bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+CD25+ T Cells Lyse Antigen-Presenting B Cells by Fas-Fas Ligand Interaction in an Epitope-Specific Manner
Authors: Janssens Wim , Carlier Vincent , Wu Bo , VanderElst Luc , Jacquemin Marc G. , Saint-Remy Jean-Marie R. 
Published: April 2014

Abstract
Suppression by regulatory T cells is now acknowledged to play a key role in the down-regulation of T cell responses to foreign and self Ags. In addition to the naturally occurring CD4+CD25+ population, several subtypes of induced regulatory cells have been reported, but their mechanisms of action remain unclear. Conversely, cytotoxic CD4+ cells that lyse cells presenting their cognate peptide have been described, but their potential role in immunoregulation remains to be delineated. A CD4+ T cell line derived from BALB/c mice immunized with peptide 21–35, containing a major T cell epitope of a common allergen, Dermatophagoides pteronyssinus group 2 allergen, was found to lyse the Ag-presenting WEHI cell line via Fas-Fas ligand and only in the presence of the cognate peptide. Cytolytic activity was likewise shown for other T cell lines and occurred even after a single cycle of in vitro stimulation. Moreover, T cells that efficiently lysed WEHI cells were unresponsive to stimulation with their cognate Ag and were dependent on IL-2 for growth and survival, which was reflected in a constitutive expression of CD25 independently of activation status. Proliferating B cells were also killed by the CTLs. By lysing Ag-presenting B cells in an epitope-specific manner, the nonproliferating CTLs were shown to down-regulate the proliferation of bystander T cells. These data demonstrate that cytotoxic CD4+CD25+ T cells that lack proliferation capacities have the potential to down-regulate an immune response by killing Ag-presenting B cells. This could represent an important and specific down-regulatory mechanism of secondary immune responses in vivo.
Ly49D Receptor Expressed on Immature B Cells Regulates Their IFN-γ Secretion, Actin Polymerization, and Homing
Authors: Hart Gili , Flaishon Liat , Becker-Herman Shirly , Shachar Idit 
Published: April 2014

Abstract
Low levels of IFN-γ secreted by immature B cells prevent their own migration and homing to the lymph nodes and premature encounter with Ag. In this study we followed the mechanism regulating IFN-γ secretion by immature B cells. We show that the MHC class I receptor, Ly49D, is expressed on immature B cells and is down-regulated during maturation. Activation of this receptor leads to increase in IFN-γ transcription and translation and results in the altered ability of B cells to polymerize actin in response to chemokine stimulation. Moreover, we show that H2-D blockage inhibits the ability of immature B cells to transcribe the IFN-γ gene and results in rescue of cytoskeletal rearrangement. Thus, Ly49D that is expressed on immature B cells recognizes MHC class I on the peripheral tissues, inducing the secretion of low levels of IFN-γ and thereby down-regulating immature B cell homing to the lymph nodes or to sites of inflammation.
A Novel Interaction between Protein Kinase D and TNF Receptor-Associated Factor Molecules Regulates B Cell Receptor-CD40 Synergy
Authors: Haxhinasto Sokol A. , Bishop Gail A. 
Published: April 2014

AbstractSignaling by Ag to the B cell Ag receptor (BCR) is enhanced by several cooperating signals, including several provided by B-T cell interactions. One of these, CD40, provides critical signals for B cell differentiation, isotype switching, and B cell memory. The molecular mechanisms by which BCR and CD40 signals synergize are not well understood. Although the BCR and CD40 share certain signaling pathways, we hypothesized that unique signals provided by each could provide mutual enhancement of their signaling pathways. The BCR, but not CD40, activates protein kinase D (PKD), while CD40, but not the BCR, employs the TNFR-associated factor (TRAF) adapter proteins in signaling. In this study, we show that genetic or pharmacologic inhibition of BCR-mediated PKD activation in B lymphocytes abrogated the synergy between the CD40 and the BCR, as measured by activation of Ig and cytokine secretion. Interestingly, the role of PKD was dependent upon the association of CD40 with TRAF2, and was inhibited by the binding of TRAF3, revealing a novel functional link between these two classes of signaling molecules.
Selection of Ig μ Heavy Chains by Complementarity-Determining Region 3 Length and Amino Acid Composition
Authors: Martin Denise A. , Bradl Harald , Collins Tara J. , Roth Edith , Jäck Hans-Martin , Wu Gillian E. 
Published: April 2014

