bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the P2Y12 Receptor in the Modulation of Murine Dendritic Cell Function by ADP
Authors: Ben Addi Abduelhakem , Cammarata Dorothée , Conley Pamela B. , Boeynaems Jean-Marie , Robaye Bernard 
Published: October 2010

Abstract
The effects of ADP on the biology of dendritic cells have been studied much less than those of ATP or adenosine. In this study, we showed that adenosine-5′-O-(2-thiodiphosphate) (ADPβS) induced intracellular Ca2+ transients in murine dendritic cells (DCs). This effect was abolished by AR-C69931MX, a dual P2Y12 and P2Y13 receptor antagonist. RT-PCR experiments revealed the expression of both P2Y12 and P2Y13 mRNA in DCs. The Ca2+ response to ADPβS was maintained in P2Y13-deficient DCs, whereas it was abolished completely in P2Y12−/− DCs. ADPβS stimulated FITC-dextran and OVA capture in murine DCs through macropinocytosis, and this effect was abolished in P2Y12−/− DCs. ADPβS had a similar effect on FITC-dextran uptake by human monocyte-derived DCs. OVA loading in the presence of ADPβS increased the capacity of DCs to stimulate OVA-specific T cells, whereas ADPβS had no effect on the ability of DCs to stimulate allogeneic T cells. Moreover, after immunization against OVA, the serum level of anti-OVA IgG1 was significantly lower in P2Y12−/− mice than that in wild-type controls. In conclusion, we have shown that the P2Y12 receptor is expressed in murine DCs and that its activation increased Ag endocytosis by DCs with subsequent enhancement of specific T cell activation.
Contributions of Edema Factor and Protective Antigen to the Induction of Protective Immunity by Bacillus anthracis Edema Toxin as an Intranasal Adjuvant
Authors: Duverger Alexandra , Carré Jeanne-Marie , Jee Junbae , Leppla Stephen H. , Cormet-Boyaka Estelle , Tang Wei-Jen , Tomé Daniel , Boyaka Prosper N. 
Published: October 2010

Abstract
We have shown that intranasal coapplication of Bacillus anthracis protective Ag (PA) together with a B. anthracis edema factor (EF) mutant having reduced adenylate cyclase activity (i.e., EF-S414N) enhances anti-PA Ab responses, but also acts as a mucosal adjuvant for coadministered unrelated Ags. To elucidate the role of edema toxin (EdTx) components in its adjuvanticity, we examined how a PA mutant lacking the ability to bind EF (PA-U7) or another mutant that allows the cellular uptake of EF, but fails to efficiently mediate its translocation into the cytosol (PA-dFF), would affect EdTx-induced adaptive immunity. Native EdTx promotes costimulatory molecule expression by macrophages and B lymphocytes, and a broad spectrum of cytokine responses by cervical lymph node cells in vitro. These effects were reduced or abrogated when cells were treated with EF plus PA-dFF, or PA-U7 instead of PA. We also intranasally immunized groups of mice with a recombinant fusion protein of Yersinia pestis F1 and LcrV Ags (F1-V) together with EdTx variants consisting of wild-type or mutants PA and EF. Analysis of serum and mucosal Ab responses against F1-V or EdTx components (i.e., PA and EF) revealed no adjuvant activity in mice that received PA-U7 instead of PA. In contrast, coimmunization with PA-dFF enhanced serum Ab responses. Finally, immunization with native PA and an EF mutant lacking adenylate cyclase activity (EF-K346R) failed to enhance Ab responses. In summary, a fully functional PA and a minimum of adenylate cyclase activity are needed for EdTx to act as a mucosal adjuvant.
The M Cell-Targeting Ligand Promotes Antigen Delivery and Induces Antigen-Specific Immune Responses in Mucosal Vaccination
Authors: Kim Sae-Hae , Seo Ki-Weon , Kim Ju , Lee Kyung-Yeol , Jang Yong-Suk 
Published: October 2010

