bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Magnitude of TCR Engagement Is a Critical Predictor of T Cell Anergy or Activation
Authors: Mirshahidi Saied , Ferris Laura C. Korb , Sadegh-Nasseri Scheherazade 
Published: April 2014

Abstract
Fast dissociation rate of peptide-MHC complexes from TCR has commonly been accepted to cause T cell anergy. In this study, we present evidence that peptides that form transient complexes with HLA-DR1 induce anergy in T cell clones in vitro and specific memory T cells in vivo. We demonstrate that similar to the low densities of long-lived agonist peptide-MHC, short-lived peptide-MHC ligands induce anergy by engagement of ∼1000 TCR and activation of a similar pattern of intracellular signaling events. These data strongly suggest that short-lived peptides induce anergy by presentation of low densities of peptide-MHC complexes. Moreover, they suggest that the traditional antagonist peptides might also trigger anergy by a similar molecular mechanism. The use of short-lived peptides to induce T cells anergy is a potential strategy for the prevention or treatment of autoimmune diseases.
Modular Nature of Blimp-1 in the Regulation of Gene Expression during B Cell Maturation
Authors: Sciammas Roger , Davis Mark M. 
Published: April 2014

Abstract
The transcription factor Blimp-1 induces the maturation of B cells into Ab-secreting plasma cells. DNA microarrays were used to analyze the transcription profiles of both Blimp-1-transduced murine B cell lines and the inducible B cell line BCL1. Hundreds of genes were differentially regulated, showing how Blimp-1 both restricts affinity maturation and promotes Ab secretion, homeostasis, migration, and differentiation. Strikingly, when different modes of plasma cell induction are used, very different genetic programs are used, suggesting that the transition from a B cell to plasma cell can occur in multiple ways, perhaps accounting for the different types of Ab-secreting cells observed in vivo. Furthermore, mutagenesis of Blimp-1 reveals multiple effector domains, which regulate distinct genes. This indicates that Blimp-1 subdivides the maturation program into select and tunable pathways.
Enteric Nematodes Induce Stereotypic STAT6-Dependent Alterations in Intestinal Epithelial Cell Function
Authors: Madden Kathleen B. , Yeung Karla Au , Zhao Aiping , Gause William C. , Finkelman Fred D. , Katona Ildy M. , Urban Joseph F. , Shea-Donohue Terez 
Published: April 2014

Abstract
Infection with gastrointestinal nematodes exerts profound effects on both the immune and physiological responses of the host. We showed previously that the Th2 cytokines, IL-4 and IL-13, induce STAT6-dependent changes in intestinal epithelial cell permeability, absorption, and secretion that are similar to those observed in a secondary infection with Heligmosomoides polygyrus. In the current study we investigated whether nematode-induced effects on epithelial cell function were 1) generic, 2) dependent upon STAT6, and 3) attributable to direct effects on the epithelial cells themselves or mediated by effects on enteric nerves. Our results demonstrate that infection of BALB/c mice with three different gastrointestinal nematodes (H. polygyrus, Nippostrongylus brasiliensis, and Trichinella spiralis) alters intestinal epithelial cell function by decreasing resistance, glucose absorption, and secretory responses to 5-hydroxytryptamine and acetylcholine, two critical mediators in the submucosal reflex pathway. These modified responses are dependent on STAT6 and are the result of both direct effects and indirect effects mediated through enteric nerves.
Suppressor of Cytokine Signaling-1 Overexpression Protects Pancreatic β Cells from CD8+ T Cell-Mediated Autoimmune Destruction
Authors: Chong Mark M. W. , Chen Ye , Darwiche Rima , Dudek Nadine L. , Irawaty Windy , Santamaria Pere , Allison Janette , Kay Thomas W. H. , Thomas Helen E. 
Published: April 2014