AbstractAlthough it is generally accepted that Ig heavy chains (HC) are selected at the pre-B cell receptor (pre-BCR) checkpoint, the characteristics of a functional HC and the role of pre-BCR assembly in their selection have remained elusive. We determined the characteristics of HCs that successfully passed the pre-BCR checkpoint by examining transcripts harboring VH81X and JH4 gene segments from JH+/− and λ5−/−mice. VH81X-JH4-HC transcripts isolated from cells before or in the absence of pre-BCR assembly had no distinguishing complementarity-determining region 3 traits. In contrast, transcripts isolated subsequent to passage through the pre-BCR checkpoint had distinctive complementarity-determining regions 3 of nine amino acids in length (49%) and a histidine at position 1 (73%). Hence, our data define specific structural requirements for a functional HC, which is instrumental in shaping the diverse B cell repertoire.
Silent Cleanup of Very Early Apoptotic Cells by Macrophages
Authors: Kurosaka Kahori , Takahashi Munehisa , Watanabe Naoko , Kobayashi Yoshiro 
Published: April 2014

Abstract
Apoptotic cells are phagocytosed as soon as they appear in vivo. In this study, we first determined precisely at what stage apoptotic cells are phagocytosed by macrophages, and then examined the subsequent cytokine production. Phagocytosis was confirmed by flow cytometry and confocal laser microscopy, whereas the subsequent response was examined by ELISA and RT-PCR for quantitative and semiquantitative measurement of the protein and mRNA levels of cytokines, respectively. Even the cell populations containing very early apoptotic cells, such as IL-2-dependent CTLL-2 cells cultured in the absence of IL-2 for 4 h and a murine leukemic cell line, P388 cells, treated with etoposide for 5 h, were phagocytosed by macrophages. Although the cell populations containing the very early apoptotic cells used in this study were FITC-Annexin V-negative and did not show a decrease in cell size as compared with untreated cells, they showed a very small increase in phosphatidylserine on the cell surface, as detected with Cy3-Annexin V, and a decrease in mitochondrial membrane potential, indicating that the cell populations had already started the apoptotic process. Phagocytosis of such populations containing very early apoptotic cells was inhibited by phospho-l-serine much more significantly than Arg-Gly-Asp-Ser. In addition, macrophages hardly produced either proinflammatory or anti-inflammatory cytokines after phagocytosis, thus being an almost null response. These results are contrary to the generally accepted concept that the phagocytosis of apoptotic cells leads to the production of anti-inflammatory cytokines, suggesting instead that cells starting to undergo apoptosis are quickly phagocytosed by macrophages without any inflammation in vivo.
TNF-α-Dependent ICAM-1- and VCAM-1-Mediated Inflammatory Responses Are Delayed in Neonatal Mice Infected with Pneumocystis carinii
Authors: Qureshi Mahboob H. , Cook-Mills Joan , Doherty Dennis E. , Garvy Beth A. 
Published: April 2014

Abstract
Neonatal mice have a delayed CD4-mediated inflammatory response to Pneumocystis carinii (PC) infection in the lungs that corresponds to a delayed TNF-α response and a delayed clearance of the organisms compared with adult mice. Since TNF-α is known to drive the up-regulation of adhesion molecules, we examined the expression and function of adhesion molecules in the lungs of neonatal mice. The expression of both ICAM-1 and VCAM-1 was significantly lower in the lungs of PC-infected neonatal mice compared with adults. Additionally, migration of neonatal T cells across endothelial cells expressing VCAM-1 and monocyte chemotactic protein-1 was aberrant compared with that in adult T cells, although α4β1 integrin-mediated adhesion of neonatal lymphocytes was comparable to that of adult lymphocytes. Treatment of neonatal mice with exogenous TNF-α resulted in increased expression of ICAM-1 and VCAM-1 as well as increased expression of chemokines, resulting in infiltration of CD4+ cells into the lungs. Treatment with exogenous TNF-α resulted in a trend (although not statistically significant) toward a reduction of PC organisms from the lungs. These data indicate that neonatal lung endothelial cells do not up-regulate ICAM-1 and VCAM-1 in response to PC infection, probably due to depressed TNF-α production. Additionally, neonatal T cells are defective in the ability to migrate across endothelial cells.
IL-4 Suppresses the Expression and the Replication of Hepatitis B Virus in the Hepatocellular Carcinoma Cell Line Hep3B
Authors: Lin Sue-Jane , Shu Pei-Yun , Chang Chungming , Ng Ah-Kau , Hu Cheng-po 
Published: April 2014

