bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human CD1D Gene Expression Is Regulated by LEF-1 through Distal Promoter Regulatory Elements
Authors: Chen Qiao-Yi , Zhang Tao , Pincus Seth H. , Wu Shixiu , Ricks David , Liu Donald , Sun Zhongsheng , Maclaren Noel , Lan Michael S. 
Published: April 2010

Abstract
CD1d-expressing cells present lipid Ag to CD1d-restricted NKT cells, which play an important role in immune regulation and tumor rejection. Lymphoid enhancer-binding factor-1 (LEF-1) is one of the regulators of the Wnt signaling pathway, which is a powerful regulator in cellular growth, differentiation, and transformation. There is little evidence connecting Wnt signaling to CD1d expression. In this study, we have identified LEF-1 as a regulator of the expression of the gene encoding the human CD1d molecule (CD1D). We found that LEF-1 binds specifically to the CD1D promoter. Overexpression of LEF-1 in K562 or Jurkat cells suppresses CD1D promoter activity and downregulates endogenous CD1D transcripts, whereas knockdown of LEF-1 using LEF-1–specific small interfering RNA increases CD1D transcripts in K562 and Jurkat cells but there are different levels of surface CD1d on these two cell types. Chromatin immunoprecipitation showed that the endogenous LEF-1 is situated at the CD1D promoter and interacts with histone deacetylase-1 to facilitate the transcriptional repressor activity. Knockdown of LEF-1 using small interfering RNA potentiates an acetylation state of histone H3/H4, supporting the notion that LEF-1 acts as a transcriptional repressor for the CD1D gene. Our finding links LEF-1 to CD1D and suggests a role of Wnt signaling in the regulation of the human CD1D gene.
Cell-Intrinsic Defects in the Proliferative Response of Antiviral Memory CD8 T Cells in Aged Mice upon Secondary Infection
Authors: Decman Vilma , Laidlaw Brian J. , DiMenna Lauren J. , Abdulla Sarah , Mozdzanowska Krystyna , Erikson Jan , Ertl Hildegund C. J. , Wherry E. John 
Published: April 2010

Abstract
Although previous studies have demonstrated delayed viral clearance and blunted effector T cell responses in aged mice during infection, memory CD8 T cells and especially secondary responses have received less attention. In this study, we show that modest differences in the number of memory CD8 T cells formed in aged versus young animals were associated with altered memory CD8 T cell differentiation. Aged immune mice had increased morbidity and mortality upon secondary viral challenge, suggesting changes in T cell immunity. Indeed, virus-specific memory CD8 T cells from aged mice showed substantially reduced proliferative expansion upon secondary infection using multiple challenge models. In addition, this defect in recall capacity of aged memory CD8 T cells was cell-intrinsic and persisted upon adoptive transfer into young mice. Thus, the poor proliferative potential of memory T cells and altered memory CD8 T cell differentiation could underlie age-related defects in antiviral immunity.
Gene Coexpression Analysis in Single Cells Indicates Lymphomyeloid Copriming in Short-Term Hematopoietic Stem Cells and Multipotent Progenitors
Authors: Gautreau Laetitia , Boudil Amine , Pasqualetto Valérie , Skhiri Lamia , Grandin Laure , Monteiro Marta , Jais Jean-Philippe , Ezine Sophie 
Published: April 2010

Abstract
Progressive restriction to a differentiation pathway results from both activation and silencing of particular gene expression programs. To identify the coexpression and the expression levels of regulatory genes during hematopoietic stem cell (HSC) differentiation toward the T cell branch, we applied a new single-cell RT-PCR technique to analyze the simultaneous expression of 13 genes in 9 functionally purified populations from the bone marrow and the thymus. We report in this paper that Lin−Sca1+ckit+ HSCs display, at the single-cell level, a homogeneous and high transcriptional activity as do early thymic progenitors. Moreover, the coexpression of lymphoid and myeloid genes is an early event detected in ∼30% of short-term HSC and most multipotent progenitors, suggesting novel sources for the generation of early thymic progenitors, common lymphoid progenitors (CLPs), and common myeloid progenitors. Loss of multipotency in Lin−Sca1+ckit+ cells directed to the lymphoid branch is characterized by Lmo2 and Gata2 gene expression downregulation. Indeed, highest levels of Gata2 expression are detected only in long-term and short-term HSC populations. Complete shutdown of Pu1 gene expression in all triple-negative (TN)3 stage thymic pre-T cells is indicative of total T cell commitment. Interestingly, this is also observed in 30% of TN2 cells and 25% of CLP in the bone marrow, suggesting a possible initiation of T cell engagement in TN2 and CLP. Also, our strategy highlights similar gene patterns among HSCs and intrathymic progenitors, proposing, therefore, that identical activation signals are maintained until further maturation and generation of CD4 and CD8 coreceptors bearing thymocytes.
Regulatory B Cells (B10 Cells) Have a Suppressive Role in Murine Lupus: CD19 and B10 Cell Deficiency Exacerbates Systemic Autoimmunity
Authors: Watanabe Rei , Ishiura Nobuko , Nakashima Hiroko , Kuwano Yoshihiro , Okochi Hitoshi , Tamaki Kunihiko , Sato Shinichi , Tedder Thomas F. , Fujimoto Manabu 
Published: April 2010