Abstract
In type 1 diabetes, cytokine action on β cells potentially contributes to β cell destruction by direct cytotoxicity, inducing Fas expression, and up-regulating class I MHC and chemokine expression to increase immune recognition. To simultaneously block β cell responsiveness to multiple cytokines, we overexpressed suppressor of cytokine signaling-1 (SOCS-1). This completely prevented progression to diabetes in CD8+ TCR transgenic nonobese diabetic (NOD) 8.3 mice without affecting pancreas infiltration and partially prevented diabetes in nontransgenic NOD mice. SOCS-1 appeared to protect at least in part by inhibiting TNF- and IFN-γ-induced Fas expression on β cells. Fas expression was up-regulated on β cells in vivo in prediabetic NOD8.3 mice, and this was inhibited by SOCS-1. Additionally, IFN-γ-induced class I MHC up-regulation and TNF- and IFN-γ-induced IL-15 expression by β cells were inhibited by SOCS-1, which correlated with suppressed 8.3 T cell proliferation in vitro. Despite this, 8.3 T cell priming in vivo appeared unaffected. Therefore, blocking β cell responses to cytokines impairs recognition by CD8+ T cells and blocks multiple mechanisms of β cell destruction, but does not prevent T cell priming and recruitment to the islets. Our findings suggest that increasing SOCS-1 expression may be useful as a strategy to block CD8+ T cell-mediated type 1 diabetes as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.
Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Conformational Disease Z α1-Antitrypsin Deficiency
Authors: Lawless Matthew W. , Greene Catherine M. , Mulgrew Alan , Taggart Clifford C. , O’Neill Shane J. , McElvaney Noel G. 
Published: April 2014

Abstract
Conformational diseases are a class of disorders associated with aberrant protein accumulation in tissues and cellular compartments. Z α1-antitrypsin (A1AT) deficiency is a genetic disease associated with accumulation of misfolded A1AT in the endoplasmic reticulum (ER) of hepatocytes. We sought to identify intracellular events involved in the molecular pathogenesis of Z A1AT-induced liver disease using an in vitro model system of Z A1AT ER accumulation. We investigated ER stress signals induced by Z A1AT and demonstrated that both the ER overload response and the unfolded protein response were activated by mutant Z A1AT, but not wild-type M A1AT. Interestingly, activation of the unfolded protein response pathway required an additional insult, whereas NF-κB activation, a hallmark of the ER overload response, was constitutive. These findings have important implications for the design of future therapeutics for Z A1AT liver disease and may also impact on drug design for other conformational diseases.
Circulating Immune Complexes Augment Severity of Antibody-Mediated Myasthenia Gravis in Hypogammaglobulinemic RIIIS/J Mice
Authors: Tüzün Erdem , Scott Benjamin G. , Yang Huan , Wu Bo , Goluszko Elzbieta , Guigneaux Michelle , Higgs Stephen , Christadoss Premkumar 
Published: April 2014

AbstractExperimental autoimmune myasthenia gravis (EAMG) is severe in RIIIS/J mice, despite a significant B cell immunodeficiency and a massive TCR Vβ gene deletion. Severity of EAMG in RIIIS/J mice is greater than MHC-identical (H-2r) B10.RIII mice, suggesting the influence of non-MHC genes as an EAMG-potentiating factor in this strain. To delineate the role of deleted TCR Vβ genes in RIIIS/J mice, we obtained (RIIIS/J × B10.RIII)F1 (Vβb/c) × RIIIS/J (Vβc) backcross mice using Mendelian genetic methods and immunized them with acetylcholine receptor. EAMG susceptibility was not elevated in mice with Vβc genotype having 70% Vβ gene deletion. Next, we performed microarray analysis on 12,488 spleen cDNAs obtained from spleens of naive RIIIS/J and B10.RIII mice. In RIIIS/J mice, 263 cDNAs were overexpressed and 303 cDNAs were underexpressed greater than 2-fold, compared with B10.RIII mice. TCR gene expression was augmented, whereas NK receptor, C1q, and C3 gene expressions were diminished in RIIIS/J mice. RIIIS/J mice also had increased lymph node T cell counts, elevated serum anti-AChR Ab levels, and serum C3 and C1q-conjugated circulating immune complex levels. A direct correlation between increased serum C1q-conjugated circulating immune complex levels and disease severity was observed in RIIIS/J mice.
Treatment with α-Galactosylceramide Attenuates the Development of Bleomycin-Induced Pulmonary Fibrosis
Authors: Kimura Toru , Ishii Yukio , Morishima Yuko , Shibuya Akira , Shibuya Kazuko , Taniguchi Masaru , Mochizuki Mie , Hegab Ahmed E. , Sakamoto Tohru , Nomura Akihiro , Sekizawa Kiyohisa 
Published: April 2014

