bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Th2-Mediated Allergic Airway Inflammatory Disease by CD137 Costimulation
Authors: Sun Yonglian , Blink Sarah E. , Liu Wenhua , Lee Youjin , Chen Bohao , Solway Julian , Weinstock Joel , Chen Lieping , Fu Yang-Xin 
Published: April 2014

AbstractThe engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8+ T cells and stimulate IFN-γ production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-γ and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.
Mechanism of IFN-β-Mediated Inhibition of IL-8 Gene Expression in Astroglioma Cells
Authors: Nozell Susan , Laver Travis , Patel Kiran , Benveniste Etty N. 
Published: April 2014

Abstract
IL-8 is a chemokine that recruits migrating neutrophils and leukocytes to areas of inflammation. In noninflamed tissue, IL-8 expression is low but can be rapidly induced by proinflammatory cytokines. Typically, inflammation and transient IL-8 expression are beneficial. However, some diseases are characterized by excessive inflammation and high levels of IL-8. Previous studies have shown that IFN-β can inhibit the expression of IL-8, although the mechanism is unknown. Using chromatin immunoprecipitation assays, we define the IL-8 transcriptional program in the absence or presence of inducing stimuli and/or inhibition by IFN-β. In the absence of stimuli, the IL-8 promoter is acetylated but negatively regulated by corepressor proteins. Upon PMA stimulation, the levels of these corepressors are reduced and the promoter is rapidly bound and activated by transcription factors, including NF-κB p65, C/EBPβ, and c-Fos. In addition, RNA polymerase II is recruited to the IL-8 promoter to initiate transcription. However, in the presence of both PMA and IFN-β, there are diminished levels of histone acetylation, reduced levels of transcription factors such as NF-κB p65 and RNA polymerase II, and an increased presence of corepressor proteins such as histone deacetylases 1 and 3 and silencing mediator of retinoic acid and thyroid hormone receptors. IFN-γ-inducible protein-10 and MCP-1 genes, also regulated by NF-κB, are unaffected by IFN-β, and IFN-β does not prevent the activation, nuclear migration, or binding of NF-κB p65 to the κB element of the IFN-γ-inducible protein-10 promoter. As such, these data show that the inhibitory effects of IFN-β are specific to the IL-8 promoter.
Stimulation History Dictates Memory CD8 T Cell Phenotype: Implications for Prime-Boost Vaccination
Authors: Masopust David , Ha Sang-Jun , Vezys Vaiva , Ahmed Rafi 
Published: April 2014

Abstract
Heterologous prime-boost vaccination results in increased frequencies of memory T cells. Although these quantitative effects of reexposure to Ag are well documented, little is known about the impact of boosting on the functional qualities of memory T cells. To address this critical issue, we have used three different types of immunization regimens and examined how boosting effects the function and anatomic location of memory CD8 T cells. We found that memory T cell phenotype differed substantially depending on the number of immunizations and that secondary and tertiary responses resulted in the generation of memory CD8 T cells that retained effector-like properties and showed preferential accumulation in nonlymphoid tissues. These results show that memory differentiation is coupled to the history of Ag experience and that prime-boost vaccination strategies have important consequences on memory CD8 T cell quality and surveillance within mucosal tissues.
Targeted Lymphoid Homing of Dendritic Cells Is Required for Prolongation of Allograft Survival
Authors: Garrod Kym R. , Chang Catherine K. , Liu Feng-Chun , Brennan Todd V. , Foster Robert D. , Kang Sang-Mo 
Published: April 2014

Abstract
Accumulating evidence that dendritic cells (DC) are important regulators of peripheral immune tolerance has led to the concept that donor-derived DC may be useful for inducing donor-specific transplantation tolerance. Although in vitro studies in this field have been encouraging, in vivo results have been inconsistent. Recent evidence has suggested a critical role of lymphoid organs in tolerance induction. In this study, we use a novel gene transduction technique to show that engineered expression of CCR7 on immature DC can markedly increase DC homing to lymphoid organs, leading to increased interaction with Ag-specific T cells. Moreover, we show that a single infusion of DC coexpressing CCR7 and the immunomodulatory molecule viral IL-10 (vIL-10) markedly prolongs cardiac allograft survival (mean survival time &gt;100 days); importantly, DC expressing either vIL-10 alone or CCR7 alone was not effective. These results demonstrate an important paradigm for immune modulation using DC.
Small Interfering RNA-Mediated Knockdown of Notch Ligands in Primary CD4+ T Cells and Dendritic Cells Enhances Cytokine Production
Authors: Stallwood Yvette , Briend Emmanuel , Ray Katrina M. , Ward George A. , Smith Beverley J. , Nye Emma , Champion Brian R. , McKenzie Grahame J. 
Published: April 2014