Abstract
B cells play critical roles in the pathogenesis of lupus. To examine the influence of B cells on disease pathogenesis in a murine lupus model, New Zealand Black and New Zealand White F1 hybrid (NZB/W) mice were generated that were deficient for CD19 (CD19−/− NZB/W mice), a B cell-specific cell surface molecule that is essential for optimal B cell signal transduction. The emergence of anti-nuclear Abs was significantly delayed in CD19−/− NZB/W mice compared with wild type NZB/W mice. However, the pathologic manifestations of nephritis appeared significantly earlier, and survival was significantly reduced in CD19−/− NZB/W mice compared with wild type mice. These results demonstrate both disease-promoting and protective roles for B cells in lupus pathogenesis. Recent studies have identified a potent regulatory B cell subset (B10 cells) within the rare CD1dhiCD5+ B cell subset of the spleen that regulates acute inflammation and autoimmunity through the production of IL-10. In wild type NZB/W mice, the CD1dhiCD5+B220+ B cell subset that includes B10 cells was increased by 2.5-fold during the disease course, whereas CD19−/− NZB/W mice lacked this CD1dhiCD5+ regulatory B cell subset. However, the transfer of splenic CD1dhiCD5+ B cells from wild type NZB/W mice into CD19−/− NZB/W recipients significantly prolonged their survival. Furthermore, regulatory T cells were significantly decreased in CD19−/− NZB/W mice, but the transfer of wild type CD1dhiCD5+ B cells induced T regulatory cell expansion in CD19−/− NZB/W mice. These results demonstrate an important protective role for regulatory B10 cells in this systemic autoimmune disease.
Protective and Pathogenic Roles for B Cells during Systemic Autoimmunity in NZB/W F1 Mice
Authors: Haas Karen M. , Watanabe Rei , Matsushita Takashi , Nakashima Hiroko , Ishiura Nobuko , Okochi Hitoshi , Fujimoto Manabu , Tedder Thomas F. 
Published: April 2010

Abstract
Delineating the relative contributions of B lymphocytes during the course of autoimmune disease has been difficult. Therefore, the effects of depleting all mature B cells using a potent CD20 mAb, or of depleting circulating and marginal zone B cells using a ligand-blocking CD22 mAb, were compared in NZB/W F1 mice, a model for human systemic lupus erythematosus. Single low-dose mAb treatments depleted B cells efficiently in both NZB/W F1 and C57BL/6 mice. Prophylactic B cell depletion by repeated CD20 mAb treatments prolonged survival during pristane-accelerated lupus in NZB/W F1 mice, whereas CD22 mAb had little effect. Despite effective B cell depletion, neither mAb treatment prevented autoantibody generation. In addition, CD20, CD22, and control mAb-treated NZB/W F1 mice developed anti-mouse IgG autoantibodies in contrast to parental NZB and NZW strains, which may have reduced the effectiveness of B cell depletion. Despite this, low-dose CD20 mAb treatment initiated in 12–28-wk-old mice, and administered every 4 wk thereafter, significantly delayed spontaneous disease in NZB/W F1 mice. By contrast, B cell depletion initiated in 4-wk-old mice hastened disease onset, which paralleled depletion of the IL-10–producing regulatory B cell subset called B10 cells. B10 cells were phenotypically similar in NZB/W F1 and C57BL/6 mice, but were expanded significantly in young NZB/W F1 mice. Thus, B cell depletion had significant effects on NZB/W F1 mouse survival that were dependent on the timing of treatment initiation. Therefore, distinct B cell populations can have opposing protective and pathogenic roles during lupus progression.
Keratinocyte-Associated B7-H1 Directly Regulates Cutaneous Effector CD8+ T Cell Responses
Authors: Ritprajak Patcharee , Hashiguchi Masaaki , Tsushima Fumihiko , Chalermsarp Narumon , Azuma Miyuki 
Published: April 2010

