bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer
Authors: Smyth Mark J. , Teng Michele W. L. , Swann Jeremy , Kyparissoudis Konstantinos , Godfrey Dale I. , Hayakawa Yoshihiro 
Published: April 2014

AbstractCD4+CD25+ regulatory T cells (Treg) that suppress T cell-mediated immune responses may also regulate other arms of an effective immune response. In particular, in this study we show that Treg directly inhibit NKG2D-mediated NK cell cytotoxicity in vitro and in vivo, effectively suppressing NK cell-mediated tumor rejection. In vitro, Treg were shown to inhibit NKG2D-mediated cytolysis largely by a TGF-β-dependent mechanism and independently of IL-10. Adoptively transferred Treg suppressed NK cell antimetastatic function in RAG-1-deficient mice. Depletion of Treg before NK cell activation via NKG2D and the activating IL-12 cytokine, dramatically enhanced NK cell-mediated suppression of tumor growth and metastases. Our data illustrate at least one mechanism by which Treg can suppress NK cell antitumor activity and highlight the effectiveness of combining Treg inhibition with subsequent NK cell activation to promote strong innate antitumor immunity.
Brain-Derived Heat Shock Protein 70-Peptide Complexes Induce NK Cell-Dependent Tolerance to Experimental Autoimmune Encephalomyelitis
Authors: Galazka Grazyna , Stasiolek Mariusz , Walczak Agata , Jurewicz Anna , Zylicz Alicja , Brosnan Celia F. , Raine Cedric S. , Selmaj Krzysztof W. 
Published: April 2014

AbstractHeat shock proteins (Hsp) are markedly up-regulated at sites of inflammation during autoimmune diseases like experimental autoimmune encephalomyelitis (EAE). In this study, we show that Hsp70-peptide complexes (pc) isolated from brains of mice with EAE prevented the development of EAE clinically and pathologically when administered before proteolipid protein 139–151 (PLP139–151) immunization. In contrast, pure Hsp70 or Hsp70-pc derived from brains of healthy mice or other inflamed tissue did not modulate the expression of EAE. In animals in which EAE had been suppressed by Hsp70-pc, lymphocytes showed increased cell death in response to PLP139–151 that correlated with elevated IFN-γ and NO production. Coculture of spleen cells from Hsp70-pc immunized mice with spleen cells from untreated EAE mice, in addition to depletion experiments, showed that NK cells reduced reactivity to PLP139–151. Transfer of NK cells from Hsp70-pc-immunized mice to recipients sensitized for EAE abolished disease development. Thus, we propose that Hsp70 demonstrate the ability to bind to peptides generated during brain inflammation and to induce a regulatory NK cell population that is capable of preventing subsequent autoimmunization for EAE.
Respiratory Syncytial Virus G Protein and G Protein CX3C Motif Adversely Affect CX3CR1+ T Cell Responses
Authors: Harcourt Jennifer , Alvarez Rene , Jones Les P. , Henderson Christine , Anderson Larry J. , Tripp Ralph A. 
Published: April 2014

Abstract
Interactions between fractalkine (CX3CL1) and its receptor, CX3CR1, mediate leukocyte adhesion, activation, and trafficking. The respiratory syncytial virus (RSV) G protein has a CX3C chemokine motif that can bind CX3CR1 and modify CXCL1-mediated responses. In this study, we show that expression of the RSV G protein or the G protein CX3C motif during infection is associated with reduced CX3CR1+ T cell trafficking to the lung, reduced frequencies of RSV-specific, MHC class I-restricted IFN-γ-expressing cells, and lower numbers of IL-4- and CX3CL1-expressing cells. In addition, we show that CX3CR1+ cells constitute a major component of the cytotoxic response to RSV infection. These results suggest that G protein and the G protein CX3C motif reduce the antiviral T cell response to RSV infection.
CD4+CD25+ Regulatory T Cells Inhibit the Antigen-Dependent Expansion of Self-Reactive T Cells In Vivo
Authors: Zwar Tricia D. , Read Simon , van Driel Ian R. , Gleeson Paul A. 
Published: April 2014

