bluuebunny/crossref_metadata_2025_split huggingface dataset:
LIGHT (a Cellular Ligand for Herpes Virus Entry Mediator and Lymphotoxin Receptor)-Mediated Thymocyte Deletion Is Dependent on the Interaction Between TCR and MHC/Self-Peptide
Authors: Wang Jing , Fu Yang-Xin 
Published: April 2014

AbstractNegative selection serves as a major mechanism to maintain self-tolerance. We previously reported that LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor), a TNF family member, plays an important role in thymocyte development via promoting apoptosis of double-positive thymocytes. Here, we demonstrated that LIGHT-mediated deletion of thymocyte requires the strong interaction of TCR with MHC/self-peptide. Transgenic mice overexpressing LIGHT in thymocytes were bred with a transgenic mouse line expressing a TCR recognizing the H-Y male Ag in the context of H-2b class I MHC molecules. In male H-Y/LIGHT double-transgenic mice, more efficient negative selection of H-Y T cells occurred, and total thymocyte number was further reduced compared with H-Y/negative littermates. In contrast, the presence of LIGHT transgene had no evident impact on the thymocyte development of female H-Y/LIGHT double-transgenic mice. Taken together, LIGHT plays a role in negative selection of thymocytes via inducing the apoptosis of thymocytes bearing high affinity TCR during negative selection.
Detection and Characterization of T Cells Specific for BDC2.5 T Cell-Stimulating Peptides
Authors: You Sylvaine , Chen Cyndi , Lee Wen-Hui , Wu Chun-Hua , Judkowski Valeria , Pinilla Clemencia , Wilson Darcy B. , Liu Chih-Pin 
Published: April 2014

Abstract
Nonobese diabetic (NOD) mice expressing the BDC2.5 TCR transgene are useful for studying type 1 diabetes. Several peptides have been identified that are highly active in stimulating BDC2.5 T cells. Herein, we describe the use of I-Ag7 tetramers containing two such peptides, p79 and p17, to detect and characterize peptide-specific T cells. The tetramers could stain CD4+ T cells in the islets and spleens of BDC2.5 transgenic mice. The percentage of CD4+, tetramer+ T cells increased in older mice, and it was generally higher in the islets than in the spleens. Our results also showed that tetAg7/p79 could stain a small population of CD4+ T cells in both islets and spleens of NOD mice. The percentage of CD4+, tetramer+ T cells increased in cells that underwent further cell division after being activated by peptides. The avidity of TCRs on purified tetAg7/p79+ T cells for tetAg7/p79 was slightly lower than that of BDC2.5 T cells. Although tetAg7/p79+ T cells, like BDC2.5 T cells, secreted a large quantity of IFN-γ, they were biased toward being IL-10-producing cells. Additionally, &lt;3% of these cells expressed TCR Vβ4. In vivo adoptive transfer experiments showed that NOD/scid recipient mice cotransferred with tetAg7/p79+ T cells and NOD spleen cells, like mice transferred with NOD spleen cells only, developed diabetes. Therefore, we have generated Ag-specific tetramers that could detect a heterogeneous population of T cells, and a very small number of NOD mouse T cells may represent BDC2.5-like cells.
Optimal Chemotactic Responses of Leukemic T Cells to Stromal Cell-Derived Factor-1 Requires the Activation of Both Class IA and IB Phosphoinositide 3-Kinases
Authors: Curnock Adam P. , Sotsios Yannis , Wright Karen L. , Ward Stephen G. 
Published: April 2014

AbstractStromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 are a multifunctional chemokine/receptor system with essential roles in the development of the immune system and other aspects of embryogenesis, including vascularization and organ development. SDF-1 is also a potent chemoattractant for T cells and has roles in both inflammation and immune homeostasis. Our group has previously demonstrated that phosphoinositide 3-kinase (PI 3-kinase) is activated in SDF-1-stimulated T cells and is indeed required for SDF-1-mediated chemotaxis. In this study Jurkat clones were established, stably expressing dominant negative constructs of class IA and class IB PI 3-kinases under the control of the tetracycline off inducible gene system, to determine the relative roles of these PI 3-kinases in SDF-1 signaling. Our results show that expression of either kinase-dead PI3Kγ (KD-PI3Kγ) or Δp85 (a construct unable to bind class IA p110α, -β, or -δ) leads to a partial inhibition of SDF-1-stimulated protein kinase B phosphorylation, but had no effect on SDF-1-induced phosphorylation of the mitogen-activated protein kinase ERK1/2. Functional studies demonstrated that expression of KD-PI3Kγ markedly inhibited SDF-1-mediated chemotaxis, typically eliciting 40–60% inhibition. Interestingly, the expression of Δp85 also leads to inhibition of the SDF-1-mediated chemotactic response, albeit to a much lesser extent than achieved with the KD-PI3Kγ mutant, typically in the range of 20–40% inhibition. Furthermore, the inhibition of chemotaxis by the expression of dominant negative class IA or class IB PI 3-kinases could be enhanced by the presence of the PI 3-kinase inhibitor LY294002. Together, these results demonstrate that optimal chemotactic response of leukemic T cells to SDF-1 requires the activation of both class IA and class IB PI 3-kinases.
CpG-A-Induced Monocyte IFN-γ-Inducible Protein-10 Production Is Regulated by Plasmacytoid Dendritic Cell-Derived IFN-α
Authors: Blackwell Sue E. , Krieg Arthur M. 
Published: April 2014

Abstract
Unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (ODN) are known for inducing a Th1 cytokine/chemokine environment, but the mechanisms regulating this have been unclear. Recent studies have defined two classes of CpG ODN, CpG-A ODN that induce plasmacytoid dendritic cells (pDC) to secrete very high levels of IFN-α, and CpG-B ODN that induce only low levels of IFN-α production, but strongly activate B cells. We now demonstrate that a CpG-A ODN directly activates pDC secretion of IFN-α and other soluble factors that secondarily induce purified monocytes to secrete high levels of the Th1-promoting chemokine IFN-γ-inducible protein-10 (IP-10). Cell contact between the monocytes and pDC is not required for this interaction. IFN-α is necessary, but only partially sufficient, for this indirect CpG-induced monocyte IP-10 production. Although CpG ODN induce human PBMC to make only very slight amounts of IFN-γ, we find that these low concentrations synergize with IFN-α for inducing monocyte production of IP-10. These studies provide a better understanding of the mechanisms through which CpG ODN create a Th1-like environment.
Mature Dendritic Cells Derived from Human Monocytes Within 48 Hours: A Novel Strategy for Dendritic Cell Differentiation from Blood Precursors
Authors: Dauer Marc , Obermaier Bianca , Herten Jan , Haerle Carola , Pohl Katrin , Rothenfusser Simon , Schnurr Max , Endres Stefan , Eigler Andreas 
Published: April 2014

Abstract
It is widely believed that generation of mature dendritic cells (DCs) with full T cell stimulatory capacity from human monocytes in vitro requires 5–7 days of differentiation with GM-CSF and IL-4, followed by 2–3 days of activation. Here, we report a new strategy for differentiation and maturation of monocyte-derived DCs within only 48 h of in vitro culture. Monocytes acquire immature DC characteristics by day 2 of culture with GM-CSF and IL-4; they down-regulate CD14, increase dextran uptake, and respond to the inflammatory chemokine macrophage inflammatory protein-1α. To accelerate DC development and maturation, monocytes were incubated for 24 h with GM-CSF and IL-4, followed by activation with proinflammatory mediators for another 24 h (FastDC). FastDC expressed mature DC surface markers as well as chemokine receptor 7 and secreted IL-12 (p70) upon CD40 ligation in the presence of IFN-γ. The increase in intracellular calcium in response to 6Ckine showed that chemokine receptor 7 expression was functional. When FastDC were compared with mature monocyte-derived DCs generated by a standard 7-day protocol, they were equally potent in inducing Ag-specific T cell proliferation and IFN-γ production as well as in priming autologous naive T cells using tetanus toxoid as a model Ag. These findings indicate that FastDC are as effective as monocyte-derived DCs in stimulating primary, Ag-specific, Th 1-type immune responses. Generation of FastDC not only reduces labor, cost, and time required for in vitro DC development, but may also represent a model more closely resembling DC differentiation from monocytes in vivo.
Direct Visualization of Cross-Reactive Effector and Memory Allo-Specific CD8 T Cells Generated in Response to Viral Infections
Authors: Brehm Michael A. , Markees Thomas G. , Daniels Keith A. , Greiner Dale L. , Rossini Aldo A. , Welsh Raymond M. 
Published: April 2014