Abstract
Keratinocytes (KCs) may play important roles for maintenance of peripheral tolerance in the upper layers of the skin. Coinhibitory signals mediated via the programmed death (PD)-1 and its ligand B7-H1 (PD-L1/CD274) are crucial for the downregulation of T cell immune responses and for the maintenance of peripheral tolerance. In this study, to investigate the role of KC-expressed B7-H1 in the regulation of T cell immune responses, we generated transgenic (tg) mice overexpressing B7-H1 under the control of keratin 14 (K14) promoter (K14-B7-H1 tg). K14-B7-H1 tg mice displayed impaired contact hypersensitivity (CH) responses to primary and secondary hapten challenges. The K14-B7-H1 tg mice did not exhibit substantial impairment of cutaneous dendritic cell migration after sensitization and of hapten-specific proliferation and IFN-γ production of CD4+ and CD8+ T cells in the draining lymph nodes, suggesting that overexpression of B7-H1 on KCs did not affect the induction phase of the CH response. The systemic or s.c. injection of hapten-sensitized T cells into the K14-B7-H1 tg mice did not efficiently induce the CH response. IFN-γ expression and apoptosis of KCs in the challenged ears were impaired in K14-B7-H1 tg mice. IFN-γ production by presensitized CD8+ T cells stimulated with hapten-pulsed KCs was markedly impaired for the KCs obtained from the K14-B7-H1 tg mice but was restored by the addition of an anti–B7-H1 mAb. These results suggest that KC-associated B7-H1 directly downregulates the effector function of CD8+ T cells by associating with PD-1 at local inflammatory sites and that it plays a role in peripheral T cell tolerance against exogenous Ags.
Th17 Polarized Cells from Nonobese Diabetic Mice Following Mycobacterial Adjuvant Immunotherapy Delay Type 1 Diabetes
Authors: Nikoopour Enayat , Schwartz Jordan A. , Huszarik Katrina , Sandrock Christian , Krougly Olga , Lee-Chan Edwin , Singh Bhagirath 
Published: April 2010

Abstract
IL-17–producing T cells are regarded as potential pathogenic T cells in the induction of autoimmune diseases. Previously, we have shown that injection of adjuvants containing Mycobacterium, such as CFA or bacillus Calmette-Guérin, can prevent type 1 diabetes in NOD mice. We injected NOD mice with mycobacterial products s.c. and analyzed the IL-17–producing cells from the draining lymph nodes and spleen by restimulating whole-cell populations or CD4+ T cells in vitro with or without IL-17–polarizing cytokines. Mice receiving CFA had a concomitant rise in the level of IL-17, IL-22, IL-10, and IFN-γ in the draining lymph node and spleen. Adoptive transfer of splenocytes from CFA-injected NOD mice polarized with TGF-β plus IL-6 or IL-23 delayed the development of diabetes in recipient mice. IL-17–producing cells induced by CFA maintained their IL-17–producing ability in the recipient mice. Injection of CFA also changed the cytokine profile of cells in pancreatic tissue by increasing IL-17, IL-10, and IFN-γ cytokine gene expression. We suggest that the rise in the level of IL-17 after adjuvant therapy in NOD mice has a protective effect on type 1 diabetes development.
Docosahexaenoic Acid-Enriched Fish Oil Attenuates Kidney Disease and Prolongs Median and Maximal Life Span of Autoimmune Lupus-Prone Mice
Authors: Halade Ganesh V. , Rahman Md Mizanur , Bhattacharya Arunabh , Barnes Jeffrey L. , Chandrasekar Bysani , Fernandes Gabriel 
Published: April 2010