Abstract
Pulmonary fibrosis is an end-stage disorder for which efficacious therapeutic options are not readily available. Although its pathogenesis is poorly understood, pulmonary fibrosis occurs as a result of various inflammations. NKT cells modulate inflammation because of their ability to produce large amounts of cytokines by stimulation with their glycolipid ligand. In the present study, we investigated the effects of α-galactosylceramide (α-GalCer), a selective NKT cell ligand, on the development of bleomycin-induced pulmonary fibrosis. Treatment of mice with α-GalCer prolonged their survival under bleomycin administration by attenuating the development of pulmonary fibrosis. The protective effects of α-GalCer were associated with an increase in the pulmonary level of IFN-γ and a decrease in the pulmonary level of fibrogenic cytokines such as TGF-β and connective tissue growth factor. The initial pulmonary inflammation caused by bleomycin was also attenuated by α-GalCer with the reduction of the macrophage inflammatory protein-2 level. The protective effects of α-GalCer were markedly reduced in mice lacking NKT cells or as a result of treatment with anti-IFN-γ Ab. These results suggest that α-GalCer suppresses bleomycin-induced acute pulmonary inflammation and thus attenuates the development of pulmonary fibrosis possibly by regulating several cytokine levels.
Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease
Authors: Lovett-Racke Amy E. , Hussain Rehana Z. , Northrop Sara , Choy Judy , Rocchini Anne , Matthes Lela , Chavis Janet A. , Diab Asim , Drew Paul D. , Racke Michael K. 
Published: April 2014

Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ ligands, which include the naturally occurring PG metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), as well as thiazolidinediones, have been shown to have anti-inflammatory activity. The PPARα agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia. In the present study, we demonstrate that these PPARα agonists can increase the production of the Th2 cytokine, IL-4, and suppress proliferation by TCR transgenic T cells specific for the myelin basic protein Ac1–11, as well as reduce NO production by microglia. Oral administration of gemfibrozil and fenofibrate inhibited clinical signs of experimental autoimmune encephalomyelitis. More importantly, gemfibrozil was shown to shift the cytokine secretion of human T cell lines by inhibiting IFN-γ and promoting IL-4 secretion. These results suggest that PPARα agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis.
Dysregulated FcεRI Signaling and Altered Fyn and SHIP Activities in Lyn-Deficient Mast Cells
Authors: Hernandez-Hansen Valerie , Smith Alexander J. , Surviladze Zurab , Chigaev Alexandre , Mazel Tomas , Kalesnikoff Janet , Lowell Clifford A. , Krystal Gerald , Sklar Larry A. , Wilson Bridget S. , Oliver Janet M. 
Published: April 2014

Abstract
Studies in B cells from Lyn-deficient mice have identified Lyn as both a kinetic accelerator and negative regulator of signaling through the BCR. The signaling properties of bone marrow-derived mast cells from Lyn−/− mice (Lyn−/− BMMCs) have also been explored, but their signaling phenotype remains controversial. We confirm that Lyn−/− BMMCs release more β-hexosaminidase than wild-type BMMCs following FcεRI cross-linking and show that multiple mast cell responses to FcεRI cross-linking (the phosphorylation of receptor subunits and other proteins, the activation of phospholipase Cγ isoforms, the mobilization of Ca2+, the synthesis of phosphatidylinositol 3,4,5-trisphosphate, the activation of the α4β1 integrin, VLA-4) are slow to initiate in Lyn−/− BMMCs, but persist far longer than in wild-type cells. Mechanistic studies revealed increased basal as well as stimulated phosphorylation of the Src kinase, Fyn, in Lyn−/− BMMCs. Conversely, there was very little basal or stimulated tyrosine phosphorylation or activity of the inositol phosphatase, SHIP, in Lyn−/− BMMCs. We speculate that Fyn may substitute (inefficiently) for Lyn in signal initiation in Lyn−/− BMMCs. The loss of SHIP phosphorylation and activity very likely contributes to the increased levels of phosphatidylinositol 3,4,5-trisphosphate and the excess FcεRI signaling in Lyn−/− BMMCs. The unexpected absence of the transient receptor potential channel, Trpc4, from Lyn−/− BMMCs may additionally contribute to their altered signaling properties.
Cooperative Prosurvival Activity by ERK and Akt in Human Alveolar Macrophages is Dependent on High Levels of Acid Ceramidase Activity
Authors: Monick Martha M. , Mallampalli Rama K. , Bradford Mary , McCoy Diann , Gross Thomas J. , Flaherty Dawn M. , Powers Linda S. , Cameron Kelli , Kelly Samuel , Merrill Alfred H. , Hunninghake Gary W. 
Published: April 2014