Abstract
The key interaction in the adaptive immune system’s response to pathogenic challenge occurs at the interface between APCs and T cells. Families of costimulatory and coinhibitory molecules function in association with the cytokine microenvironment to orchestrate appropriate T cell activation programs. Recent data have demonstrated that the Notch receptor and its ligands also function at the APC:T interface. In this study, we describe synthetic small interfering RNA (siRNA) sequences targeting the human Notch ligands Delta1, Jagged1 and Jagged2. Transfection of these siRNAs into human primary CD4+ T cells and monocyte-derived dendritic cells leads to knockdown of endogenous Notch ligand message. Knockdown of any one of these three Notch ligands in dendritic cells enhanced IFN-γ production from allogeneic CD4+ T cells in MLR. In contrast, Delta1 knockdown in CD4+ T cells selectively enhanced production of IFN-γ, IL-2, and IL-5 in response to polyclonal stimulation, while Jagged1 or Jagged2 knockdown had no effect. Strikingly, blockade of Notch cleavage with a γ secretase inhibitor failed to affect cytokine production in this system, implying that Delta1 can influence cytokine production via a Notch cleavage-independent mechanism. These data show for the first time that the Notch pathway can be targeted by siRNA, and that its antagonism may be a unique therapeutic opportunity for immune enhancement.
Antigen-Experienced T Cells Limit the Priming of Naive T Cells during Infection withLeishmania major
Authors: Gray Peter M. , Reiner Steven L. , Smith Deborah F. , Kaye Paul M. , Scott Phillip 
Published: April 2014

AbstractOne mechanism to control immune responses following infection is to rapidly down-regulate Ag presentation, which has been observed in acute viral and bacterial infections. In this study, we describe experiments designed to address whether Ag presentation is decreased after an initial response to Leishmania major. Naive αβ-Leishmania-specific (ABLE) TCR transgenic T cells were adoptively transferred into mice at various times after L. major infection to determine the duration of presentation of parasite-derived Ags. ABLE T cells responded vigorously at the initiation of infection, but the ability to prime these cells quickly diminished, independent of IL-10, regulatory T cells, or Ag load. However, Ag-experienced clonal and polyclonal T cell populations could respond, indicating that the diminution in naive ABLE cell responses was not due to lack of Ag presentation. Because naive T cell priming could be restored by removal of the endogenous T cell population, or adoptive transfer of Ag-pulsed dendritic cells, it appears that T cells that have previously encountered Ag during infection compete with naive Ag-specific T cells. These results suggest that during L. major infection Ag-experienced T cells, rather than naive T cells, may be primarily responsible for sustaining the immune response.
Novel Function of IFN-γ: Negative Regulation of Dendritic Cell Migration and T Cell Priming
Authors: Wu Xiaodong , Hou Wanqiu , Sun Shuhui , Bi Enguang , Wang Yuan , Shi Mude , Zang Jingwu , Dong Chen , Sun Bing 
Published: April 2014

AbstractIFN-γ is considered to be a Th1 cytokine with immunomodulatory effects on a variety of immune cells. In this study, we determined whether dendritic cell (DC) function was aberrant in IFN-γ knockout (GKO) mice. The results demonstrated that IFN-γ deficiency did not interfere with bone marrow-derived DC development and maturation in vitro. However, functional analysis showed that bone marrow-derived DC from GKO mice had altered cytokine secretion, allostimulatory and Ag presentation capacity, chemokine receptor expression, and in vitro chemotaxis. LPS induced the recruitment of DC from different organs into the spleen; epicutaneously sensitized DC with hapten (FITC) accumulated in the draining lymph nodes and CD11c+ DC levels in the draining lymph nodes from autoantigen (interphotoreceptor retinoid-binding protein) immunized mice were enhanced in GKO mice as compared with wild-type mice. After treatment of GKO mice with i.p. IFN-γ injection restored IFN-γ levels in vivo, DC migration decreased in response to LPS or FITC. IFN-γ altered the adaptive immune responses in vivo, since T cell priming and IL-2 production were increased in interphotoreceptor retinoid-binding protein-immunized GKO mice. Furthermore, in IFN-γ-treated GKO mice, experimental autoimmune uveitis score enhancement and T cell activation were eliminated. Taken together, IFN-γ appears to play a negative regulatory role on in vivo DC function, resulting in suppression of Ag-specific T cell priming.
Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells
Authors: Valmori Danila , Tosello Valeria , Souleimanian Naira E. , Godefroy Emmanuelle , Scotto Luigi , Wang Yu , Ayyoub Maha 
Published: April 2014