Abstract
The therapeutic efficacy of individual components of fish oils (FOs) in various human inflammatory diseases still remains unresolved, possibly due to low levels of n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or lower ratio of DHA to EPA. Because FO enriched with DHA (FO-DHA) or EPA (FO-EPA) has become available recently, we investigated their efficacy on survival and inflammatory kidney disease in a well-established animal model of human systemic lupus erythematosus. Results show for the first time that FO-DHA dramatically extends both the median (658 d) and maximal (848 d) life span of (NZB × NZW)F1 (B × W) mice. In contrast, FO-EPA fed mice had a median and maximal life span of ∼384 and 500 d, respectively. Investigations into possible survival mechanisms revealed that FO-DHA (versus FO-EPA) lowers serum anti-dsDNA Abs, IgG deposition in kidneys, and proteinuria. Further, FO-DHA lowered LPS-mediated increases in serum IL-18 levels and caspase-1–dependent cleavage of pro–IL-18 to mature IL-18 in kidneys. Moreover, FO-DHA suppressed LPS-mediated PI3K, Akt, and NF-κB activations in kidney. These data indicate that DHA, but not EPA, is the most potent n-3 fatty acid that suppresses glomerulonephritis and extends life span of systemic lupus erythematosus-prone short-lived B × W mice, possibly via inhibition of IL-18 induction and IL-18–dependent signaling.
Intercellular Adhesion Molecule-1 Enrichment near Tricellular Endothelial Junctions Is Preferentially Associated with Leukocyte Transmigration and Signals for Reorganization of These Junctions To Accommodate Leukocyte Passage
Authors: Sumagin Ronen , Sarelius Ingrid H. 
Published: April 2010

AbstractLeukocyte transmigration occurs at specific locations (portals) on the endothelium, but the nature of these portals is not clear. Using intravital confocal microscopy of anesthetized mouse cremaster muscle in combination with immunofluorescence labeling, we showed that in microvessels transmigration is mainly junctional and preferentially occurs at tricellular endothelial junctional regions. Our data suggest that enrichment of ICAM-1 near ∼43% of these junctions makes these locations preferred for transmigration by signaling the location of a nearby portal, as well as preparing the endothelial cell (EC) junctions, to accommodate leukocyte passage. Blockade of the extracellular domain of the ICAM-1 significantly reduced transmigration (by 68.8 ± 4.5%) by reducing the ability of leukocytes to get to these portals. In contrast, blockade of the cytoplasmic tail of ICAM-1 reduced transmigration (by 71.1 ± 7.0%) by disabling VE-cadherin rearrangement. Importantly, venular convergences are optimally equipped to support leukocyte transmigration. Differences in EC morphology result in a significantly higher number of tricellular junctions in convergences compared with straight venular regions (20.7 ± 1.2 versus 12.43 ± 1.1/6000 μm2, respectively). Consequently, leukocyte adhesion and transmigration are significantly higher in convergences compared with straight regions (1.6- and 2.6-fold, respectively). Taken together, these data identify an important role for EC morphology and expression patterns of ICAM-1 in leukocyte transmigration.
Cutting Edge: Human Latency-Associated Peptide+ T Cells: A Novel Regulatory T Cell Subset
Authors: Gandhi Roopali , Farez Mauricio F. , Wang Yue , Kozoriz Deneen , Quintana Francisco J. , Weiner Howard L. 
Published: April 2010

Abstract
Regulatory T cells (Tregs) play an important role in the maintenance of peripheral tolerance. Several molecules including TGF-β have been linked to the function and differentiation of Tregs. In this study, we describe a unique population of T cells expressing a membrane bound form of TGF-β, the latency-associated peptide (LAP), and having regulatory properties in human peripheral blood. These CD4+LAP+ T cells lack Foxp3 but express TGF-βR type II and the activation marker CD69. CD4+LAP+ T cells are hypoproliferative compared with CD4+LAP− T cells, secrete IL-8, IL-9, IL-10, IFN-γ, and TGF-β upon activation, and exhibit TGF-β– and IL-10–dependent suppressive activity in vitro. The in vitro activation of CD4+LAP− T cells results in the generation of LAP+ Tregs, which is further amplified by IL-8. In conclusion, we have characterized a novel population of human LAP+ Tregs that is different from classic CD4+Foxp3+CD25high natural Tregs.
Chemerin Peptides Promote Phagocytosis in a ChemR23- and Syk-Dependent Manner
Authors: Cash Jenna L. , Christian Annabel R. , Greaves David R. 
Published: April 2010