Abstract
A deficiency of CD4+CD25+ regulatory T cells (CD25+ Tregs) in lymphopenic mice can result in the onset of autoimmune gastritis. The gastric H/K ATPase α (H/Kα) and β (H/Kβ) subunits are the immunodominant autoantigens recognized by effector CD4+ T cells in autoimmune gastritis. The mechanism by which CD25+ Tregs suppress autoimmune gastritis in lymphopenic mice is poorly understood. To investigate the antigenic requirements for the genesis and survival of gastritis-protecting CD25+ Tregs, we analyzed mice deficient in H/Kβ and H/Kα, as well as a transgenic mouse line (H/Kβ-tsA58 Tg line 224) that lacks differentiated gastric epithelial cells. By adoptive transfer of purified T cell populations to athymic mice, we show that the CD25+ Treg population from mice deficient in either one or both of H/Kα and H/Kβ, or from the H/Kβ-tsA58 Tg line 224 mice, is equally effective in suppressing the ability of polyclonal populations of effector CD4+ T cells to induce autoimmune gastritis. Furthermore, CD25+ Tregs, from either wild-type or H/Kα-deficient mice, dramatically reduced the expansion of pathogenic H/Kα-specific TCR transgenic T cells and the induction of autoimmune gastritis in athymic recipient mice. Proliferation of H/Kα-specific T cells in lymphopenic hosts occurs predominantly in the paragastric lymph node and was dependent on the presence of the cognate H/Kα Ag. Collectively, these studies demonstrate that the gastritis-protecting CD25+ Tregs do not depend on the major gastric Ags for their thymic development or their survival in the periphery, and that CD25+ Tregs inhibit the Ag-specific expansion of pathogenic T cells in vivo.
MR1-Restricted Vα19i Mucosal-Associated Invariant T Cells Are Innate T Cells in the Gut Lamina Propria That Provide a Rapid and Diverse Cytokine Response
Authors: Kawachi Izumi , Maldonado Jorge , Strader Carey , Gilfillan Susan 
Published: April 2014

Abstract
Mucosal-associated invariant T (MAIT) cells reside primarily in the gut lamina propria and require commensal flora for selection/expansion. They are restricted by the highly conserved MHC class I-related molecule MR1 and, like most NK T cells, express an invariant TCRα chain. Although they probably contribute to gut immunity, MAIT cells have not been functionally characterized because they are so rare. To create a model in which they are more abundant, we generated transgenic mice expressing only the TCRα chain (Vα19i) that defines MAIT cells. By directly comparing Vα19i transgenic mice on MR1+/+ and MR1−/− backgrounds, we were able to distinguish and characterize a population of Vα19i T cells dependent on MR1 for development. MR1-restricted Vα19i transgenic T cells recapitulate what is known about MAIT cell development. Furthermore, a relatively high proportion of transgenic MAIT cells express NK1.1, and most have a cell surface phenotype similar to that of Vα14i NK T cells. Finally, MR1-restricted Vα19i T cells secrete IFN-γ, IL-4, IL-5, and IL-10 following TCR ligation, and we provide evidence for what may be two functionally distinct MAIT cell populations. These data strongly support the idea that MAIT cells contribute to the innate immune response in the gut mucosa.
Cross-Positive Selection of Thymocytes Expressing a Single TCR by Multiple Major Histocompatibility Complex Molecules of Both Classes: Implications for CD4+ versus CD8+ Lineage Commitment
Authors: Eshima Koji , Suzuki Harumi , Shinohara Nobukata 
Published: April 2014

AbstractThis study has investigated the cross-reactivity upon thymic selection of thymocytes expressing transgenic TCR derived from a murine CD8+ CTL clone. The Idhigh+ cells in this transgenic mouse had been previously shown to mature through positive selection by class I MHC, Dq or Lq molecule. By investigating on various strains, we found that the transgenic TCR cross-reacts with three different MHCs, resulting in positive or negative selection. Interestingly, in the TCR-transgenic mice of H-2q background, mature Idhigh+ T cells appeared among both CD4+ and CD8+ subsets in periphery, even in the absence of RAG-2 gene. When examined on β2-microglobulin−/− background, CD4+, but not CD8+, Idhigh+ T cells developed, suggesting that maturation of CD8+ and CD4+ Idhigh+ cells was MHC class I (Dq/Lq) and class II (I-Aq) dependent, respectively. These results indicated that this TCR-transgenic mouse of H-2q background contains both classes of selecting MHC ligands for the transgenic TCR simultaneously. Further genetic analyses altering the gene dosage and combinations of selecting MHCs suggested novel asymmetric effects of class I and class II MHC on the positive selection of thymocytes. Implications of these observations in CD4+/CD8+ lineage commitment are discussed.
Early Autoimmune Destruction of Islet Grafts Is Associated with a Restricted Repertoire of IGRP-Specific CD8+ T Cells in Diabetic Nonobese Diabetic Mice
Authors: Wong Carmen P. , Li Li , Frelinger Jeffrey A. , Tisch Roland 
Published: April 2014