AbstractOral mucosal immunization can induce protective immunity in both systemic compartments and the mucosa. Successful mucosal immunization depends on Ag delivery to the mucosal immune induction site. The high transcytotic activity of M cells within the mucosa makes these cells attractive targets for mucosal Ag delivery, although it remains unclear whether delivery of Ag to M cells only can guarantee the induction of effective immune responses. In this study, we evaluated the ability of an M cell-targeting ligand with adjuvant activity to induce immunity against ligand-fused Ag. We selected M cell-targeting ligands through biopanning of a phage display library against differentiated in vitro M-like cells and produced the recombinant Ags fused to the selected ligands using the model Ag. One of the selected peptide ligands, Co1, promoted the binding of ligand-fused Ag to mouse Peyer’s patch M cells and human M-like cells that had been defined by binding with the M cell-specific and anti-GP2 Abs. In addition, Co1 ligand enhanced the uptake of fused Ag by immunogenic tissue in an ex vivo loop assay and in vivo oral administration experiments. After oral administration, the ligand-fused Ag enhanced immune responses against the fused Ag compared with those of the control Ag without ligand. In addition, this use of the ligand supported a skewed Th2-type immune response against the fused Ag. Collectively, these results suggest that the ligand selected through biopanning against cultured M-like cells could be used as an adjuvant for targeted Ag delivery into the mucosal immune system to enhance immune induction.
TIM-3: A Novel Regulatory Molecule of Alloimmune Activation
Authors: Boenisch Olaf , D’Addio Francesca , Watanabe Toshihiko , Elyaman Wassim , Magee Ciara N. , Yeung Melissa Y. , Padera Robert F. , Rodig Scott J. , Murayama Takaya , Tanaka Katsunori , Yuan Xueli , Ueno Takuya , Jurisch Anke , Mfarrej Bechara , Akiba Hisaya , Yagita Hideo , Najafian Nader 
Published: October 2010

Abstract
T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4+FoxP3− and CD8+ T cells in acutely rejecting graft recipients. A blocking anti–TIM-3 mAb accelerated allograft rejection only in the presence of host CD4+ T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-γ–, IL-6–, and IL-17–producing splenocytes, enhanced CD8+ cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4+ T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4+ T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response.
A Ligand for CD5 Is CD5
Authors: Brown Marion H. , Lacey Erica 
Published: October 2010

Abstract
Recognition by scavenger receptor cysteine-rich domains on membrane proteins regulates innate and adaptive immune responses. Two receptors expressed primarily on T cells, CD5 and CD6, are linked genetically and are structurally similar, both containing three scavenger receptor cysteine-rich domains in their extracellular regions. A specific cell surface interaction for CD5 has been difficult to define at the molecular level because of the susceptibility of CD5 protein to denaturation. By using soluble CD5 purified at neutral pH to preserve biological activity, we show that CD5 mediates species-specific homophilic interactions. CD5 domain 1 only is involved in the interaction. CD5 mAbs that have functional effects in humans, rats, and mice block homophilic binding. Ag-specific responses by mouse T cells in vitro were increased when engagement of human CD5 domain 1 was inhibited by mutation or by IgG or Fab fragment from a CD5 mAb. This showed that homophilic binding results in productive engagement. Enhancement of polyclonal immune responses of rat lymph node cells by a Fab fragment from a CD5 mAb shown to block homophilic interactions provided evidence that the extracellular region of CD5 regulates inhibition in normal cells. These biochemical and in vitro functional assays provide evidence that the extracellular region of CD5 regulates immunity through species-specific homophilic interactions.
A Critical Function of Th17 Proinflammatory Cells in the Development of Atherosclerotic Plaque in Mice
Authors: Gao Qi , Jiang Yang , Ma Tian , Zhu Faliang , Gao Fei , Zhang Pin , Guo Chun , Wang Qun , Wang Xiaoyan , Ma Chunhong , Zhang Yun , Chen Wanjun , Zhang Lining 
Published: October 2010

