bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses
Authors: Kanaoka Yoshihide , Boyce Joshua A. 
Published: April 2014

Abstract
The cysteinyl leukotrienes (cys-LTs) are a family of potent bioactive lipids that act through two structurally divergent G protein-coupled receptors, termed the CysLT1 and CysLT2 receptors. The cloning and characterization of these two receptors has not only reconciled findings of previous pharmacologic profiling studies of contractile tissues, but also has uncovered their expression on a wide array of circulating and tissue-dwelling leukocytes. With the development of receptor-selective reagents, as well as mice lacking critical biosynthetic enzymes, transporter proteins, and the CysLT1 receptor, diverse functions of cys-LTs and their receptors in immune and inflammatory responses have been identified. We review cys-LT biosynthesis; the molecular biology and distribution of the CysLT1 and CysLT2 receptors; the functions of cys-LTs and their receptors in the recruitment and activation of effector leukocytes and induction of adaptive immunity; and the development of fibrosis and airway remodeling in animal models of lung injury and allergic inflammation.
Regulation of IFN Regulatory Factor-7 and IFN-α Production by Enveloped Virus and Lipopolysaccharide in Human Plasmacytoid Dendritic Cells
Authors: Dai Jihong , Megjugorac Nicholas J. , Amrute Sheela B. , Fitzgerald-Bocarsly Patricia 
Published: April 2014

Abstract
Human plasmacytoid dendritic cells (PDC) are a major source of IFN-α upon exposure to enveloped viruses and TLR-7 and TLR-9 ligands. Although IFN regulatory factor-7 (IRF-7) is known to play an essential role in virus-activated transcription of IFN-α genes, the molecular mechanisms of IFN-α production in human PDC remain poorly understood. We and others have recently reported high constitutive levels of IRF-7 expression in PDC as compared with other PBMC. In this study, we demonstrate that both LPS and HSV up-regulate the expression of IRF-7 in PDC, and that this enhancement of IRF-7 is dependent on NF-κB activation. The NF-κB inhibitors MG132 and pyrrolidinedithiocarbamate efficiently inhibited the induction of IRF-7 by HSV or LPS, and also down-regulated the constitutive expression of IRF-7 in PDC and blocked the HSV-induced production of IFN-α. In addition, we found that nuclear translocation of IRF-7 occurred rapidly in response to HSV stimulation, but not in response to LPS, which is consistent with the stimulation of IFN-α production by virus and not by LPS. Although LPS by itself was not able to induce IFN-α production, it led to rapid up-regulation of TLR-4 on PDC and increased the magnitude and accelerated the kinetics of HSV-induced IFN-α production in PDC, providing a mechanism that might be operative in a scenario of mixed infection. In contrast to the current concept of IFN-α regulation established in cell lines, this study strongly supports the immediate availability of high constitutive levels of IRF-7 expression in PDC, and suggests an activation required for IRF-7 that contributes to IFN-α production in virus-stimulated PDC.
Ectopic Expression of HLA-DO in Mouse Dendritic Cells Diminishes MHC Class II Antigen Presentation
Authors: Fallas Jennifer L. , Tobin Helen M. , Lou Olivia , Guo Donglin , Sant’Angelo Derek B. , Denzin Lisa K. 
Published: April 2014

Abstract
The MHC class II-like molecule HLA-DM (DM) (H-2M in mice) catalyzes the exchange of CLIP for antigenic peptides in the endosomes of APCs. HLA-DO (DO) (H-2O in mice) is another class II-like molecule that is expressed in B cells, but not in other APCs. Studies have shown that DO impairs or modifies the peptide exchange activity of DM. To further evaluate the role of DO in Ag processing and presentation, we generated transgenic mice that expressed the human HLA-DOA and HLA-DOB genes under the control of a dendritic cell (DC)-specific promoter. Our analyses of DCs from these mice showed that as DO levels increased, cell surface levels of Ab-CLIP also increased while class II-peptide levels decreased. The presentation of some, but not all, exogenous Ags to T cells or T hybridomas was significantly inhibited by DO. Surprisingly, H-2M accumulated in DO-expressing DCs and B cells, suggesting that H-2O/DO prolongs the half-life of H-2M. Overall, our studies showed that DO expression impaired H-2M function, resulting in Ag-specific down-modulation of class II Ag processing and presentation.
Ligand Binding to Inhibitory Killer Cell Ig-Like Receptors Induce Colocalization with Src Homology Domain 2-Containing Protein Tyrosine Phosphatase 1 and Interruption of Ongoing Activation Signals
Authors: Vyas Yatin M. , Maniar Hina , Lyddane Clay E. , Sadelain Michel , Dupont Bo 
Published: April 2014