Abstract
Human alveolar macrophages are unique in that they have an extended life span in contrast to precursor monocytes. In evaluating the role of sphingolipids in alveolar macrophage survival, we found high levels of sphingosine, but not sphingosine-1-phosphate. Sphingosine is generated by the action of ceramidase(s) on ceramide, and alveolar macrophages have high constitutive levels of acid ceramidase mRNA, protein, and activity. The high levels of acid ceramidase were specific to alveolar macrophages, because there was little ceramidase protein or activity (or sphingosine) in monocytes from matching donors. In evaluating prolonged survival of alveolar macrophages, we observed a requirement for constitutive activity of ERK MAPK and the PI3K downstream effector Akt. Blocking acid ceramidase but not sphingosine kinase activity in alveolar macrophages led to decreased ERK and Akt activity and induction of cell death. These studies suggest an important role for sphingolipids in prolonging survival of human alveolar macrophages via distinct survival pathways.
Inducing Experimental Arthritis and Breaking Self-Tolerance to Joint-Specific Antigens with Trackable, Ovalbumin-Specific T Cells
Authors: Maffia Pasquale , Brewer James M. , Gracie J. Alastair , Ianaro Angela , Leung Bernard P. , Mitchell Paul J. , Smith Karen M. , McInnes Iain B. , Garside Paul 
Published: April 2014

Abstract
The importance of T cell Ag specificity and Th1 vs Th2 phenotype in synovial inflammation remains controversial. Using OVA-specific TCR transgenic T cells from DO11.10 mice, we demonstrate that mice receiving Th1, but not Th2, cells display a transient arthritis following immunization that is characterized by synovial hyperplasia, cellular infiltration, and cartilage erosion. OVA-specific T cells also accumulated in inflamed joints, suggesting that they could exert their inflammatory effect locally in the joint or in the draining lymph node. Importantly, this pathology was accompanied by a breakdown in self-tolerance, as evidenced by the induction of collagen-specific T and B cell responses. This model directly demonstrates a pivotal role for Th1 cells of an irrelevant specificity in the development of inflammatory arthritis. Furthermore, the ability to track these cells in vivo will make feasible studies revealing the dynamic role of T cells in arthritis.
Cutting Edge: Physiologic Attenuation of Proinflammatory Transcription by the Gs Protein-Coupled A2A Adenosine Receptor In Vivo
Authors: Lukashev Dmitriy , Ohta Akio , Apasov Sergey , Chen Jiang-Fan , Sitkovsky Michail 
Published: April 2014

Abstract
The A2A adenosine receptor plays a critical role in the physiologic immunosuppressive pathway that protects normal tissues from excessive collateral damage by overactive immune cells and their proinflammatory cytokines. In this study, we examine and clarify the mechanism of tissue protection by extracellular adenosine using A2AR-deficient mice and show that the A2AR inhibits TLR-induced transcription of proinflammatory cytokines in vivo. The observed increase in proinflammatory cytokines mRNA in A2AR-deficient mice was associated with enhanced activity of the NF-κB transcription factor. These observations provide the genetic in vivo evidence for attenuation of proinflammatory transcriptional activity of NF-κB by a “metabokine” adenosine and point to the need to re-evaluate the regulation of other transcription factors in hypoxic and adenosine-rich microenvironments of inflamed normal tissues and solid tumors.
Alteration of Cell Surface Sialylation Regulates Antigen-Induced Naive CD8+ T Cell Responses
Authors: Pappu Bhanu P. , Shrikant Protul A. 
Published: April 2014

AbstractThe strength of interactions with APC instructs naive T cells to undergo programmed expansion and differentiation, which is largely determined by the peptide affinity and dose as well as the duration of TCR ligation. Although, most ligands mediating these interactions are terminally sialylated, the impact of the T cell sialylation status on Ag-dependent response remains poorly understood. In this study, by monitoring TCR transgenic CD8+ T cells, OT-I, we show that biochemical desialylation of naive OT-I T cells increases their sensitivity for agonist as well as partial agonist peptides. Desialylation enhances early activation and shortens the duration of TCR stimulation required for proliferation and differentiation, without increasing apoptosis. Moreover, desialylation of naive OT-I T cells augments their response to tumor-presented Ag. These results provide direct evidence for a regulatory role for sialylation in Ag-dependent CD8+ T cell responses and offer a new approach to sensitize or dampen Ag-specific CD8+ T cell responses.
Sustained Early Growth Response Gene 3 Expression Inhibits the Survival of CD4/CD8 Double-Positive Thymocytes
Authors: Xi Hongkang , Kersh Gilbert J. 
Published: April 2014