Abstract
Chemerin peptides represent a recently identified component of the endogenous anti-inflammatory network that act via the G protein-coupled receptor ChemR23. The role of the chemerin peptide/ChemR23 pathway in phagocytosis, the clearance of apoptotic cells (efferocytosis), and the resolution of inflammation is unknown. In this article, we report that low picomolar concentrations of the chemerin peptide chemerin15 (C15) enhance macrophage (MΦ) phagocytosis of microbial particles and apoptotic cells by up to 360% in vitro. These prophagocytic effects of C15 are significantly impaired in ChemR23−/− MΦs and are associated with increased actin polymerization and localization of F-actin to the phagocytic cup. Importantly, pharmacological inhibition of Syk activity completely abrogates the prophagocytic activities of C15 and associated changes in actin polymerization and phagocytic cup formation, suggesting that C15 promotes phagocytosis by facilitating phagocytic cup development in a Syk-dependent manner. During peritoneal inflammation, C15 administration (8 pg/mouse) enhances microbial particle clearance and apoptotic neutrophil ingestion by MΦs in wild-type but not ChemR23−/− mice, such that levels of apoptotic and necrotic cells at the inflammatory site are profoundly reduced. In contrast, neutralization of endogenous chemerin species during peritoneal inflammation significantly impairs MΦ ingestion of apoptotic neutrophils and zymosan. Our data identify a key role of the chemerin peptide/ChemR23 axis in the efficient clearance of foreign material, efferocytosis, and, hence, the resolution of inflammation. Manipulation of the chemerin peptide/ChemR23 axis may represent a novel therapeutic approach for the treatment of inflammatory pathologies, especially if failure to efficiently clear phagocytic targets has been implicated in their pathogenesis.
IFN-γ Promotes Complement Expression and Attenuates Amyloid Plaque Deposition in Amyloid β Precursor Protein Transgenic Mice
Authors: Chakrabarty Paramita , Ceballos-Diaz Carolina , Beccard Amanda , Janus Christopher , Dickson Dennis , Golde Todd E. , Das Pritam 
Published: April 2010

AbstractReactive gliosis surrounding amyloid β (Aβ) plaques is an early feature of Alzheimer’s disease pathogenesis and has been postulated to represent activation of the innate immune system in an apparently ineffective attempt to clear or neutralize Aβ aggregates. To evaluate the role of IFN-γ–mediated neuroinflammation on the evolution of Aβ pathology in transgenic (Tg) mice, we have expressed murine IFN-γ (mIFN-γ) in the brains of Aβ precursor protein (APP) Tg mice using recombinant adeno-associated virus serotype 1. Expression of mIFN-γ in brains of APP TgCRND8 mice results in robust noncell autonomous activation of microglia and astrocytes, and a concomitant significant suppression of Aβ deposition. In these mice, mIFN-γ expression upregulated multiple glial activation markers, early components of the complement cascade as well as led to infiltration of Ly-6c positive peripheral monocytes but no significant effects on APP levels, APP processing or steady-state Aβ levels were noticed in vivo. Taken together, these results suggest that mIFN-γ expression in the brain suppresses Aβ accumulation through synergistic effects of activated glia and components of the innate immune system that enhance Aβ aggregate phagocytosis.
Interdisciplinary Analysis of HIV-Specific CD8+ T Cell Responses against Variant Epitopes Reveals Restricted TCR Promiscuity
Authors: Hoof Ilka , Pérez Carina L. , Buggert Marcus , Gustafsson Rasmus K. L. , Nielsen Morten , Lund Ole , Karlsson Annika C. 
Published: April 2010

Abstract
HIV-1–specific CTL responses play a key role in limiting viral replication. CTL responses are sensitive to viral escape mutations, which influence recognition of the virus. Although CTLs have been shown to recognize epitope variants, the extent of this cross-reactivity has not been quantitatively investigated in a genetically diverse cohort of HIV-1–infected patients. Using a novel bioinformatic binding prediction method, we aimed to explain the pattern of epitope-specific CTL responses based on the patients’ HLA genotype and autologous virus sequence quantitatively. Sequences covering predicted and tested HLA class I-restricted epitopes (peptides) within the HIV-Gag, Pol, and Nef regions were obtained from 26 study subjects resulting in 1492 patient-specific peptide pairs. Epitopes that were recognized in ELISPOT assays were found to be significantly more similar to the autologous virus than those that did not elicit a response. A single substitution in the presented epitope decreased the chance of a CTL response by 40%. The impact of sequence similarity on cross-recognition was confirmed by testing immune responses against multiple variants of six selected epitopes. Substitutions at central positions in the epitope were particularly likely to result in abrogation of recognition. In summary, the presented data demonstrate a highly restricted promiscuity of HIV-1–specific CTL in the recognition of variant epitopes. In addition, our results illustrate that bioinformatic prediction methods are useful to study the complex pattern of CTL responses exhibited by an HIV-1–infected patient cohort and for identification of optimal targets for novel therapeutic or vaccine approaches.