Abstract
Interaction of NK cells with target cells leads to formation of an immunological synapse (IS) at the contact site. NK cells form two distinctly different IS, the inhibitory NK cell IS (NKIS) and the cytolytic NKIS. Cognate ligand binding is sufficient to induce clustering of inhibitory killer cell Ig-like receptors (KIR) and phosphorylation of both the receptor and the phosphatase Src homology domain 2-containing protein tyrosine phosphatase 1 (SHP-1). Recruitment and activation of SHP-1 by a signaling competent inhibitory receptor are essential early events for NK cell inhibition. We have in the present study used three-dimensional immunofluorescence microscopy to analyze distribution of inhibitory KIR, SHP-1, LFA-1, and lipid rafts within the NKIS during cytolytic and noncytolytic interactions. NK clones retrovirally transduced with the inhibitory KIR2DL3 gene fused to GFP demonstrate colocalization of KIR2DL3 with SHP-1 in the center of early inhibitory NKIS. Ligand binding translocates the receptor to the center of the IS where activation signals are accumulating and provides a docking site for SHP-1. SHP-1 and rafts cluster in the center of early inhibitory NKIS and late cytolytic NKIS, and whereas rafts continue to increase in size in cytolytic conjugates, they are rapidly dissolved in inhibitory conjugates. Furthermore, rafts are essential only for cytolytic, not for inhibitory, outcome. These results indicate that the outcome of NK cell-target cell interactions is dictated by early quantitative differences in cumulative activating and inhibitory signals.
IκB Kinase 2 Deficiency in T Cells Leads to Defects in Priming, B Cell Help, Germinal Center Reactions, and Homeostatic Expansion
Authors: Schmidt-Supprian Marc , Tian Jane , Ji Hongbin , Terhorst Cox , Bhan Atul K. , Grant Ethan P. , Pasparakis Manolis , Casola Stefano , Coyle Anthony J. , Rajewsky Klaus 
Published: April 2014

Abstract
Signal transduction from proinflammatory stimuli leading to NF-κB-dependent gene expression is mediated by the IκB kinase 2 (IKK2/IKKβ). Therefore, IKK2 has become an important drug target for treatment of inflammatory conditions. T cells, whose activation depends to a large extent on the activity of NF-κB transcription factors, play important roles in inflammation and autoimmunity. Ablation of IKK2 specifically in T cells in CD4cre/Ikk2FL mice allows their survival and activation by polyclonal stimuli in vitro, suggesting that IKK2 is dispensable for T cell activation. We report in this study that IKK2-deficient T cells expand efficiently in response to superantigen administration in vivo, but are completely deficient in recall responses, most likely due to inefficient priming. IKK2-deficient T cells provide suboptimal B cell help and fail to support germinal center reactions. Finally, IKK2 is essential for homeostatic expansion of naive T cells, reflected by the inability of IKK2-deficient T cells to induce colitis in lymphopenic hosts.
Critical Roles of CXC Chemokine Ligand 16/Scavenger Receptor that Binds Phosphatidylserine and Oxidized Lipoprotein in the Pathogenesis of Both Acute and Adoptive Transfer Experimental Autoimmune Encephalomyelitis
Authors: Fukumoto Noriko , Shimaoka Takeshi , Fujimura Harutoshi , Sakoda Saburo , Tanaka Makoto , Kita Toru , Yonehara Shin 
Published: April 2014