Abstract
β cell replacement via islet or pancreas transplantation is currently the only approach to cure type 1 diabetic patients. Recurrent β cell autoimmunity is a critical factor contributing to graft rejection along with alloreactivity. However, the specificity and dynamics of recurrent β cell autoimmunity remain largely undefined. Accordingly, we compared the repertoire of CD8+ T cells infiltrating grafted and endogenous islets in diabetic nonobese diabetic mice. In endogenous islets, CD8+ T cells specific for an islet-specific glucose-6-phosphatase catalytic subunit-related protein derived peptide (IGRP206–214) were the most prevalent T cells. Similar CD8+ T cells dominated the early graft infiltrate but were expanded 6-fold relative to endogenous islets. Single-cell analysis of the TCR α and β chains showed restricted variable gene usage by IGRP206–214-specific CD8+ T cells that was shared between the graft and endogenous islets of individual mice. However, as islet graft infiltration progressed, the number of IGRP206–214-specific CD8+ T cells decreased despite stable numbers of CD8+ T cells. These results demonstrate that recurrent β cell autoimmunity is characterized by recruitment to the grafts and expansion of already prevalent autoimmune T cell clonotypes residing in the endogenous islets. Furthermore, depletion of IGRP206–214-specific CD8+ T cells by peptide administration delayed islet graft survival, suggesting IGRP206–214-specific CD8+ T cells play a role early in islet graft rejection but are displaced with time by other specificities, perhaps by epitope spread.
NKT Cells and IFN-γ Establish the Regulatory Environment for the Control of Diabetogenic T Cells in the Nonobese Diabetic Mouse
Authors: Cain Judith A. , Smith Judith A. , Ondr Jennifer K. , Wang Bo , Katz Jonathan D. 
Published: April 2014

Abstract
In type 1 diabetes mellitus (T1DM), T cell-mediated destruction of insulin-producing pancreatic β cells leads to the acute onset of hyperglycemia. The nonobese diabetic mouse model of human T1DM reveals that T cells capable of inducing diabetes can escape normal central tolerance, and can cause T1DM if left unchecked. However, several regulatory T cell subsets can temper autoaggressive T cells, although it remains undetermined when and how, and by which subset, homeostatic control of diabetogenic T cells is normally achieved in vivo. Using a cotransfer model, we find that NKT cells efficiently dampen the action of diabetogenic CD4+ T cells, and do so in an indirect manner by modifying the host environment. Moreover, the NKT cell-containing population modifies the host via production of IFN-γ that is necessary for driving the inhibition of diabetogenic T cells in vivo.
The Nucleotide Targets of Somatic Mutation and the Role of Selection in Immunoglobulin Heavy Chains of a Teleost Fish
Authors: Yang Feixue , Waldbieser Geoffrey C. , Lobb Craig J. 
Published: April 2014

AbstractSequence analysis of H chain cDNA derived from the spleen of an individual catfish has shown that somatic mutation occurs within both the VH- and JH-encoded regions. Somatic mutation preferentially targets G and C nucleotides with approximately balanced frequencies, resulting in the predominant accumulation of G-to-A and C-to-T substitutions that parallel the activation-induced cytidine deaminase nucleotide exchanges known in mammals. The overall mutation rate of A nucleotides is not significantly different from that expected by sequence-insensitive mutations, and a significant bias exists against mutations occurring in T. Targeting of mutations is dependent upon the sequence of neighboring nucleotides, allowing statistically significant hotspot motifs to be identified. Dinucleotide, trinucleotide, and RGYW analyses showed that mutational targets in catfish are restricted when compared with the spectrum of targets known in mammals. The preferential targets for G and C mutation are the central GC positions in both AGCT and AGCA. The WA motif, recognized as a mammalian hotspot for A mutations, was not a significant target for catfish mutations. The only significant target for A mutations was the terminal position in AGCA. Lastly, comparisons of mutations located in framework region and CDR codons coupled with multinomial distribution studies found no substantial evidence in either independent or clonally related VDJ rearrangements to indicate that somatic mutation coevolved with mechanisms that select B cells based upon nonsynonymous mutations within CDR-encoded regions. These results suggest that the principal role of somatic mutation early in phylogeny was to diversify the repertoire by targeting hotspot motifs preferentially located within CDR-encoded regions.
Phosphatidylinositol 3-Kinase Functions as a Ras Effector in the Signaling Cascade That Regulates Dephosphorylation of the Actin-Remodeling Protein Cofilin after Costimulation of Untransformed Human T Lymphocytes
Authors: Wabnitz Guido H. , Nebl Gabriele , Klemke Martin , Schröder Andreas J. , Samstag Yvonne 
Published: April 2014