Abstract
CD8 T cell cross-reactivity between heterologous viruses has been shown to provide protective immunity, induce immunopathology, influence the immunodominance of epitope-specific T cell responses, and shape the overall memory population. Virus infections also induce cross-reactive allo-specific CTL responses. In this study, we quantified the allo-specific CD8 T cells elicited by infection of C57BL/6 (B6) mice with lymphocytic choriomeningitis virus (LCMV). Cross-reactive LCMV-specific CD8 T cells were directly visualized using LCMV peptide-charged MHC tetramers to costain T cells that were stimulated to produce intracellular IFN-γ in response to allogeneic target cells. The cross-reactivity between T cells specific for LCMV and allogeneic Ags was broad-based, in that it involved multiple LCMV-derived peptides, but there were distinctive patterns of reactivity against allogeneic cells with different haplotypes. Experiments indicated that this cross-reactivity was not due to the expression of two TCR per cell, and that the patterns of allo-reactivity changed during sequential infection with heterologous viruses. The allo-specific CD8 T cells generated by LCMV infection were maintained at relatively high frequencies in the memory pool, indicating that memory allo-specific CD8 T cell populations can arise as a consequence of viral infections. Mice previously infected with LCMV and harboring allo-specific memory T cells were refractory to the induction of tolerance to allogeneic skin grafts.
The gp49B1 Inhibitory Receptor Regulates the IFN-γ Responses of T Cells and NK Cells
Authors: Gu Xiaogang , Laouar Amale , Wan Junmei , Daheshia Massoud , Lieberman Judy , Yokoyama Wayne M. , Katz Howard R. , Manjunath N. 
Published: April 2014

AbstractThe magnitude and diversity of Ag-specific T cell effector activity have been proposed to be controlled by an integration of positive signals transduced by the TCR and negative signals originating from inhibitory cell surface molecules. Although the lectin family of NK cell-associated inhibitory receptors has been reported to regulate the function of murine CTLs, gp49B1, the Ig superfamily member is not known to be expressed on T cells. Moreover, the consequences of the lack of an endogenously expressed NK cell-associated inhibitory receptor on T cell functions are not known. We report that gp49B1 is expressed by nearly all activated CD8 and CD4 T cells in addition to NK cells during an immune response to viral, bacterial, or tumor challenge. Kinetics of gp49B1 expression parallel functional capability and subside in the memory phase. Following vaccinia viral infection, IFN-γ production by both subsets of T cells and NK cells is enhanced in gp49B1-deficient mice compared with gp49B1+/+ mice. The stimulation threshold for IFN-γ production is also lower in gp49B1-deficient T cells. In contrast, no significant differences were observed in the cytotoxic responses. We conclude that gp49B1 is a unique inhibitory receptor that is induced in multiple lineages of innate and adaptive immune cells during an infection and controls their IFN-γ, but not cytotoxic responses.
A Subset of Toll-Like Receptor Ligands Induces Cross-presentation by Bone Marrow-Derived Dendritic Cells
Authors: Datta Sandip K. , Redecke Vanessa , Prilliman Kiley R. , Takabayashi Kenji , Corr Maripat , Tallant Thomas , DiDonato Joseph , Dziarski Roman , Akira Shizuo , Schoenberger Stephen P. , Raz Eyal 
Published: April 2014

AbstractDendritic cells (DCs) are capable of cross-presenting exogenous Ag to CD8+ CTLs. Detection of microbial products by Toll-like receptors (TLRs) leads to activation of DCs and subsequent orchestration of an adaptive immune response. We hypothesized that microbial TLR ligands could activate DCs to cross-present Ag to CTLs. Using DCs and CTLs in an in vitro cross-presentation system, we show that a subset of microbial TLR ligands, namely ligands of TLR3 (poly(inosinic-cytidylic) acid) and TLR9 (immunostimulatory CpG DNA), induces cross-presentation. In contrast to presentation of Ag to CD4+ T cells by immature DCs, TLR-induced cross-presentation is mediated by mature DCs, is independent of endosomal acidification, and relies on cytosolic Ag processing machinery.
APCs Present Aβk-Derived Peptides That Are Autoantigenic to Type B T Cells
Authors: Lovitch Scott B. , Walters James J. , Gross Michael L. , Unanue Emil R. 
Published: April 2014