Abstract
The scavenger receptor that binds phosphatidylserine and oxidized lipoprotein (SR-PSOX)/CXCL16 is a chemokine expressed on macrophages and dendritic cells, while its receptor expresses on T and NK T cells. We investigated the role of SR-PSOX/CXCL16 on acute and adoptive experimental autoimmune encephalomyelitis (EAE), which is Th1-polarized T cell-mediated autoimmune disease of the CNS. Administration of mAb against SR-PSOX/CXCL16 around the primary immunization decreased disease incidence of acute EAE with associated reduced infiltration of mononuclear cells into the CNS. Its administration was also shown to inhibit elevation of serum IFN-γ level at primary immune response, as well as subsequent generation of Ag-specific T cells. In adoptive transfer EAE, treatment of recipient mice with anti-SR-PSOX/CXCL16 mAb also induced not only decreased clinical disease incidence, but also diminished traffic of mononuclear cells into the CNS. In addition, histopathological analyses showed that clinical development of EAE correlates well with expression of SR-PSOX/CXCL16 in the CNS. All the results show that SR-PSOX/CXCL16 plays important roles in EAE by supporting generation of Ag-specific T cells, as well as recruitment of inflammatory mononuclear cells into the CNS.
In Vivo Generated Th1 Cells Can Migrate to B Cell Follicles to Support B Cell Responses
Authors: Smith Karen M. , Brewer James M. , Rush Catherine M. , Riley Jillian , Garside Paul 
Published: April 2014

Abstract
The description of Th1 and Th2 T cell subsets rationalized the inverse correlation between humoral and cell-mediated immunity. Although Th1 cells were described to support cell-mediated immune responses, their role in supporting certain B cell responses was firmly established. However, there is now a prevailing preconception that provision of B cell help is entirely the domain of Th2 cells and that Th1 cells lack this capacity. Previous studies demonstrated that immunization using aluminum hydroxide adjuvants induces Ag-specific Th2 responses, whereas incorporation of IL-12 with aluminum hydroxide produces a Th1 inducing adjuvant. By immunizing TCR transgenic recipient mice in this fashion, we have generated Ag-specific, traceable Th1 and Th2 cells in vivo and assessed their follicular migration and ability to support B cell responses. In this study we have shown that in vivo polarized Th1 and Th2 cells clonally expand to similar levels and migrate into B cell follicles in which they support B cell responses to a similar degree. Critically, we present direct evidence that in vivo polarized, IFN-γ secreting Th1 cells migrate into B cell follicles where they can interact with Ag-specific B cells.
Differential Roles for Wiskott-Aldrich Syndrome Protein in Immune Synapse Formation and IL-2 Production
Authors: Cannon Judy L. , Burkhardt Janis K. 
Published: April 2014

Abstract
Wiskott-Aldrich syndrome protein (WASP)-deficient T cells exhibit defects in IL-2 production that are widely believed to stem from primary defects in actin remodeling and immune synapse formation. Surprisingly, however, we find that WASP-deficient T cells responding to Ag-specific APCs polymerize actin and organize talin and PKCθ normally, forming an immune synapse that is stable for at least 3 h. At low doses of peptide, WASP-deficient T cells show less efficient talin and PKCθ polarization. Thus, although WASP may facilitate immune synapse formation at low peptide concentrations, WASP is not required for this process. Defects in IL-2 production are observed even under conditions in which immune synapse formation proceeds normally, suggesting that the role of WASP in regulating IL-2 production is independent of its role in immune synapse formation.
Cross-Reactive TCR Responses to Self Antigens Presented by Different MHC Class II Molecules
Authors: Mycko Marcin P. , Waldner Hanspeter , Anderson David E. , Bourcier Katarzyna D. , Wucherpfennig Kai W. , Kuchroo Vijay K. , Hafler David A. 
Published: April 2014