AbstractRapamycin is an immunosuppressive drug currently used in different clinical settings. Although the capacity of rapamycin to inhibit the mammalian target of rapamycin serine/threonine protein kinase and therefore T cell cycle progression is well known, its effects are complex and not completely understood. It has been reported recently that TCR-mediated stimulation of murine CD4+ T cells in the presence of rapamycin results in increased proportions of CD4+ T cells with suppressive functions, suggesting that the drug may also exert its immunosuppressive activity by promoting the selective expansion of naturally occurring CD4+ regulatory T cells (Treg). In this study, we show that stimulation of human circulating CD4+ T cells in the presence of rapamycin results indeed in highly increased suppressor activity. By assessing the effect of rapamycin on the growth of nonregulatory and Treg populations of defined differentiation stages purified ex vivo from circulating CD4+ T cells, we could demonstrate that this phenomenon is not due to a selective expansion of naturally occurring Tregs, but to the capacity of rapamycin to induce, upon TCR-mediated stimulation, suppressor functions in conventional CD4+ T cells. This condition, however, is temporary and reversible as it is dependent upon the continuous presence of rapamycin.
Protein Kinase Cδ Is Essential to Maintain CIITA Gene Expression in B Cells
Authors: Kwon Myung-Ja , Soh Jae-Won , Chang Cheong-Hee 
Published: April 2014

Abstract
Expression of MHC class II genes requires CIITA. Although the transactivation function of CIITA is well characterized, the signaling events that regulate CIITA expression are less understood. In this study, we report that CIITA expression in B cells depends on protein kinase Cδ (PKCδ). PKCδ controls CIITA gene transcription mainly via modulating CREB recruitment to the CIITA promoter without affecting CIITA mRNA stability. Inhibition of PKCδ by a pharmacological inhibitor or knocking down of endogenous PKCδ expression by small interfering RNA reduced CREB binding to the CIITA promoter. The decrease of CIITA gene expression in the presence of the PKCδ inhibitor was prevented by ectopically expressing a constitutively active form of CREB. In addition, histone acetylation of the CIITA promoter is regulated by PKCδ since the PKCδ inhibitor treatment or PKCδ small interfering RNA resulted in decreased histone acetylation. Taken together, our study reveals that PKCδ is an important signaling molecule necessary to maintain CIITA and MHC class II expression in B cells.
Functional Specialization of Memory Th Cells Revealed by Expression of Integrin CD49b
Authors: Kassiotis George , Gray David , Kiafard Ziba , Zwirner Jörg , Stockinger Brigitta 
Published: April 2014

Abstract
Infection or immunization induces heterogeneous memory T cell subsets, but their origin and protective value against infection are unclear. In this study, we report the functional characterization of two memory Th subsets, defined by expression of integrin CD49b. Stable CD49b expression is induced in up to one-half of all memory Th cells. More importantly, the CD49b− and CD49b+ subsets display distinct helper activities, typified by the production of IL-10 and TNF-α, respectively. Although the inflammatory properties of the CD49b+ subset are protective against intracellular bacterial infection, they are associated with immunopathology in acute viral infection. Modulation of the CD49b-defined memory Th subsets may provide infection type-specific interventions, where either enhancement of the inflammatory response or reduction of immunopathology is essential.
Generation of T Cell Help through a MHC Class I-Restricted TCR
Authors: Kessels Helmut W. H. G. , Schepers Koen , van den Boom Marly D. , Topham David J. , Schumacher Ton N. M. 
Published: April 2014