AbstractType B T cells recognize peptide provided exogenously but are ignorant of the same epitope derived from intracellular processing. In this study, we demonstrate the existence of type B T cells to an abundant autologous peptide derived from processing of the I-Ak β-chain. T cell hybridomas raised against this peptide fail to recognize syngeneic APC despite abundant presentation of the naturally processed epitope but react in a dose-dependent manner to exogenous peptide. Moreover, these hybridomas respond to Aβk peptide extracted from the surface of I-Ak-expressing APC. This peptide was isolated from B cell lines where it was found in high abundance; it was also present in lines lacking HLA-DM, but in considerably lower amounts. Therefore, type B T cells exist in the naive repertoire to abundant autologous peptides. We discuss the implications of these findings to the potential biological role of type B T cells in immune responses and autoimmune pathology.
Host Absence of CCR5 Potentiates Dendritic Cell Vaccination
Authors: Ng-Cashin Judith , Kuhns Jennifer J. , Burkett Susan E. , Powderly John D. , Craven Robin R. , van Deventer Hank W. , Kirby Suzanne L. , Serody Jonathan S. 
Published: April 2014

Abstract
Previous work has shown that dendritic cells (DCs) express specific chemokine receptors that allow for coordinated movement in vivo. To test the in vivo relevance of this, we used a murine melanoma system and knockout mice to investigate the function of the chemokine receptor CCR5 and its ligands, CCR ligand (CCL)3 and CCL5. We found that the lack of CCR5 in the host mouse resulted in delayed tumor growth, but this effect was overcome at a higher tumor load. With the administration of tumor charged DCs, CCR5−/− mice that had previously been injected with tumor were completely protected from tumor. This effect was dependent on the dose of tumor cells and the expression of CCR5 on the DC and its absence in the host. In contrast, the loss of the CCR5 ligand, CCL3, led to an early delay in tumor growth that did not persist, while the absence of the CCR5 ligand, CCL5, had no effect. Blocking the activity of CCR5 in the host may represent a new strategy for enhancing the activity of a therapeutic melanoma DC vaccine.
Hyperoxia Mediates Acute Lung Injury and Increased Lethality in MurineLegionellaPneumonia: The Role of Apoptosis
Authors: Tateda Kazuhiro , Deng Jane C. , Moore Thomas A. , Newstead Michael W. , Paine Robert , Kobayashi Nobuyuki , Yamaguchi Keizo , Standiford Theodore J. 
Published: April 2014

AbstractLegionella pneumophila is a major cause of life-threatening pneumonia, which is characterized by a high incidence of acute lung injury and resultant severe hypoxemia. Mechanical ventilation using high oxygen concentrations is often required in the treatment of patients with L. pneumophila pneumonia. Unfortunately, oxygen itself may propagate various forms of tissue damage, including acute lung injury. The effect of hyperoxia as a cofactor in the course of L. pneumophila pneumonia is poorly understood. In this study, we show that exposure to hyperoxic conditions during the evolution of pneumonia results in a marked increase in lethality in mice with Legionella pneumonia. The enhanced lethality was associated with an increase in lung permeability, but not changes in either lung bacterial burden or leukocyte accumulation. Interestingly, accelerated apoptosis as evidenced by assessment of histone-DNA fragments and caspase-3 activity were noted in the infected lungs of mice exposed to hyperoxia. TUNEL staining of infected lung sections demonstrated increased apoptosis in hyperoxic mice, predominantly in macrophages and alveolar epithelial cells. In vitro exposure of primary murine alveolar epithelial cells to Legionella in conjunction with hyperoxia accelerated apoptosis and loss of barrier function. Fas-deficient mice demonstrated partial resistance to the lethal effects of Legionella infection induced by hyperoxia, which was associated with attenuated apoptosis in the lung. These results demonstrate that hyperoxia serves as an important cofactor for the development of acute lung injury and lethality in L. pneumophila pneumonia. Exaggerated apoptosis, in part through Fas-mediated signaling, may accelerate hyperoxia-induced acute lung injury in Legionella pneumonia.
A Chimeric Multi-Human Epidermal Growth Factor Receptor-2 B Cell Epitope Peptide Vaccine Mediates Superior Antitumor Responses
Authors: Dakappagari Naveen K. , Pyles John , Parihar Robin , Carson William E. , Young Donn C. , Kaumaya Pravin T. P. 
Published: April 2014