Abstract
Autoreactive T cells represent a natural repertoire of T cells in both diseased patients and healthy individuals. The mechanisms regulating the function of these autoreactive T cells are still unknown. Ob1A12 is a myelin basic protein (MBP)-reactive Th cell clone derived from a patient with relapsing-remitting multiple sclerosis. Mice transgenic for this human TCR and DRA and DRB1*1501 chains develop spontaneous experimental autoimmune encephalomyelitis. The reactivity of Ob1A12 is reported to be restricted to recognition of MBP peptide 85–99 in the context of DRB1*1501. DRA/DRB1*1501 and the patient’s other restriction element, DRA/DRB1*0401, differ significantly in their amino acid sequences. In this study we describe an altered peptide ligand derived from MBP85–99 with a single amino acid substitution at position 88 (Val to Lys; 88V→K), that could stimulate the Ob1A12.TCR in the context of both DRA/DRB1*1501 and DRA/DRB1*0401. Analysis of a panel of transfected T cell hybridomas expressing Ob1A12.TCR and CD4 indicated that Ob1A12.TCR cross-reactivity in the context of DRA/DRB1*0401 is critically dependent on the presence of the CD4 coreceptor. Furthermore, we found that activation of Ob1A12.TCR with MBP altered peptide ligand 85–99 88V→K presented by DRB1*1501 or DRB1*0401 resulted in significant differences in TCRζ phosphorylation. Our data indicate that injection of altered peptide ligand into patients heterozygous for MHC class II molecules may result in unexpected cross-reactivities, leading to activation of autoreactive T cells.
HLA-B27 Heavy Chain Homodimers Are Expressed in HLA-B27 Transgenic Rodent Models of Spondyloarthritis and Are Ligands for Paired Ig-Like Receptors
Authors: Kollnberger Simon , Bird Lucy A. , Roddis Matthew , Hacquard-Bouder Cecile , Kubagawa Hiromi , Bodmer Helen C. , Breban Maxime , McMichael Andrew J. , Bowness Paul 
Published: April 2014

AbstractHLA-B27 transgenic rats and strains of HLA-B27-transgenic β2-microglobulin (β2m)-deficient mice develop a multisystem inflammatory disease affecting the joints, skin, and bowel with strong similarity to human spondyloarthritis. We show that HLA-B27 transgenic mice and rats express HC10-reactive, β2m-free HLA-B27 homodimers (B272) and multimers, both intracellularly and at the cell surface of leukocytes, including rat dendritic cells. Fluorescent-labeled tetrameric complexes of HLA-B27 homodimers (B272 tetramers) bind to populations of lymphocytes, monocytes, and dendritic cells. The murine (and probably rat) paired Ig-like receptors (PIRs) are ligands for B272. Thus, B272 tetramers stain RBL cells transfected with murine activating PIR-A4 and inhibitory PIR-B receptors. Murine PIR-A and -B can be immunoprecipitated from the RAW264.7 macrophage cell line, and murine PIR-A can be immunoprecipitated from the J774.A1 line using B272. B272 tetramer staining corresponds to the distribution of PIR expression on lymphoid and myeloid cells and on murine macrophage cell lines. B272 can induce TNF-α release from the J774.A1 macrophage cell line. The binding of B272 to PIR is inhibited by HC10, an mAb that ameliorates arthritis in HLA-B27+ β2m−/− mice. The expression and PIR recognition of B272 could explain the pathogenesis of rodent spondyloarthritis.
The Gads (GrpL) Adaptor Protein Regulates T Cell Homeostasis
Authors: Yankee Thomas M. , Yun Theodore J. , Draves Kevin E. , Ganesh Kolumam , Bevan Michael J. , Murali-Krishna Kaja , Clark Edward A. 
Published: April 2014

