bluuebunny/crossref_metadata_2025_split huggingface dataset:
Negative Control of Store-Operated Ca2+ Influx by B Cell Receptor Cross-Linking
Authors: Hashimoto Akiko , Hirose Kenzo , Kurosaki Tomohiro , Iino Masamitsu 
Published: April 2014

AbstractAn increase in the intracellular Ca2+ concentration by B cell receptor (BCR) cross-linking plays important roles in the regulation of B cell functions. [Ca2+]i is regulated by Ca2+ release from the Ca2+ store as well as store-operated Ca2+ influx (SOC). Protein tyrosine kinases downstream of BCR cross-linking were shown to regulate the mechanism for Ca2+ release. However, it remains elusive whether BCR cross-linking regulates SOC or not. In this study, we examined the effect of BCR cross-linking on thapsigargin-induced SOC in the DT40 B cells. We found that the SOC-mediated increase in intracellular Ca2+ concentration was inhibited by BCR cross-linking. Using a membrane-potential-sensitive dye, we found that BCR cross-linking induced depolarization, which is expected to decrease the driving force of Ca2+ influx and SOC channel conductance. When membrane potential was held constant by the transmembrane K+ concentration gradient in the presence of valinomycin, the BCR-mediated inhibition of SOC was still observed. Thus, the BCR-mediated inhibition of SOC involves both depolarization-dependent and depolarization-independent mechanisms of SOC inhibition. The depolarization-independent inhibition of the SOC was abolished in Lyn-deficient, but not in Bruton’s tyrosine kinase-, Syk- or SHIP (Src homology 2 domain containing phosphatidylinositol 5′-phosphatase)-deficient cells, indicating that Lyn is involved in the inhibition. These results show novel pathways of BCR-mediated SOC regulations.
Lymphotoxin α−/− Mice Develop Functionally Impaired CD8+ T Cell Responses and Fail to Contain Virus Infection of the Central Nervous System
Authors: Kumaraguru Udayasankar , Davis Ila A. , Deshpande Shilpa , Tevethia Satvir S. , Rouse Barry T. 
Published: April 2014

Abstract
Recent observations have indicated that viral persistence and tumor spreading could occur because of effector function-defective CD8+ T cells. Although chronic exposure to Ag, lack of CD4 help, and epitope dominance are suggested to interfere with CTL differentiation, mechanisms underlying the defective effector function remain obscure. We demonstrate in this report that lymphotoxin α-deficient mice develop CD8+ T cells at normal frequencies when infected with HSV or immunized with OVA Ag but show impaired cytotoxic and cytokine-mediated effector functions resulting in enhanced susceptibility to HSV-induced encephalitis. Although these cells display near normal levels of perforin and Fas ligand, they remain largely at a naive state as judged by high expression of CD62 ligand and failure to up-regulate activation or memory markers. In particular, these CD8+ T cells revealed inadequate expression of the IL-12 receptor, thus establishing a link between CTL differentiation and LTα possibly through regulation of IL-12 receptor. Viruses and tumors could evade immunity by targeting the same pathway.
Transcriptional Down-Regulation of CXC Chemokine Receptor 4 Induced by Impaired Association of Transcription Regulator YY1 with c-Myc in Human Herpesvirus 6-Infected Cells
Authors: Hasegawa Atsuhiko , Yasukawa Masaki , Sakai Ikuya , Fujita Shigeru 
Published: April 2014

Abstract
We have recently reported that down-regulation of CXC chemokine receptor (CXCR) 4 in CD4+ T lymphocytes is induced by human herpesvirus (HHV) 6 infection. In this study, we further studied the mechanisms of HHV-6-induced CXCR4 down-regulation, focusing on the regulation of CXCR4 transcription. Down-regulation of CXCR4 transcription was detected in HHV-6A-infected JJHAN and HHV-6B-infected MT-4 cell lines, as we had previously reported for HHV-6-infected peripheral blood CD4+ T lymphocytes. Luciferase assays revealed that a YY1-binding site around −320 relative to the transcription start site is important for down-regulation of CXCR4 transcription in HHV-6-infected cells. The binding activity of YY1, which is a repressor of CXCR4 transcription, to the CXCR4 promoter appeared to significantly increase in HHV-6-infected cells compared with the binding activity in mock-infected cells. Immunoprecipitation assays showed that in HHV-6-infected cells association of c-Myc with YY1 was decreased and that of Max with c-Myc was increased, whereas association of Mad with Max appeared to be decreased. The amounts of each of YY1, c-Myc, Max, and Mad proteins synthesized in cells were not altered by HHV-6 infection. These data indicate that the decreased association of YY1 with c-Myc that is caused by impaired interaction in the c-Myc/Max/Mad network results in increased binding activity of YY1 to the CXCR4 promoter, mediating down-regulation of CXCR4 production in HHV-6-infected cells.
Rac2 Is an Essential Regulator of Neutrophil Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activation in Response to Specific Signaling Pathways
Authors: Kim Chaekyun , Dinauer Mary C. 
Published: April 2014