Abstract
Considerable evidence supports that the CD4+ T cell-mediated immune response contributes to the development of atherosclerotic plaque. However, the effects of Th17 cells on atherosclerosis are not thoroughly understood. In this study, we evaluated the production and function of Th17 and Th1 cells in atherosclerotic-susceptible ApoE−/− mice. We observed that the proportion of Th17 cells, as well as Th1, increased in atherosclerotic ApoE−/− mice compared with nonatherosclerotic wild-type littermates. In ApoE−/− mice with atherosclerosis, the expression of IL-17 and retinoic acid-related orphan receptor γt was substantially higher in the arterial wall with plaque than in the arterial wall without plaque. Increased Th17 cells were associated with the magnitude of atherosclerotic plaque in ApoE−/− mice. Importantly, treatment of ApoE−/− mice with neutralizing anti–IL-17 Ab dramatically inhibited the development of atherosclerotic plaque, whereas rIL-17 application significantly promoted the formation of atherosclerotic plaque. These data demonstrate that Th17 cells play a critical role in atherosclerotic plaque formation in mice, which may have implications in patients with atherosclerosis.
The Rapid Induction of HLA-E Is Essential for the Survival of Antigen-Activated Naive CD4 T Cells from Attack by NK Cells
Authors: Takao Sumiko , Ishikawa Takayuki , Yamashita Kouhei , Uchiyama Takashi 
Published: October 2010

Abstract
Increasing evidence shows that NK cells regulate adaptive immunity, but the underlying mechanisms are not well understood. In this study, we show that activated human NK cells suppress autologous naive CD4 T cell proliferation in response to allogeneic dendritic cells (DCs) by selectively killing Ag-activated T cells. Naive CD4 T cells, which were initially resistant to NK cell-mediated cytotoxicity, became substantially susceptible to NK cells within a day after priming with DCs. Ag-activated T cells showed various degrees of susceptibility to NK cells. After 1 d of priming with LPS-matured DCs, T cells were less susceptible to NK cells than were T cells primed with TNF-α–matured DCs. Subsequently at day 3, Ag-activated T cells regained resistance to NK cells. The level of HLA-E expression on Ag-activated T cells was closely correlated with resistance to NK cells. HLA-E was highly expressed at day 1 by T cells primed with LPS-matured DCs but not by T cells primed with TNF-α–matured DCs. An Ab blockade revealed a critical role for the HLA-E–NKG2A interaction in the protection of Ag-activated T cells from NK cells. Collectively, this study demonstrates that NK cells impact adaptive immunity through the finely controlled kinetics of HLA-E expression on T cells. Thus, HLA-E may be a new target for immunoregulation.
The Protein Tyrosine Phosphatase SHP-1 Modulates the Suppressive Activity of Regulatory T Cells
Authors: Iype Tessy , Sankarshanan Mohan , Mauldin Ileana S. , Mullins David W. , Lorenz Ulrike 
Published: October 2010

Abstract
The importance of regulatory T cells (Tregs) for immune tolerance is well recognized, yet the signaling molecules influencing their suppressive activity are relatively poorly understood. In this article, through in vivo studies and complementary ex vivo studies, we make several important observations. First, we identify the cytoplasmic tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) as an endogenous brake and modifier of the suppressive ability of Tregs; consistent with this notion, loss of SHP-1 expression strongly augments the ability of Tregs to suppress inflammation in a mouse model. Second, specific pharmacological inhibition of SHP-1 enzymatic activity via the cancer drug sodium stibogluconate potently augmented Treg suppressor activity both in vivo and ex vivo. Finally, through a quantitative imaging approach, we directly demonstrate that Tregs prevent the activation of conventional T cells and that SHP-1–deficient Tregs are more efficient suppressors. Collectively, our data reveal SHP-1 as a critical modifier of Treg function and a potential therapeutic target for augmenting Treg-mediated suppression in certain disease states.
Mast Cell Fibroblastoid Differentiation Mediated by Airway Smooth Muscle in Asthma
Authors: Kaur Davinder , Saunders Ruth , Hollins Fay , Woodman Lucy , Doe Camille , Siddiqui Salman , Bradding Peter , Brightling Christopher 
Published: October 2010

