ag presentation, apoptosis, and protein phosphatases involved in signal transduction. Expression of 33 overexpressed and 24 underexpressed genes were confirmed using quantitative real-time PCR. Protein expression of several genes, including FcεRIγ subunit and CXCR5, which are &gt;50-fold higher, was also confirmed using FACS. These findings shed light on the mechanisms by which DN Treg cells down-regulate immune responses and prolong cardiac allograft survival.
Role for Glycogen Synthase Kinase-3 in NK Cell Cytotoxicity and X-Linked Lymphoproliferative Disease
Authors: Aoukaty Ala , Tan Rusung 
Published: April 2014

AbstractNK cells from individuals with X-linked lymphoproliferative (XLP) disease exhibit functional defects when stimulated through the NK receptor, 2B4 (CD244). These defects are likely a consequence of aberrant intracellular signaling initiated by mutations of the adaptor molecule SLAM-associated protein. In this report, we show that NK cells from individuals with XLP but not healthy individuals fail to phosphorylate and thereby inactivate glycogen synthase kinase-3 (GSK-3) following 2B4 stimulation. Lack of GSK-3 phosphorylation prevented the accumulation of the transcriptional coactivator β-catenin in the cytoplasm and its subsequent translocation to the nucleus. Potential signaling pathways leading from 2B4 stimulation to GSK-3 phosphorylation were also investigated. Ligation of 2B4 resulted in the phosphorylation of the guanine nucleotide exchange factor, Vav-1, and subsequent activation of the GTP-binding protein Rac-1 (but not Ras) and the serine-threonine kinase Raf-1 in healthy but not XLP-derived NK cells. In addition, the activity of MEK-2 (but not MEK-1) was up-regulated, and Erk1/2 was phosphorylated in normal NK cells but not those from an individual with XLP suggesting that these proteins relay SLAM-associated protein-dependent signals from 2B4. Finally, inactivation of GSK-3 using a specific inhibitor of GSK-3β increased the cytotoxicity and cytokine secretion of both healthy and XLP NK cells. These data indicate that the signaling of 2B4 in NK cells is mediated by GSK-3 and β-catenin, possibly through a signal transduction pathway that involves Vav-1, Rac-1, Raf-1, MEK-2, and Erk1/2 and that this pathway is aberrant in individuals with XLP.
Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen
Authors: Phan Tri Giang , Gardam Sandra , Basten Antony , Brink Robert 
Published: April 2014

AbstractThe early responses of follicular (Fo) and marginal zone (MZ) B cells to T cell-dependent Ag were compared using anti-hen egg lysozyme (HEL+) B cells capable of class switch recombination and somatic hypermutation (SHM). Purified CD21/35intCD23high Fo and CD21/35highCD23low MZ splenic B cells from SWHEL Ig-transgenic mice were transferred into wild-type recipients and challenged with HEL-sheep RBC. Responding HEL+ B cells from both populations switched efficiently to IgG1, generated syndecan-1+ Ab-secreting cells, and exhibited equivalent rates of proliferation. However, the expansion of HEL+ MZ B cells lagged significantly behind that of HEL+ Fo B cells due to less efficient homing to the outer periarteriolar lymphatic sheath and reduced recruitment into the proliferative response. Despite the equivalent rates of class switch recombination, the onset of SHM was delayed in the MZ subset, indicating that these two activation-induced cytidine deaminase-dependent events are uncoupled in the early response of MZ B cells. Migration of HEL+ B cells into germinal centers coincided with the onset of SHM, occurring more rapidly with Fo vs MZ responders. These results are consistent with the concept that Fo and MZ B cells have evolved to specialize in T cell-dependent and T-independent responses respectively.
NK Cells Inhibit T Cell Proliferation via p21-Mediated Cell Cycle Arrest
Authors: Trivedi Prachi P. , Roberts Paul C. , Wolf Norbert A. , Swanborg Robert H. 
Published: April 2014