Abstract
Little is known about the role of the Gads (GrpL) adaptor protein in mature T cell populations. In this study we show that the effects of Gads deficiency on murine CD4+ and CD8+ T cells are markedly different. Gads−/− CD4+ T cells were markedly deficient in the spleen and had an activated phenotype and a rapid turnover rate. When transferred into a wild-type host, Gads−/− CD4+ T cells continued to proliferate at a higher rate than wild-type CD4+ T cells, demonstrating a defect in homeostatic proliferation. Gads−/− CD8+ T cells had a memory-like phenotype, produced IFN-γ in response to ex vivo stimulation, and underwent normal homeostatic proliferation in wild-type hosts. Gads−/− T cells had defective TCR-mediated calcium responses, but had normal activation of ERK. Gads−/− CD4+ T cells, but not CD8+ T cells, had a severe block of TCR-mediated proliferation and a high rate of spontaneous cell death and were highly susceptible to CD95-induced apoptosis. This suggests that the rapid turnover of Gads−/− CD4+ T cells is due to a defect in cell survival. The intracellular signaling pathways that regulate homeostasis in CD4+ and CD8+ T cells are clearly different, and the Gads adaptor protein is critical for homeostasis of CD4+ T cells.
MUC1/sec-Expressing Tumors Are Rejected In Vivo by a T Cell-Dependent Mechanism and Secrete High Levels of CCL2
Authors: Grosso Joseph F. , Herbert Lynn M. , Owen Jennifer L. , Lopez Diana M. 
Published: April 2014

AbstractMUC1/sec is a secreted form of the glycoprotein mucin 1 (MUC1). To characterize the role that MUC1 and MUC1/sec have in tumor progression, these genes were expressed in DA-3 mammary tumor cells. DA-3 cells and DA-3 cells expressing the transmembrane MUC1 gene (DA-3/TM) grow with similar kinetics in BALB/c mice. Surprisingly, DA-3 cells expressing and secreting MUC1/sec (DA-3/sec) fail to form tumors in vivo. The mechanism of rejection was evaluated using mice deficient in constituents of the immune system. All mice lacking IFN-γ, NK, NKT, or macrophages formed DA-3/sec tumors that regressed shortly after implantation. However, progressively growing DA-3/sec tumors developed in mice devoid of T lymphocytes. The importance of T lymphocytes in the rejection of DA-3/sec tumors was further supported by detection of DA-3-specific CTL in mice challenged with the DA-3/sec tumor. Recruitment of appropriate APC and effector cells is an important first step in the tumor clearance. Indeed, DA-3/sec cells or cell supernatants recruited 3–4 times as many macrophages as DA-3/TM cells in vivo, suggesting that a secreted chemotactic product is produced from DA-3/sec cells. RNA and protein analysis of DA-3/sec cells revealed that several genes are up-regulated by MUC1/sec expression, including MCP-1 (CCL-2). These results suggest DA-3/sec cells are capable of recruiting immune cells, and that rejection of DA-3/sec tumors, although aided by cells of the innate immune response, is ultimately due to T cell-mediated events.
Antigen Presentation to Celiac Lesion-Derived T Cells of a 33-Mer Gliadin Peptide Naturally Formed by Gastrointestinal Digestion
Authors: Qiao Shuo-Wang , Bergseng Elin , Molberg Øyvind , Xia Jiang , Fleckenstein Burkhard , Khosla Chaitan , Sollid Ludvig M. 
Published: April 2014

Abstract
Celiac disease is an HLA-DQ2-associated disorder characterized by intestinal T cell responses to ingested wheat gluten proteins. A peptide fragment of 33 residues (α2-gliadin 56–88) produced by normal gastrointestinal proteolysis contains six partly overlapping copies of three T cell epitopes and is a remarkably potent T cell stimulator after deamidation by tissue transglutaminase (TG2). This 33-mer is rich in proline residues and adopts the type II polyproline helical conformation in solution. In this study we report that after deamidation, the 33-mer bound with higher affinity to DQ2 compared with other monovalent peptides harboring gliadin epitopes. We found that the TG2-treated 33-mer was presented equally effectively by live and glutaraldehyde-fixed, EBV-transformed B cells. The TG2-treated 33-mer was also effectively presented by glutaraldehyde-fixed dendritic cells, albeit live dendritic cells were the most effective APCs. A strikingly increased T cell stimulatory potency of the 33-mer compared with a 12-mer peptide was also seen with fixed APCs. The 33-mer showed binding maximum to DQ2 at pH 6.3, higher than maxima found for other high affinity DQ2 binders. The 33-mer is thus a potent T cell stimulator that does not require further processing within APC for T cell presentation and that binds to DQ2 with a pH profile that promotes extracellular binding.
α-Fetoprotein Impairs APC Function and Induces Their Apoptosis
Authors: Um Soon Ho , Mulhall Catherine , Alisa Akeel , Ives Annette Robyn , Karani John , Williams Roger , Bertoletti Antonio , Behboudi Shahriar 
Published: April 2014