Abstract
Mast cell microlocalization to the airway smooth muscle (ASM) bundle is a key feature of asthma, but whether these mast cells have an altered phenotype is uncertain. In this paper, we report that in vivo, mast cells within the ASM bundle, in contrast to mast cells in the bronchial submucosa, commonly expressed fibroblast markers and the number of these cells was closely related to the degree of airway hyperresponsiveness. In vitro human lung mast cells and mast cell lines cultured with fibronectin or with primary human ASM cells acquired typical fibroblastic markers and morphology. This differentiation toward a fibroblastoid phenotype was mediated by ASM-derived extracellular matrix proteins, independent of cell adhesion molecule-1, and was attenuated by α5β1 blockade. Fibroblastoid mast cells demonstrated increased chymase expression and activation with exaggerated spontaneous histamine release. Together these data indicate that in asthma, ASM-derived extracellular matrix proteins mediate human mast cell transition to a fibroblastoid phenotype, suggesting that this may be pivotal in the development of airway dysfunction in asthma.
Endothelin-1–Induced Macrophage Inflammatory Protein-1β Expression in Monocytic Cells Involves Hypoxia-Inducible Factor-1α and AP-1 and Is Negatively Regulated by microRNA-195
Authors: Gonsalves Caryn , Kalra Vijay K. 
Published: October 2010

Abstract
Patients with sickle cell disease (SCD) exhibit a chronic inflammatory state manifested by leukocytosis and increased circulating levels of proinflammatory cytochemokines. Our studies show that placenta growth factor levels are high in SCD, and placental growth factor induces the release of the vasoconstrictor endothelin-1 (ET-1) from pulmonary microvascular endothelial cells. In this study, we observed that ET-1 increased the expression of the chemokines MIP-1β or CCL4. ET-1–induced MIP-1β mRNA expression in THP-1 cells and human peripheral blood monocytes occurred via the activation of PI3K, NADPH oxidase, p38 MAPK, and JNK-1 but not JNK-2. ET-1–induced MIP-1β expression involved hypoxia-inducible factor-1α (HIF-1α), independent of hypoxia, as demonstrated by silencing with HIF-1α small interfering RNA, EMSA, and chromatin immunoprecipitation analysis. ET-1–induced MIP-1β promoter luciferase activity was attenuated when any of the five hypoxia-response elements, AP-1, or NF-κB binding motifs in the proximal MIP-1β promoter (−1053/+43 bp) were mutated. Furthermore, ET-1 significantly downregulated the expression of a key microRNA, microRNA-195a, which showed a complementary binding site in the 3′ untranslated region of MIP-1β mRNA. Moreover, ET-1–induced MIP-1β mRNA expression in either THP-1 cells or peripheral blood monocytes was reduced upon expression of microRNA-195a. Conversely, transfection of monocytes with anti–microRNA-195a oligonucleotide augmented several-fold ET-1–induced MIP-1β expression. Taken together, these studies showed that ET-1–mediated MIP-1β gene expression is regulated via hypoxia-response elements, AP-1, and NF-κB cis-binding elements in its promoter and negatively regulated by microRNA-195, which targets the 3′ untranslated region of MIP-1β RNA. These studies provide what we believe are new avenues, based on targets of HIF-1α and microRNAs, for ameliorating inflammation in SCD.
Impaired Apoptotic Cell Clearance in the Germinal Center by Mer-Deficient Tingible Body Macrophages Leads to Enhanced Antibody-Forming Cell and Germinal Center Responses
Authors: Rahman Ziaur S. M. , Shao Wen-Hai , Khan Tahsin N. , Zhen Yuxuan , Cohen Philip L. 
Published: October 2010