Abstract
CD4+ T cells that are activated by a MHC class II/peptide encounter can induce maturation of APCs and promote cytotoxic CD8+ T cell responses. Unfortunately, the number of well-defined tumor-specific CD4+ T cell epitopes that can be exploited for adoptive immunotherapy is limited. To determine whether Th cell responses can be generated by redirecting CD4+ T cells to MHC class I ligands, we have introduced MHC class I-restricted TCRs into postthymic murine CD4+ T cells and examined CD4+ T cell activation and helper function in vitro and in vivo. These experiments indicate that Ag-specific CD4+ T cell help can be induced by the engagement of MHC class I-restricted TCRs in peripheral CD4+ T cells but that it is highly dependent on the coreceptor function of the CD8β-chain. The ability to generate Th cell immunity by infusion of MHC class I-restricted Th cells may prove useful for the induction of tumor-specific T cell immunity in cases where MHC class II-associated epitopes are lacking.
CD8α Coreceptor to Improve TCR Gene Transfer to Treat Melanoma: Down-Regulation of Tumor-Specific Production of IL-4, IL-5, and IL-10
Authors: Willemsen Ralph A. , Sebestyén Zsolt , Ronteltap Cees , Berrevoets Cor , Drexhage Joost , Debets Reno 
Published: April 2014

AbstractTherapeutic success of TCR gene transfer to treat tumors depends on the ability of redirected T cells to become activated upon tumor recognition in vivo. Help provided by tumor-specific Th1 cells is reported to relieve T cells from an anergized state and to induce tumor regression. We recently demonstrated the ability to generate melanoma-specific Th1 cells by genetic introduction of both a CD8-dependent TCR and the CD8α coreceptor into CD4+ T cells. In this study, we analyzed a TCR that binds Ag independently of CD8, a property generally preferred to induce tumor-specific T cell responses, and addressed the contribution of CD8α following introduction into TCR-transduced CD4+ T cells. To this end, primary human CD4+ T cells were gene transferred with a high-avidity TCR, and were shown not only to bind peptide/MHC class I, but also to effectively kill Ag-positive tumor cells in the absence of CD8α. The introduction of CD8α up-regulates the tumor-specific production of TNF-α and IL-2 to some extent, but significantly down-regulates production of IL-4, IL-5, and IL-10 in CD4+ T cells. The introduction of a mutated cysteine motif in CD8α, which prevents its binding to LCK and linker for activation of T cells, did not adversely affect expression and T cell cytotoxicity, but counteracted the CD8α-mediated down-regulation of IL-4 and IL-5, but not IL-10. In conclusion, CD8α down-regulates the production of major Th2-type cytokines, in part mediated by LCK and/or linker for activation of T cells, and may induce differentiation of tumor-specific Th1 cells, which makes this coreceptor an interesting candidate to improve the clinical potential of TCR gene transfer to treat cancer.
TRAIL Deficiency Delays, but Does Not Prevent, Erosion in the Quality of “Helpless” Memory CD8 T Cells
Authors: Badovinac Vladimir P. , Messingham Kelly A. Nordyke , Griffith Thomas S. , Harty John T. 
Published: April 2014

AbstractIn this study, we investigated the role of TRAIL in Ag-specific CD8 T cell homeostasis after viral infection. TRAIL deficiency does not influence the kinetics of the Ag-specific CD8 T cell responses, and CD8 T cells in TRAIL-deficient mice were able to expand, contract, and generate functional memory cell numbers that were indistinguishable from TRAIL-sufficient wild-type CD8 T cells after acute lymphocytic choriomeningitis virus infection. Interestingly, the ability of “helpless” CD8 T cells to retain their memory phenotypic and functional (i.e., secondary expansion) characteristics was prolonged in TRAIL-deficient mice compared with wild-type CD4-depleted controls. However, TRAIL deficiency only delayed, but did not prevent, the eventual erosion in the quality of helpless memory CD8 T cells, and that correlated with their inability to respond to a second round of Ag-driven proliferation. These data, which suggest that CD4 help consists of both TRAIL-dependent and -independent components, may help to resolve the current controversy between the early programming and maintenance models that were put forward to explain the role of CD4 T cell help in Ag-specific CD8 T cell homeostasis.
Cutting Edge: Dexamethasone Negatively Regulates Syk in Mast Cells by Up-Regulating Src-Like Adaptor Protein
Authors: Hiragun Takaaki , Peng Ze , Beaven Michael A. 
Published: April 2014