AbstractNK cells have been shown to influence immune responses via direct interaction with cells of the adaptive immune system, such as dendritic cells, B cells, and T cells. A role for NK cells in down-regulation of T cell responses has been implicated in several studies; however, the underlying mechanism of this suppression has remained elusive. In this study we show that dark Agouti rat NK cells inhibit syngeneic T cell proliferation via up-regulation of the cell cycle inhibitor, p21, resulting in a G0/G1 stage cell cycle arrest. The inhibition is cell-cell contact dependent, reversible, and Ag nonspecific. Interestingly, NK cells do not inhibit IL-2 secretion or IL-2R up-regulation and do not induce T cell death. Thus, our results show that NK cells do not affect early T cell activation events, but specifically inhibit T cell proliferation by direct interaction with T cells. Our findings suggest that NK cells may play an important role in maintaining immune homeostasis by directly regulating clonal expansion of activated T cells. This novel mechanism of T cell regulation by NK cells provides insight into NK cell-mediated regulation of adaptive immunity and provides a mechanistic link between NK cell function and suppression of T cell responses.
HIV Type 1 Can Act as an APC upon Acquisition from the Host Cell of Peptide-Loaded HLA-DR and CD86 Molecules
Authors: Roy Jocelyn , Martin Geneviève , Giguère Jean-François , Bélanger Dave , Pétrin Myriam , Tremblay Michel J. 
Published: April 2014

Abstract
It is well documented that a wide range of host-derived cell surface constituents is inserted within HIV type 1 (HIV-1) and located on the exterior of the virion. Although no virus-associated protein of host origin has been shown to be absolutely required for virus replication, studies have revealed that many of these proteins are functional and can affect several steps of the virus life cycle. In this study, we found that HIV-1 acquires peptide-loaded class II MHC (MHC-II) and the costimulatory CD86 molecules from the host cell. Moreover, we present evidence that virions bearing such peptide-loaded MHC-II and CD86 proteins can lead to activation of the transcription factors NF-κB and NF-AT in an Ag-specific human T cell line. A linear correlation was found between activation of NF-κB and the amount of peptide-loaded MHC-II molecules inserted within HIV-1. Finally, transcription of unintegrated and integrated HIV-1 DNA was promoted upon exposure of peptide-specific human T cells to viruses bearing both peptide-loaded MHC-II and CD86 proteins. These data suggest that HIV-1 can operate as an APC depending on the nature of virus-anchored host cell membrane components. It can be proposed that HIV-1 can manipulate one of its primary targets through the process of incorporation of host-derived proteins.
The Enlarged Population of Marginal Zone/CD1dhigh B Lymphocytes in Nonobese Diabetic Mice Maps to Diabetes Susceptibility RegionIdd11
Authors: Rolf Julia , Motta Vinicius , Duarte Nadia , Lundholm Marie , Berntman Emma , Bergman Marie-Louise , Sorokin Lydia , Cardell Susanna L. , Holmberg Dan 
Published: April 2014

AbstractThe NOD mouse is an important experimental model for human type 1 diabetes. T cells are central to NOD pathogenesis, and their function in the autoimmune process of diabetes has been well studied. In contrast, although recognized as important players in disease induction, the role of B cells is not clearly understood. In this study we characterize different subpopulations of B cells and demonstrate that marginal zone (MZ) B cells are expanded 2- to 3-fold in NOD mice compared with nondiabetic C57BL/6 (B6) mice. The NOD MZ B cells displayed a normal surface marker profile and localized to the MZ region in the NOD spleen. Moreover, the MZ B cell population developed early during the ontogeny of NOD mice. By 3 wk of age, around the time when autoreactive T cells are first activated, a significant MZ B cell population of adult phenotype was found in NOD, but not B6, mice. Using an F2(B6 × NOD) cross in a genome-wide scan, we map the control of this trait to a region on chromosome 4 (logarithm of odds score, 4.4) which includes the Idd11 and Idd9 diabetes susceptibility loci, supporting the hypothesis that this B cell trait is related to the development of diabetes in the NOD mouse.