AbstractRac2 is a hematopoietic-specific Rho family GTPase implicated as an important constituent of the NADPH oxidase complex and shares 92% amino acid identity with the ubiquitously expressed Rac1. In bone marrow (BM) neutrophils isolated from rac2−/− mice generated by gene targeting, we previously reported that PMA-induced superoxide production was reduced by about 4-fold, which was partially corrected in TNF-α-primed BM neutrophils and in peritoneal exudate neutrophils. We investigated receptor-mediated activation of the NADPH oxidase in the current study, finding that superoxide production in rac2−/− BM and peritoneal exudate neutrophils was normal in response to opsonized zymosan, reduced to 22% of wild type in response to IgG-coated SRBC, and almost absent in response to fMLP. In wild-type murine BM neutrophils, phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and Akt was induced by PMA or fMLP, which was decreased in rac2−/− neutrophils for ERK1/2 and p38. Activation of p38 by either opsonized zymosan or IgG-coated SRBC was similar in wild-type and rac2−/− cells. Inhibition of ERK1/2 or p38 activation using either PD98059 or SB203580, respectively, had only a modest effect on fMLP-elicited superoxide production and no effect on the PMA-induced response. These data provide genetic evidence supporting an important role for Rac2 in regulating neutrophil NADPH oxidase activation downstream of chemoattractant and Fcγ receptors. The effect of Rac2 deficiency on superoxide production is probably exerted through multiple pathways, including those independent of mitogen-activated protein kinase activation.
Hepatocyte Growth Factor Is a Regulator of Monocyte-Macrophage Function
Authors: Galimi Francesco , Cottone Erika , Vigna Elisa , Arena Nicolò , Boccaccio Carla , Giordano Silvia , Naldini Luigi , Comoglio Paolo M. 
Published: April 2014

Abstract
Hepatocyte growth factor (HGF) is a potent paracrine mediator of stromal/epithelial interactions, which is secreted as a matrix-associated inactive precursor (pro-HGF) and locally activated by tightly controlled urokinase cleavage. It induces proliferation and motility in epithelial and endothelial cells, and plays a role in physiological and pathological processes involving invasive cell growth, such as angiogenesis and parenchymal regeneration. We now report that HGF induces directional migration and cytokine secretion in human monocytes. Monocyte activation by endotoxin and IL-1β results in the up-regulation of the HGF receptor expression and in the induction of cell-associated pro-HGF convertase activity, thus enhancing cell responsiveness to the factor. Furthermore, we provide evidence for the secretion of biologically active HGF by activated monocytes, implying an autocrine stimulation. Altogether, these data indicate that monocyte function is modulated by HGF in a paracrine/autocrine manner, and provide a new link between stromal environment and mononuclear phagocytes.
Neutral Endopeptidase Terminates Substance P-Induced Inflammation in Allergic Contact Dermatitis
Authors: Scholzen Thomas E. , Steinhoff Martin , Bonaccorsi Paola , Klein Robin , Amadesi Silvia , Geppetti Piero , Lu Bao , Gerard Norma P. , Olerud John E. , Luger Thomas A. , Bunnett Nigel W. , Grady Eileen F. , Armstrong Cheryl A. , Ansel John C. 
Published: April 2014

AbstractSensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP−/− knockout and NEP+/+ wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP−/− animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP−/− mice, the acute inhibition of NEP in NEP+/+ animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP−/− compared with NEP+/+ animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.
Type 1 Diabetes-Predisposing MHC Alleles Influence the Selection of Glutamic Acid Decarboxylase (GAD) 65-Specific T Cells in a Transgenic Model
Authors: Abraham Roshini S. , Wen Li , Marietta Eric V. , David Chella S. 
Published: April 2014