Abstract
The activity of cofilin, an actin-remodeling protein, is required for T lymphocyte activation with regard to formation of the immunological synapse, cytokine production, and proliferation. In unstimulated T PBL (PB-T), cofilin is present in its Ser3-phosphorylated inactive form. Costimulation of TCR/CD3 and CD28 induces dephosphorylation and, thus, activation of cofilin. In this study we characterized the signaling cascades leading to cofilin activation in untransformed human PB-T. We show that a Ras-PI3K cascade regulates dephosphorylation of cofilin in PB-T. The GTPase Ras is a central mediator of this pathway; transient expression of an activated form of H-Ras in PB-T triggered the dephosphorylation of cofilin. Inhibition of either MAPK/ERK kinase or PI3K blocked both Ras-induced and costimulation-induced cofilin dephosphorylation in PB-T, showing that the combined activities of both signaling proteins are required to activate cofilin. That Ras functions as a central regulator of cofilin dephosphorylation after costimulation through CD3 × CD28 was finally proven by transient expression of a dominant negative form of H-Ras in primary human PB-T. It clearly inhibited costimulation-induced cofilin dephosphorylation, and likewise, activation of PI3K was diminished. Our data, in addition, demonstrate that regarding the downstream effectors of Ras, a clear difference exists between untransformed human PB-T and the T lymphoma line Jurkat. Thus, in PB-T the Ras signaling cascade is able to activate PI3K, whereas in Jurkat cells this is not the case. In addition to the insights into the regulation of cofilin, this finding discloses a to date unrecognized possibility of PI3K activation in T lymphocytes.
Opioids Trigger α5β1 Integrin-Mediated Monocyte Adhesion
Authors: Pello Oscar M. , Duthey Béatrice , García-Bernal David , Rodríguez-Frade José Miguel , Stein Jens V. , Teixido Joaquín , Martínez-A. Carlos , Mellado Mario 
Published: April 2014

Abstract
Inflammatory reactions involve a network of chemical and molecular signals that initiate and maintain host response. In inflamed tissue, immune system cells generate opioid peptides that contribute to potent analgesia by acting on specific peripheral sensory neurons. In this study, we show that opioids also modulate immune cell function in vitro and in vivo. By binding to its specific receptor, the opioid receptor-specific ligand DPDPE triggers monocyte adhesion. Integrins have a key role in this process, as adhesion is abrogated in cells treated with specific neutralizing anti-α5β1 integrin mAb. We found that DPDPE-triggered monocyte adhesion requires PI3Kγ activation and involves Src kinases, the guanine nucleotide exchange factor Vav-1, and the small GTPase Rac1. DPDPE also induces adhesion of pertussis toxin-treated cells, indicating involvement of G proteins other than Gi. These data show that opioids have important implications in regulating leukocyte trafficking, adding a new function to their known effects as immune response modulators.
Characterization of Functional Oligosaccharide Mimics of the Shigella flexneri Serotype 2a O-Antigen: Implications for the Development of a Chemically Defined Glycoconjugate Vaccine
Authors: Phalipon Armelle , Costachel Corina , Grandjean Cyrille , Thuizat Audrey , Guerreiro Catherine , Tanguy Myriam , Nato Farida , Vulliez-Le Normand Brigitte , Bélot Frédéric , Wright Karen , Marcel-Peyre Véronique , Sansonetti Philippe J. , Mulard Laurence A. 
Published: April 2014

Abstract
Protection against reinfection with noncapsulated Gram-negative bacteria, such as Shigella, an enteroinvasive bacterium responsible for bacillary dysentery, is mainly achieved by Abs specific for the O-Ag, the polysaccharide part of the LPS, the major bacterial surface Ag. The use of chemically defined glycoconjugates encompassing oligosaccharides mimicking the protective determinants carried by the O-Ag, thus expected to induce an efficient anti-LPS Ab response, has been considered an alternative to detoxified LPS-protein conjugate vaccines. The aim of this study was to identify such functional oligosaccharide mimics of the S. flexneri serotype 2a O-Ag. Using protective murine mAbs specific for S. flexneri serotype 2a and synthetic oligosaccharides designed to analyze the contribution of each sugar residue of the branched pentasaccharide repeating unit of the O-Ag, we demonstrated that the O-Ag exhibited an immunodominant serotype-specific determinant. We also showed that elongating the oligosaccharide sequence improved Ab recognition. From these antigenicity data, selected synthetic oligosaccharides were assessed for their potential to mimic the O-Ag by analyzing their immunogenicity in mice when coupled to tetanus toxoid via single point attachment. Our results demonstrated that induction of an efficient serotype 2a-specific anti-O-Ag Ab response was dependent on the length of the oligosaccharide sequence. A pentadecasaccharide representing three biological repeating units was identified as a potential candidate for further development of a chemically defined glycoconjugate vaccine against S. flexneri 2a infection.
Glucocorticoids Engage Different Signal Transduction Pathways to Induce Apoptosis in Thymocytes and Mature T Cells
Authors: Wang Dapeng , Müller Nora , McPherson Kirsty G. , Reichardt Holger M. 
Published: April 2014