Abstract
Germinal centers (GCs) are specialized microenvironments that generate high-affinity Ab-forming cells (AFCs) and memory B cells. Many B cells undergo apoptosis during B cell clonal selection in GCs. Although the factors that regulate the AFC and GC responses are not precisely understood, it is widely believed that dysregulated AFCs and GCs contribute to autoimmunity. The Mer receptor tyrosine kinase (Mer) facilitates macrophage clearance of apoptotic cells. The Tyro-3, Axl, and Mer receptors, including Mer, suppress TLRs and cytokine-mediated inflammatory responses. We report in this study that tingible body macrophages (TBMϕs) in GCs express Mer. Compared to C57BL/6 (B6) controls, Mer-deficient (Mer−/−) mice had significantly higher AFC, GC, and Th1-skewed IgG2 Ab (especially IgG2c) responses against the T cell-dependent Ag (4-hydroxy-3-nitrophenyl) acetyl-chicken γ globulin. Mer−/− mice had a significantly higher percentage of GC B cells on days 9, 14, and 21 postimmunization compared with B6 controls. Significantly increased numbers of apoptotic cells accumulated in Mer−/− GCs than in B6 GCs, whereas the number of TBMϕs remained similar in both strains. Our data are the first, to our knowledge, to demonstrate a critical role for Mer in GC apoptotic cell clearance by TBMϕs and have interesting implications for Mer in the regulation of B cell tolerance operative in the AFC and GC pathways.
Innate Immune Activation during Salmonella Infection Initiates Extramedullary Erythropoiesis and Splenomegaly
Authors: Jackson Amy , Nanton Minelva R. , O’Donnell Hope , Akue Adovi D. , McSorley Stephen J. 
Published: October 2010

Abstract
Systemic Salmonella infection commonly induces prolonged splenomegaly in murine or human hosts. Although this increase in splenic cellularity is often assumed to be due to the recruitment and expansion of leukocytes, the actual cause of splenomegaly remains unclear. We monitored spleen cell populations during Salmonella infection and found that the most prominent increase is found in the erythroid compartment. At the peak of infection, the majority of spleen cells are immature CD71−Ter119+ reticulocytes, indicating that massive erythropoiesis occurs in response to Salmonella infection. Indeed, this increase in RBC precursors corresponded with marked elevation of serum erythropoietin (EPO). Furthermore, the increase in RBC precursors and EPO production required innate immune signaling mediated by Myd88/TRIF. Neutralization of EPO substantially reduced the immature RBC population in the spleen and allowed a modest increase in host control of infection. These data indicate that early innate immunity to Salmonella initiates marked splenic erythropoiesis and may hinder bacterial clearance.
BLT2 Is Upregulated in Allergen-Stimulated Mast Cells and Mediates the Synthesis of Th2 Cytokines
Authors: Cho Kyung-Jin , Seo Ji-Min , Lee Min-Goo , Kim Jae-Hong 
Published: October 2010

AbstractMast cells are effector cells that mediate the allergic response through Ag stimulation of IgE bound to FcεRI. In allergic reactions, cross-linking of the surface receptors for IgE on mast cells results in the synthesis of Th2 cytokines such as IL-4 and IL-13, which are critical for the initiation and progression of the allergic response. Despite the important roles of these cytokines, the signaling mechanism by which Ag stimulation mediates the production of IL-4 and IL-13 in mast cells is not clearly understood. In the present study, we found that Ag-stimulated bone marrow-derived mast cells (BMMCs) highly upregulated the expression of BLT2, a leukotriene B4 receptor, and that blockade of BLT2 with the specific antagonist LY255283 or small interfering RNA knockdown completely abolished the production of Th2 cytokines. Furthermore, BMMCs overexpressing BLT2 showed significantly enhanced production of Th2 cytokines compared with wild-type BMMCs. Additionally, we found that the generation of Nox1-derived reactive oxygen species occurs downstream of BLT2, thus mediating the synthesis of Th2 cytokines. Taken together, our results suggest that the BLT2-Nox1-reactive oxygen species cascade is a previously unsuspected mediatory signaling mechanism to Th2 cytokine production in Ag-stimulated BMMCs, thus contributing to allergic response.
A Role for Lymphotoxin in Primary Sjögren’s Disease
Authors: Shen Long , Suresh Lakshmanan , Wu Jing , Xuan Jingxiu , Li Hong , Zhang Chongjie , Pankewycz Oleh , Ambrus Julian L. 
Published: October 2010

Abstract
The etiology of salivary gland injury in primary Sjögren’s disease is not well understood. We have previously described a mouse model of Sjögren’s disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren’s disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA−/− mice, the IL14αTG.LTA−/− mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA−/− mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA−/− mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren’s disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren’s disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren’s disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.