Abstract
Immunotherapeutic approaches to cancer should focus on novel undertakings that modulate immune responses by synergistic enhancement of antitumor immunological parameters. Cancer vaccines should preferably be composed of multiple defined tumor Ag-specific B and T cell epitopes. To develop a multiepitope vaccine, 12 high ranking B cell epitopes were identified from the extracellular domain of the human epidermal growth factor receptor-2 (HER-2) oncoprotein by computer-aided analysis. Four novel HER-2 B cell epitopes were synthesized as chimeras with a promiscuous T cell epitope (aa 288–302) from the measles virus fusion protein (MVF). Two chimeric peptide vaccines, MVF HER-2316–339 and MVF HER-2485–503 induced high levels of Abs in outbred rabbits, which inhibited tumor cell growth. In addition, Abs induced by a combination of two vaccines, MVF HER-2316–339 and MVF HER-2628–647 down-modulated receptor expression and activated IFN-γ release better than the individual vaccines. Furthermore, this multiepitope vaccine in combination with IL-12 caused a significant reduction (p = 0.004) in the number of pulmonary metastases induced by challenge with syngeneic tumor cells overexpressing HER-2. Peptide Abs targeting specific sites in the extracellular domain may be used for exploring the oncoprotein’s functions. The multiepitope vaccine may have potential application in the treatment of HER-2-associated cancers.
TCR Vβ8+ T Cells Prevent Development of Toxoplasmic Encephalitis in BALB/c Mice Genetically Resistant to the Disease
Authors: Kang Hoil , Liesenfeld Oliver , Remington Jack S. , Claflin Jennifer , Wang Xisheng , Suzuki Yasuhiro 
Published: April 2014

Abstract
BALB/c are genetically resistant to development of toxoplasmic encephalitis (TE) when infected with Toxoplasma gondii, whereas CBA/Ca mice are susceptible. We compared TCR Vβ chain usage in lymphocytes infiltrated into brains between these animals following infection. TCR Vβ8+ cells were the most frequent T cell population in brains of infected, resistant BALB/c mice, whereas TCR Vβ6+ T cells were more prevalent than Vβ8+ T cells in brains of infected, susceptible CBA/Ca mice. Adoptive transfer of Vβ8+ immune T cells, obtained from infected BALB/c mice, prevented development of TE and mortality in infected athymic nude mice that lack T cells. In contrast, adoptive transfer of Vβ6+ immune T cells did not prevent development of TE or mortality in the nude mice. The protective activity of Vβ8+ immune T cells was greater than that of the total Vβ8− population. In addition, Vβ8+ immune T cells produced markedly greater amounts of IFN-γ than did the Vβ8− population after stimulation with tachyzoite lysate Ags in vitro. Thus, Vβ8+ T cells appear to play a crucial role in the genetic resistance of BALB/c mice against development of TE.
Identification and Characterization of the Immunodominant Rat HER-2/neu MHC Class I Epitope Presented by Spontaneous Mammary Tumors from HER-2/neu-Transgenic Mice
Authors: Ercolini Anne M. , Machiels Jean-Pascal H. , Chen Yi Cheng , Slansky Jill E. , Giedlen Martin , Reilly R. Todd , Jaffee Elizabeth M. 
Published: April 2014

Abstract
The HER-2/neu (neu-N)-transgenic mice are a clinically relevant model of breast cancer. They are derived from the parental FVB/N mouse strain and are transgenic for the rat form of the proto-oncogene HER-2/neu (neu). In this study, we report the identification of a MHC class I peptide in the neu protein that is recognized by CD8+ T cells derived from vaccinated FVB/N mice. This 10-mer was recognized by all tumor-specific FVB/N T cells generated regardless of the TCR Vβ region expressed by the T cell or the method of vaccination used, establishing it as the immunodominant MHC class I epitope in neu. T cells specific for this epitope were able to cure FVB/N mice of transplanted neu-expressing tumor cells, demonstrating that this is a naturally processed peptide. Altered peptide analogs of the epitope were analyzed for immunogenicity. Vaccination with dendritic cells pulsed with a heteroclitic peptide provided FVB/N and neu-N mice with increased protection against tumor challenge as compared with mice immunized with dendritic cells loaded with either wild-type or irrelevant peptide. Discovery of this epitope allows for better characterization of the CD8+ T cell responses in the neu-N mouse model in which neu-specific tolerance must be overcome to produce effective antitumor immunity.