Abstract
In the absence of selection, CD4+, CD8+ double-positive (DP) thymocytes will die after 3–4 days. The mechanism for regulating the life span of DP cells is unknown. Previously, we demonstrated that the zinc finger transcription factor, early growth response gene 3 (Egr3), promotes proliferation during the transition from double negative (DN) to DP. In this study we demonstrate a novel role for Egr3 in controlling DP thymocyte survival in mice. Constitutive transgenic expression of Egr3 in thymocytes increases apoptosis among DP cells and shortens their survival in vitro. In addition, DP cells in Egr3 transgenic mice have poor expression of TCRα, and based on the predominant usage of 3′ Vα and 5′ Jα gene segments, the low level of TCRα expression is a result of DP death soon after the initiation of TCRα rearrangements. Constitutive transgenic expression of Egr3 results in poor expression of Bcl-xL and the thymic isoform of retinoic acid receptor-related orphan receptor γ (RORγt) in DP thymocytes, two molecules that are required in DP cells for normal life span. Egr3 expression induced by pre-TCR signals in nontransgenic mice is transient and returns to background levels before RORγt or Bcl-xL is induced. The data support a model in which Egr3 must be transiently induced in response to pre-TCR signals, so that the expression of the prosurvival molecules, RORγt and Bcl-xL, can be elevated only after the proliferative signal provided by Egr3 has subsided.
Lipopolysaccharide-Induced Macrophage Inflammatory Response Is Regulated by SHIP
Authors: Fang Huiqing , Pengal Ruma A. , Cao Xianhua , Ganesan Latha P. , Wewers Mark D. , Marsh Clay B. , Tridandapani Susheela 
Published: April 2014

Abstract
LPS stimulates monocytes/macrophages through TLR4, resulting in the activation of a series of signaling events that potentiate the production of inflammatory mediators. Recent reports indicated that the inflammatory response to LPS is diminished by PI3K, through the activation of the serine/threonine kinase Akt. SHIP is an inositol phosphatase that can reverse the activation events initiated by PI3K, including the activation of Akt. However, it is not known whether SHIP is involved in TLR4 signaling. In this study, we demonstrate that LPS stimulation of Raw 264.7 mouse macrophage cells induces the association of SHIP with lipid rafts, along with IL-1R-associated kinase. In addition, SHIP is tyrosine phosphorylated upon LPS stimulation. Transient transfection experiments analyzing the function of SHIP indicated that overexpression of a wild-type SHIP, but not the SHIP Src homology 2 domain-lacking catalytic activity, up-regulates NF-κB-dependent gene transcription in response to LPS stimulation. These results suggest that SHIP positively regulates LPS-induced activation of Raw 264.7 cells. To test the validity of these observations in primary macrophages, LPS-induced events were compared in bone marrow macrophages derived from SHIP+/+ and SHIP−/− mice. Results indicated that LPS-induced MAPK phosphorylation is enhanced in SHIP+/+ cells, whereas Akt phosphorylation is enhanced in SHIP−/− cells compared with SHIP+/+ cells. Finally, LPS-induced TNF-α and IL-6 production was significantly lower in SHIP−/− bone marrow-derived macrophages. These results are the first to demonstrate a role for SHIP in TLR4 signaling, and propose that SHIP is a positive regulator of LPS-induced inflammation.
The Structure of H-2Kb and Kbm8 Complexed to a Herpes Simplex Virus Determinant: Evidence for a Conformational Switch That Governs T Cell Repertoire Selection and Viral Resistance
Authors: Webb Andrew I. , Borg Natalie A. , Dunstone Michelle A. , Kjer-Nielsen Lars , Beddoe Travis , McCluskey James , Carbone Francis R. , Bottomley Stephen P. , Aguilar Marie-Isabel , Purcell Anthony W. , Rossjohn Jamie 
Published: April 2014

AbstractPolymorphism within the MHC not only affects peptide specificity but also has a critical influence on the T cell repertoire; for example, the CD8 T cell response toward an immunodominant HSV glycoprotein B peptide is more diverse and of higher avidity in H-2bm8 compared with H-2b mice. We have examined the basis for the selection of these distinct antiviral T cell repertoires by comparing the high-resolution structures of Kb and Kbm8, in complex with cognate peptide Ag. Although Kb and Kbm8 differ by four residues within the Ag-binding cleft, the most striking difference in the two structures was the disparate conformation adopted by the shared residue, Arg62. The altered dynamics of Arg62, coupled with a small rigid-body movement in the α1 helix encompassing this residue, correlated with biased Vα usage in the B6 mice. Moreover, an analysis of all known TCR/MHC complexes reveals that Arg62 invariably interacts with the TCR CDR1α loop. Accordingly, Arg62 appears to function as a conformational switch that may govern T cell selection and protective immunity.