Abstract
IL-4 has been known as a Th2 cytokine and can act on B cells, T cells, and monocytes. In this study we demonstrate that IL-4Rs are expressed on human hepatocellular carcinoma (HCC) cells. We found that IL-4 suppresses hepatitis B surface Ag (HBsAg) mRNA and HBsAg production in the Hep3B cell line, which contains an integrated hepatitis B virus (HBV) genome and constitutively secretes HBsAg. When Hep3B cells are further transfected with the plasmid pHBV3.6 that contains &gt;1 U of HBV genome, IL-4 could suppress the production of all HBV RNA and secreted HBsAg and hepatitis B virus e Ag. Furthermore, an endogenous DNA polymerase activity assay shows a decrease in HBV DNA after IL-4 treatment. Using luciferase reporter assays we have demonstrated that IL-4 could suppress the activity of the surface promoter II and the core promotor (CP). To delineate how IL-4 suppressed the transcription of HBV genes, we have examined the effect of IL-4 on the expression of transcription factors that are known to bind to the core upstream regulatory sequence, which colocalizes with enhancer II of the HBV genome. Our results demonstrate that IL-4 suppresses the expression of C/EBPα. Furthermore, overexpression of C/EBPα blocked 43 and 30% of the IL-4-mediated suppression of CP activity and IL-4-induced suppression of pregenomic RNA, respectively. Finally, we have demonstrated that mutations affecting the C/EBPα-binding sites on core upstream regulatory sequence/enhancer II completely abolish the IL-4-mediated suppression of CP activity. Thus, down-regulation of C/EBPα may be involved in the anti-HBV effect of IL-4 in Hep3B cells.
M Cell DNA Vaccination for CTL Immunity to HIV
Authors: Wang Xinhai , Hone David M. , Haddad Asmahan , Shata Mohamed T. , Pascual David W. 
Published: April 2014

Abstract
To facilitate invasion, reovirus has evolved to attach to M cells, a specialized epithelium residing within the follicle-associated epithelium that covers mucosal inductive tissues. Thus, we questioned adapting reovirus protein σ1 to ferry DNA vaccines to the mucosa to immunize against HIV. Three expression plasmids encoding HIV(Ba-L) gp160, cytoplasmic gp140, and secreted gp140 were tested in mice as protein σ1-poly-l-lysine-DNA complexes (formulated vaccine) via the intranasal route. Evaluation of cell-mediated immunity showed that the formulated gp160 DNA vaccine was more effective for stimulating envelope (Env)-specific CTL responses in lungs, lower respiratory lymph nodes (LN), cervical LN, submaxillary gland LN, and spleens. Three doses of vaccine were required for CTL responses, and intranasal naked DNA immunizations were ineffective. The greatest CTL activity was observed between weeks 8 and 10 for gp160-vaccinated mice, and activity remained detectable by week 16. These Env-specific CTL responses were perforin dependent in peripheral tissues, but mostly Fas dependent in the lungs. These Env-specific CTLs also produced IFN-γ. Mice vaccinated with the formulated gp160 DNA vaccine showed potent antiviral immunity against vaccinia virus-env replication in ovaries. Thus, compared with live vectors, protein σ1-mediated DNA delivery represents an alternative mucosal formulation for inducing cellular immunity against HIV-1.
Innate Inhibition of Adaptive Immunity:Mycobacterium tuberculosis-Induced IL-6 Inhibits Macrophage Responses to IFN-γ
Authors: Nagabhushanam Vijaya , Solache Alejandra , Ting Li-Min , Escaron Claire J. , Zhang Jennifer Y. , Ernst Joel D. 
Published: April 2014