AbstractThe genetic factors that contribute to the etiology of type 1 diabetes are still largely uncharacterized. However, the genes of the MHC (HLA in humans) have been consistently associated with susceptibility to disease. We have used several transgenic mice generated in our laboratory, bearing susceptible or resistant HLA alleles, in the absence of endogenous MHC class II (Aβo), to study immune responses to the autoantigen glutamic acid decarboxylase (GAD) 65 and its relevance in determining the association between autoreactivity and disease pathogenesis. Mice bearing diabetes-susceptible haplotypes, HLA DR3 (DRB1*0301) or DQ8 (DQB1*0302), singly or in combination showed spontaneous T cell reactivity to rat GAD 65, which is highly homologous to the self Ag, mouse GAD 65. The presence of diabetes-resistant or neutral alleles, such as HLA DQ6 (DQB1*0602) and DR2 (DRB1*1502) prevented the generation of any self-reactive responses to rat GAD. In addition, unmanipulated Aβo/DR3, Aβo/DQ8, and Aβo/DR3/DQ8 mice recognized specific peptides, mainly from the N-terminal region of the GAD 65 molecule. Most of these regions are conserved between human, mouse, and rat GAD 65. Further analysis revealed that the reactivity was mediated primarily by CD4+ T cells. Stimulation of these T cells by rat GAD 65 resulted in the generation of a mixed Th1/Th2 cytokine profile in the Aβo/DR3/DQ8, Aβo/DR3, and Aβo/DQ8 mice. Thus, the presence of diabetes-associated genes determines whether immune tolerance is maintained to islet autoantigens, but autoreactivity in itself is not sufficient to induce diabetes.
Both γδ T Cells and NK Cells Inhibit the Engraftment of Xenogeneic Rat Bone Marrow Cells and the Induction of Xenograft Tolerance in Mice
Authors: Nikolic Boris , Cooke David T. , Zhao Guiling , Sykes Megan 
Published: April 2014

Abstract
In murine allogeneic bone marrow transplantation recipients, treatment of the hosts with a nonmyeloablative regimen, including depleting anti-CD4 and anti-CD8 mAbs, allows establishment of long-term mixed chimerism and donor-specific tolerance. However, in the xenogeneic rat-to-mouse combination, additional anti-Thy1.2 and anti-NK1.1 mAbs are required. We have now attempted to identify the xenoresistant mouse cell populations that are targeted by anti-NK1.1 and anti-Thy1.2 mAbs. C57BL/6 (B6) wild-type, B6 TCRβ−/−, and B6 TCRδ−/− mice received anti-CD4 and anti-CD8 mAbs, followed by 3 Gy of whole body irradiation, 7 Gy of thymic irradiation, and transplantation of T cell-depleted rat bone marrow cells. Anti-NK1.1 and anti-Thy1.2 mAbs were additionally administered to some groups. Increased rat chimerism was observed in TCRδ−/− mice treated with anti-CD4, anti-CD8, and anti-NK1.1 mAbs compared with similarly treated TCRβ−/− mice. In TCRβ−/− mice, but not in TCR δ−/− mice, donor chimerism was increased by treatment with anti-Thy1.2 mAb, indicating that CD4−CD8−TCRγδ+Thy1.2+NK1.1− cells (γδ T cells) are involved in the rejection of rat marrow. In addition, chimerism was enhanced in both TCRβ−/− and TCRδ−/− mice treated with anti-CD4, anti-CD8, and anti-Thy1.2 mAbs by the addition of anti-NK1.1 mAb to the conditioning regimen. Donor-specific skin graft prolongation was enhanced by anti-Thy1.2 and anti-NK1.1 mAbs in TCRδ−/− mice. Therefore, in addition to CD4 and CD8 T cells, γδ T cells and NK cells play a role in resisting engraftment of rat marrow and the induction of xenograft tolerance in mice.
Targeting Murine Immune Responses to Selected T Cell- or Antibody-Defined Determinants of the Hepatitis B Surface Antigen by Plasmid DNA Vaccines Encoding Chimeric Antigen
Authors: Schirmbeck Reinhold , Zheng Xin , Roggendorf Michael , Geissler Michael , Chisari Francis V. , Reimann Jörg , Lu Mengji 
Published: April 2014