Abstract
Glucocorticoids (GC) induce apoptosis in a variety of cells, but their exact mode of action is controversial. Although initiation relies on the GC receptor (GR) and de novo gene expression, the effector phase differs among cell types. Proteasomal degradation as well as caspase-3, - 8, and -9 activity are essential for GC-induced apoptosis in murine thymocytes, but the same enzymes are dispensable in splenic T cells. Live imaging by confocal microscopy revealed that lysosomal cathepsin B, an unrecognized component of this pathway to date, becomes rapidly activated in thymocytes after GC exposure. This is followed by leakage of cathepsin B into the cytosol, nuclear condensation, and processing of caspase-8 and -3. According to our model, activation of caspase-3 by caspase-9 in thymocytes occurs both directly as well as indirectly via a lysosomal amplification loop. Interestingly, acute T lymphoblastic leukemia cells depend on caspase activity to undergo GC-induced cell death similar to thymocytes. Collectively, the apoptotic program induced by GCs comprises cell type-specific as well as common features.
Qa-1b and CD94-NKG2a Interaction Regulate Cytolytic Activity of Herpes Simplex Virus-Specific Memory CD8+ T Cells in the Latently Infected Trigeminal Ganglia
Authors: Suvas Susmit , Azkur Ahmet Kursat , Rouse Barry T. 
Published: April 2014

AbstractAfter ocular infection, HSV-specific CD8+ T cells migrate to and are specifically retained in the ophthalmic branch of the trigeminal ganglia (TG) even at the time when replicating virus is no longer evident. Virus-specific CD8+ T cells maintain an activation phenotype and secrete IFN-γ in the latent TG. In this report we demonstrated that activated virus-specific memory CD8+ T cells, although potentially cytolytic, also expressed the CD94-NK cell receptor subfamily G2a inhibitory molecule and were unable to exert cytotoxicity when engaged by Qa-1b expressing targets. Interestingly, many neurons in the latent TG expressed Qa-1b, and blocking of Qa-1b/CD94-NKG2a interaction in an ex vivo TG culture resulted in neuronal cell lysis. The expression of the inhibitory CD94-NKG2a molecule could be induced by TGF-β1, which was shown to present as a bioactive molecule in the latent TG. Additionally, CD4+ forkhead/winged helix transcription factor 3+ T cells were also determined in the latent TG. Our results demonstrate the operation of a regulatory system in vivo that serves to protect irreplaceable neurons from destruction by the immune system.
Immunity and Tolerance to Aspergillus Involve Functionally Distinct Regulatory T Cells and Tryptophan Catabolism
Authors: Montagnoli Claudia , Fallarino Francesca , Gaziano Roberta , Bozza Silvia , Bellocchio Silvia , Zelante Teresa , Kurup Wiswanath P. , Pitzurra Lucia , Puccetti Paolo , Romani Luigina 
Published: April 2014

Abstract
The inherent resistance to diseases caused by Aspergillus fumigatus suggests the occurrence of regulatory mechanisms that provide the host with adequate defense without necessarily eliminating the fungus or causing unacceptable levels of host damage. In this study, we show that a division of labor occurs between functionally distinct regulatory T cells (Treg) that are coordinately activated by a CD28/B-7-dependent costimulatory pathway after exposure of mice to Aspergillus conidia. Early in infection, inflammation is controlled by the expansion, activation and local recruitment of CD4+CD25+ Treg capable of suppressing neutrophils through the combined actions of IL-10 and CTLA-4 on indoleamine 2,3-dioxygenase. The levels of IFN-γ produced in this early phase set the subsequent adaptive stage by conditioning the indoleamine 2,3-dioxygenase-dependent tolerogenic program of dendritic cells and the subsequent activation and expansion of tolerogenic Treg, which produce IL-10 and TGF-β, inhibit Th2 cells, and prevent allergy to the fungus. The coordinate activation of Treg may, however, be subverted by the fungus, as germinating conidia are capable of interfering with anti-inflammatory and tolerogenic Treg programs. Thus, regulation is an essential component of the host response in infection and allergy to the fungus, and its manipulation may allow the pathogen to overcome host resistance and promote disease.