AbstractIn humans and in mice, control of the intracellular pathogen, Mycobacterium tuberculosis (Mtb), requires IFN-γ. Although the adaptive immune response results in production of substantial amounts of IFN-γ in response to Mtb, the immune response is unable to eradicate the infection in most cases. We have previously reported evidence that Mtb inhibits macrophage responses to IFN-γ, suggesting that this may limit the ability of IFN-γ to stimulate macrophages to kill Mtb. We have also observed that uninfected macrophages, adjacent to infected macrophages in culture, exhibit decreased responses to IFN-γ. Here we report that IL-6 secreted by Mtb-infected macrophages inhibits the responses of uninfected macrophages to IFN-γ. IL-6 selectively inhibits a subset of IFN-γ-responsive genes at the level of transcriptional activation without inhibiting activation or function of STAT1. Inhibition of macrophage responses to IFN-γ by IL-6 requires new protein synthesis, but this effect is not attributable to suppressor of cytokine signaling 1 or 3. These results reveal a novel function for IL-6 and indicate that IL-6 secreted by Mtb-infected macrophages may contribute to the inability of the cellular immune response to eradicate infection.
Mice Lacking Myeloid Differentiation Factor 88 Display Profound Defects in Host Resistance and Immune Responses to Mycobacterium avium Infection Not Exhibited by Toll-Like Receptor 2 (TLR2)- and TLR4-Deficient Animals
Authors: Feng Carl G. , Scanga Charles A. , Collazo-Custodio Carmen M. , Cheever Allen W. , Hieny Sara , Caspar Patricia , Sher Alan 
Published: April 2014

Abstract
To assess the role of Toll-like receptor (TLR) signaling in host resistance to Mycobacterium avium infection, mice deficient in the TLR adaptor molecule myeloid differentiation factor 88 (MyD88), as well as TLR2−/− and TLR4−/− animals, were infected with a virulent strain of M. avium, and bacterial burdens and immune responses were compared with those in wild-type (WT) animals. MyD88−/− mice failed to control acute and chronic M. avium growth and succumbed 9–14 wk postinfection. Infected TLR2−/− mice also showed increased susceptibility, but displayed longer survival and lower bacterial burdens than MyD88−/− animals, while TLR4−/− mice were indistinguishable from their WT counterparts. Histopathological examination of MyD88−/− mice revealed massive destruction of lung tissue not present in WT, TLR2−/−, or TLR4−/− mice. In addition, MyD88−/− and TLR2−/−, but not TLR4−/−, mice displayed marked reductions in hepatic neutrophil infiltration during the first 2 h of infection. Although both MyD88−/− and TLR2−/− macrophages showed profound defects in IL-6, TNF, and IL-12p40 responses to M. avium stimulation in vitro, in vivo TNF and IL-12p40 mRNA induction was impaired only in infected MyD88−/− mice. Similarly, MyD88−/− mice displayed a profound defect in IFN-γ response that was not evident in TLR2−/− or TLR4−/− mice or in animals deficient in IL-18. These findings indicate that resistance to mycobacterial infection is regulated by multiple MyD88-dependent signals in addition to those previously attributed to TLR2 or TLR4, and that these undefined elements play a major role in determining bacterial induced proinflammatory as well as IFN-γ responses.
Novel and Detrimental Effects of Lipopolysaccharide on In Vitro Generation of Immature Dendritic Cells: Involvement of Mitogen-Activated Protein Kinase p38
Authors: Xie Jin , Qian Jianfei , Wang Siqing , Freeman Muta E. , Epstein Joshua , Yi Qing 
Published: April 2014

Abstract
Dendritic cells (DCs) are recognized as major players in the regulation of immune responses to a variety of Ags, including bacterial agents. LPS, a Gram-negative bacterial cell wall component, has been shown to fully activate DCs both in vitro and in vivo. LPS-induced DC maturation involves activation of p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases, and NF-κB. Blocking p38 inhibits LPS-induced maturation of DCs. In this study we investigated the role of LPS in the in vitro generation of immature DCs. We report here that in contrast to the observed beneficial effects on DCs, the presence of LPS in monocyte culture retarded the generation of immature DCs. LPS not only impaired the morphology and reduced the yields of the cultured cells, but also inhibited the up-regulation of surface expression of CD1a, costimulatory and adhesion molecules. Furthermore, LPS up-regulated the secretion of IL-1β, IL-6, IL-8, IL-10, and TNF-α; reduced Ag presentation capacity; and inhibited phosphorylation of ERK, but activated p38, leading to a reduced NF-κB activity in treated cells. Neutralizing Ab against IL-10, but not other cytokines, partially blocked the effects of LPS. Inhibiting p38 (by inhibitor SB203580) restored the morphology, phenotype, and Ag presentation capacity of LPS-treated cells. SB203580 also inhibited LPS-induced production of IL-1β, IL-10, and TNF-α; enhanced IL-12 production; and recovered the activity of ERK and NF-κB. Thus, our study reveals that LPS has dual effects on DCs that are biologically important: activating existing DCs to initiate an immune response, and inhibiting the generation of new DCs to limit such a response.
DNA Vaccination Against Specific Pathogenic TCRs Reduces Proteinuria in Active Heymann Nephritis by Inducing Specific Autoantibodies
Authors: Wu Huiling , Walters Giles , Knight John F. , Alexander Stephen I. 
Published: April 2014