AbstractBy exchanging sequences from the middle-surface (MS) and small-surface (S) Ag of hepatitis B virus (HBV) with corresponding sequences of the MS Ag of woodchuck hepatitis virus, we constructed chimeric MS variants. Using these constructs as DNA vaccines in mice, we selectively primed highly specific (non-cross-reactive) Ab responses to pre-S2 of the HBV MS Ag and the “a” determinant of the HBV S Ag, as well as Ld- or Kb-restricted CTL responses to HBV S epitopes. In transgenic mice that constitutively express large amounts of HBV surface Ag in the liver we could successfully suppress serum antigenemia (but not Ag production in the liver) by adoptive transfer of anti-pre-S2 or anti-“a” immunity but not CTL immunity. DNA vaccines greatly facilitate construction of chimeric fusion Ags that efficiently prime specific, high-affinity Ab and CTL responses. Such vaccines, in which sequences of an Ag of interest are exchanged between different but related viruses, are interesting tools for focusing humoral or cellular immunity on selected antigenic determinants and elucidating their biological role.
Cutting Edge: Two Distinct Mechanisms Lead to Impaired T Cell Homeostasis in Janus Kinase 3- and CTLA-4-Deficient Mice
Authors: Gozalo-Sanmillan Sara , McNally James M. , Lin Meei Y. , Chambers Cynthia A. , Berg Leslie J. 
Published: April 2014

Abstract
Cytokine receptor signaling and costimulatory receptor signaling play distinct roles in T cell activation. Nonetheless, deficiencies in either of these pathways lead to seemingly similar phenotypes of impaired T cell homeostasis. A dramatic expansion of CD4+ peripheral T cells with an activated phenotype has been observed in both Janus kinase (Jak) 3-deficient and CTLA-4-deficient mice. Despite these similarities, the mechanisms driving T cell expansion may be distinct. To address this possibility, we examined the TCR repertoire of peripheral T cells in Jak3−/− and CTLA-4−/− mice using complementarity-determining region 3 spectratype analysis. Interestingly, a restricted and highly biased TCR repertoire was observed in the Jak3−/− T cells, strongly supporting a role for foreign Ag in the activation and expansion of these cells. In contrast, CTLA-4−/− T cells had a diverse and unbiased TCR repertoire, suggestive of a universal, Ag-independent mechanism of activation and expansion. These findings provide insight into the diverse mechanisms controlling T cell homeostasis.
Cutting Edge: Restoration of the Ability to Generate CTL in Mice Immune to Adenovirus by Delivery of Virus in a Collagen-Based Matrix
Authors: Siemens D. Robert , Elzey Bennett D. , Lubaroff David M. , Bohlken Caitlin , Jensen Robert J. , Swanson Axel Karl , Ratliff Timothy L. 
Published: April 2014

AbstractViruses are commonly used for the delivery of genes coding for tumor-associated Ags to elicit tumor-specific immune responses. The success of viral vectors has been limited in preclinical and clinical trials in part because of antiviral immunity. We investigated the ability of a collagen-based matrix (Gelfoam; Pharmacia and Upjohn, Kalamazoo, MI) to improve CTL activation by recombinant adenovirus. The data show that coinjection of Gelfoam with type 5 adenovirus recombinant for prostate-specific Ag (Ad5-PSA) enhanced CTL activation. Ad5-PSA priming in Gelfoam also abrogated the inhibitory effects of adenoviral immunity on CTL activation in mice naive to PSA but immune to adenovirus. Finally, Gelfoam enhanced immunization in a self-Ag model using type 5 adenovirus recombinant for membrane-bound OVA (Ad5-mOVA) in rat insulin promoter (RIP)-mOVA-transgenic mice. Thus, Gelfoam enhances CTL activation by recombinant viral vectors in a setting where preformed Ab to the virus is present and also in a tolerant self-Ag model.
Stem Cell Factor and FLT3-Ligand Are Strictly Required to Sustain the Long-Term Expansion of Primitive CD34+DR− Dendritic Cell Precursors
Authors: Curti Antonio , Fogli Miriam , Ratta Marina , Tura Sante , Lemoli Roberto M. 
Published: April 2014