Abstract
α-Fetoprotein (AFP) is a tumor-associated Ag, and its serum level is elevated in patients with hepatocellular carcinoma (HCC). In vitro, AFP induces functional impairment of dendritic cells (DCs). This was demonstrated by the down-regulation of CD40 and CD86 molecules and the impairment of allostimulatory function. Also, AFP was found to induce significant apoptosis of DCs, and AFP-treated DCs produced low levels of IL-12 and TNF-α, a cytokine pattern that could hamper an efficient antitumor immune response. Ex vivo, APCs of patients with HCC and high levels of AFP produced lower levels of TNF-α than that of healthy individuals. In conclusion, these results illustrate that AFP induces dysfunction and apoptosis of APCs, thereby offering a mechanism by which HCC escapes immunological control.
Inactivation of c-Cbl or Cbl-b Differentially Affects Signaling from the High Affinity IgE Receptor
Authors: Zhang Juan , Chiang Yungping J. , Hodes Richard J. , Siraganian Reuben P. 
Published: April 2014

Abstract
The Cbl family of proteins negatively regulate signaling from tyrosine kinase-coupled receptors. Among the three members of this family, only c-Cbl and Cbl-b are expressed in hemopoietic cells. To examine the role of c-Cbl and Cbl-b in FcεRI signaling, mast cell cultures from wild-type, c-Cbl−/−, and Cbl-b−/− mice were generated. Cell growth rates and cell surface expression of FcεRI were similar in the different cell populations. Compared with control cells, Cbl-b inactivation resulted in increases in FcεRI-induced Ca2+ response and histamine release. FcεRI-induced tyrosine phosphorylation of total cellular proteins, Syk, and phospholipase C-γ was also enhanced by Cbl-b deficiency, whereas receptor-initiated phosphorylation of Vav, JNK, and p38 kinases was not changed in these cells. In contrast to Cbl-b, c-Cbl deficiency had no detectable effect on FcεRI-induced histamine release or on the phosphorylation of total cellular proteins or Syk. The absence of c-Cbl increased the phosphorylation of ERK after receptor stimulation, but resulted in slightly reduced p38 phosphorylation and Ca2+ response. These results suggest that Cbl-b and c-Cbl have divergent effects on FcεRI signal transduction and that Cbl-b, but not c-Cbl, functions as a negative regulator of FcεRI-induced degranulation.
Characterization of Distinct Conventional and Plasmacytoid Dendritic Cell-Committed Precursors in Murine Bone Marrow
Authors: Diao Jun , Winter Erin , Chen Wenhao , Cantin Claude , Cattral Mark S. 
Published: April 2014

Abstract
The developmental pathways and differentiation relationship of dendritic cell (DC) subsets remain unclear. We report that murine CD11c+MHC II− bone marrow cells, which are immediate DC precursors of CD8α+, CD8α−, and B220+ DC in vivo, can be separated into B220+ and B220− DC precursor subpopulations. Purified B220− DC precursors expand, and generate exclusively mature CD11c+CD11b+B220− DC in vitro and after adoptive transfer. B220+ DC precursors, which resemble plasmacytoid pre-DC, have a lower proliferative potential than B220− DC precursors and generate both CD11b− B220+ and CD11b+B220− DC populations. Both DC precursor populations can give rise to CD8α+ and CD8α− DC subtypes. Our findings indicate that CD11c+MHC II−B220+ and CD11c+MHC II−B220− bone marrow cells are distinct DC lineage-restricted precursors.