AbstractWe have identified Src-like adaptor protein (SLAP) as one of several dexamethasone-inducible inhibitory regulators in mast cells. SLAP is a known inhibitor of T cell signaling and interacts with the tyrosine kinase, Zap70. Exposure of RBL-2H3 mast cells to dexamethasone markedly increased expression of SLAP. Cells so exposed or made to overexpress SLAP exhibited reduced Ag-stimulated phosphorylation of Syk (a cognate of Zap70), linker for activation of T cells, phospholipase Cγ, and ERK. Ca2+ mobilization, Ca2+-dependent degranulation, and ERK-dependent release of arachidonic acid were suppressed as well. Small interfering RNA directed against SLAP blocked the induction of SLAP and reversed the inhibitory effects of dexamethasone on phosphorylation of Syk, linker for activation of T cells, and phospholipase Cγ, but not downstream events, which are likely suppressed by up-regulation of downstream of tyrosine kinase-1 and MAPK phosphatase-1. The induction of these inhibitory regulators may contribute to the immunosuppressive activity of dexamethasone in mast cells.
Mesenchymal Stem Cells Inhibit Generation and Function of Both CD34+-Derived and Monocyte-Derived Dendritic Cells
Authors: Nauta Alma J. , Kruisselbrink Alwine B. , Lurvink Ellie , Willemze Roel , Fibbe Willem E. 
Published: April 2014

AbstractMesenchymal stem cells (MSCs) are not only able to evade the immune system, but they have also been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the present study, the effects of human MSCs on the differentiation and function of both CD34+-derived DCs and monocyte-derived DCs were investigated. The presence of MSCs during differentiation blocked the differentiation of CD14+CD1a− precursors into dermal/interstitial DCs, without affecting the generation of CD1a+ Langerhans cells. In line with these observations, MSCs also completely prevented the generation of immature DCs from monocytes. The inhibitory effect of MSCs on DC differentiation was dose dependent and resulted in both phenotypical and functional modifications, as demonstrated by a reduced expression of costimulatory molecules and hampered capacity to stimulate naive T cell proliferation. The inhibitory effect of MSCs was mediated via soluble factors. Taken together, these data demonstrate that MSCs, next to the antiproliferative effect on T cells, have a profound inhibitory effect on the generation and function of both CD34+-derived and monocyte-derived DCs, indicating that MSCs are able to modulate immune responses at multiple levels.
RUNX3 Negatively Regulates CD36 Expression in Myeloid Cell Lines
Authors: Puig-Kröger Amaya , Domínguez-Soto Angeles , Martínez-Muñoz Laura , Serrano-Gómez Diego , Lopez-Bravo María , Sierra-Filardi Elena , Fernández-Ruiz Elena , Ruiz-Velasco Natividad , Ardavín Carlos , Groner Yoram , Tandon Narendra , Corbí Angel L. , Vega Miguel A. 
Published: April 2014

AbstractCD36 is a member of the scavenger receptor type B family implicated in the binding of lipoproteins, phosphatidylserine, thrombospondin-1, and the uptake of long-chain fatty acids. On mononuclear phagocytes, recognition of apoptotic cells by CD36 contributes to peripheral tolerance and prevention of autoimmunity by impairing dendritic cell (DC) maturation. Besides, CD36 acts as a coreceptor with TLR2/6 for sensing microbial diacylglycerides, and its deficiency leads to increased susceptibility to Staphylococcus aureus infections. The RUNX3 transcription factor participates in reprogramming DC transcription after pathogen recognition, and its defective expression leads to abnormally accelerated DC maturation. We present evidence that CD36 expression is negatively regulated by the RUNX3 transcription factor during myeloid cell differentiation and activation. In molecular terms, RUNX3 impairs the activity of the proximal regulatory region of the CD36 gene in myeloid cells through in vitro recognition of two functional RUNX-binding elements. Moreover, RUNX3 occupies the CD36 gene proximal regulatory region in vivo, and its overexpression in myeloid cells results in drastically diminished CD36 expression. The down-regulation of CD36 expression by RUNX3 implies that this transcription factor could impair harmful autoimmune responses by contributing to the loss of pathogen- and apoptotic cell-recognition capabilities by mature DCs.