Abstract
We studied cytokine-driven differentiation of primitive human CD34+HLA-DR− cells to myeloid dendritic cells (DC). Hemopoietic cells were grown in long-term cultures in the presence of various combinations of early acting cytokines such as FLT3-ligand (FLT3-L) and stem cell factor (SCF) and the differentiating growth factors GM-CSF and TNF-α. Two weeks of incubation with GM-CSF and TNF-α generated fully functional DC. However, clonogenic assays demonstrated that CFU-DC did not survive beyond 1 wk in liquid culture regardless of whether FLT3-L and/or SCF were added. FLT3-L or SCF alone did not support DC maturation. However, the combination of the two early acting cytokines allowed a 100-fold expansion of CFU-DC for &gt;1 month. Phenotypic analysis demonstrated the differentiation of CD34+DR− cells into CD34−CD33+DR+CD14+ cells, which were intermediate progenitors capable of differentiating into functionally active DC upon further incubation with GM-CSF and TNF-α. As expected, GM-CSF and TNF-α generated DC from committed CD34+DR+ cells. However, only SCF, with or without FLT3-L, induced the expansion of DC precursors for &gt;4 wk, as documented by secondary clonogenic assays. This demonstrates that although GM-CSF and TNF-α do not require additional cytokines to generate DC from primitive human CD34+DR− progenitor cells, they do force terminal differentiation of DC precursors. Conversely, FLT3-L and SCF do not directly affect DC differentiation, but instead sustain the long-term expansion of CFU-DC, which can be induced to produce mature DC by GM-CSF and TNF-α.
The Generation of Th Memory in Neonates Versus Adults: Prolonged Primary Th2 Effector Function and Impaired Development of Th1 Memory Effector Function in Murine Neonates
Authors: Adkins Becky , Bu Yurong , Guevara Patricia 
Published: April 2014

Abstract
Immunization during the neonatal period often results in Th2-biased secondary responses. To understand the regulation of this phenomenon, we have examined all phases of Th development, from the generation of primary effectors to the duration of the primary effector stage to the production of memory effector function. First, we had previously reported that although primary responses in the neonatal lymph nodes are mature, mixed Th1/Th2-like, primary responses in the spleens of the same animals are exclusively Th2-like. To determine whether Th2-dominant secondary responses are due to the Th2-polarized primary function in the spleen, neonates were splenectomized before immunization. Even in the absence of primary neonatal splenic responses, the secondary responses of neonates were Th2 dominant. Thus, the overwhelmingly Th2 primary responses in the neonatal spleen are not required to generate Th2-dominant memory in the lymph nodes. Second, we have compared the kinetics of the primary response phase in neonates and adults. In adults, Ag-specific Th2 function disappeared rapidly from both the lymph nodes and spleen. In contrast, primary Th2 function persisted out to 5 wk in both neonatal organs. Third, the generation of Th memory responses was examined in animals initially immunized as neonates and in adults. These experiments demonstrated that neonates are selectively impaired in the development of Th1 memory effector function. Together, these results indicate that neonates are biased to Th2 function at all phases of an immune response.
IL-18 Enhances IL-4 Production by Ligand-Activated NKT Lymphocytes: A Pro-Th2 Effect of IL-18 Exerted Through NKT Cells
Authors: Leite-de-Moraes Maria C. , Hameg Agathe , Pacilio Maria , Koezuka Yasuhiko , Taniguchi Masaru , Van Kaer Luc , Schneider Elke , Dy Michel , Herbelin André 
Published: April 2014

Abstract
NKT cells are a remarkably versatile population whose functional capacities are determined by cytokines present in their microenvironment. In this study, we provide evidence for a new immunoregulatory effect of the proinflammatory cytokine IL-18 on NKT cells. We found that IL-18, mainly known for its involvement in NK cell activation and in Th 1 immune responses, substantially enhanced IL-4 production as well as the percentage of IL-4+ cells among NKT lymphocytes activated by their specific ligand α-galactosylceramide (α-GalCer). The effect of IL-18 on IL-4 production by activated NKT cells took place both in vivo and in vitro and was not affected by IL-12 which increased IFN-γ secretion in the same conditions. We show that NKT cells are the main targets for IL-18-induced IL-4 production since it occurred neither in NKT-deficient mice nor after stimulation of Th2 lymphocytes. Finally, we provide evidence that the IL-4 promptly generated by NKT cells in response to IL-18 plus α-galactosylceramide in vivo can effectively contribute to the adaptive Th2 immune response by up-regulating the early activation marker CD69 on B cells. Our data support the notion that, in contrast to the exclusive IFN-γ inducer IL-12, IL-18 acts in a more subtle manner as a costimulatory factor in both pro-Th1 and pro-Th2 responses depending on the nature of the stimulation and the target cells.