Abstract
We have previously identified potential pathogenic T cells within glomeruli that use TCR encoding Vβ5, Vβ7, and Vβ13 in combination with Jβ2.6 in Heymann nephritis (HN), a rat autoimmune disease model of human membranous nephritis. Vaccination of Lewis rats with naked DNA encoding these pathogenic TCRs significantly protected against HN. Proteinuria was reduced at 6, 8, 10, and 12 wk after immunization with Fx1A (p &lt; 0.001). Glomerular infiltrates of macrophages and CD8+ T cells (p &lt; 0.005) and glomerular IFN-γ mRNΑ expression (p &lt; 0.01) were also significantly decreased. DNA vaccination (DV) causes a loss of clonality of T cells in the HN glomeruli. T lymphocytes with surface binding of Abs were found in DNA vaccinated rats. These CD3+/IgG+ T cells expressed Vβ5 and Vβ13 that the DV encoded. Furthermore, FACS shows that these CD3+/IgG+ cells were CD8+ T cells. Analysis of cytokine mRNA expression showed that IL-10 and IFN-γ mRNA were not detected in these CD3+/IgG+ T cells. These results suggest that TCR DNA vaccination produces specific autoantibodies bound to the TCRs encoded by the vaccine, resulting in blocking activation of the specific T cells. In this study, we have shown that treatment with TCR-based DV, targeting previously identified pathogenic Vβ families, protects against HN, and that the mechanism may involve the production of specific anti-TCR Abs.
IL-1 Induces Vesicular Secretion of IL-6 without Degranulation from Human Mast Cells
Authors: Kandere-Grzybowska Kristiana , Letourneau Richard , Kempuraj Duraisamy , Donelan Jill , Poplawski Sarah , Boucher William , Athanassiou Achilles , Theoharides Theoharis C. 
Published: April 2014

Abstract
FcεRI cross-linkage in mast cells results in release of granule-associated mediators, such as histamine and proteases, as well as the production of numerous cytokines, including IL-6. Mast cells have been increasingly implicated in inflammatory processes where explosive degranulation is not commonly observed. Here, we show that IL-1 stimulates secretion of IL-6 without release of the granule-associated protease tryptase in normal human umbilical cord blood-derived mast cells (hCBMCs). IL-6 secretion stimulated by IL-1 in hCBMCs is potentiated by priming with IL-4 and reflects the higher levels of IL-6 secreted from human leukemic mast cell line (HMC-1). Stimulating HMC-1 cells by both IL-1 and TNF-α results in synergistic secretion of IL-6. IL-6 is de novo synthesized, as its secretion is blocked by inhibitors of transcription or protein synthesis. IL-1 does not increase intracellular calcium ion levels in either hCBMCs or HMC-1 cells, and IL-6 stimulation proceeds in the absence of extracellular calcium ions. Ultrastructural Immunogold localization shows that IL-6 is excluded from the secretory granules and is compartmentalized in 40- to 80-nm vesicular structures. Selective secretion of IL-6 from mast cells appears distinct from degranulation and may contribute to the development of inflammation, where the importance of IL-6 has been recognized.
Transcriptional Regulation of Type I Diabetes by NF-κB
Authors: Lamhamedi-Cherradi Salah-Eddine , Zheng Shijun , Hilliard Brendan A. , Xu Lingyun , Sun Jing , Alsheadat Saaib , Liou Hsiou-Chi , Chen Youhai H. 
Published: April 2014

Abstract
Development of type I diabetes requires coordinated expression of myriad genes responsible for the initiation and progression of the disease. Expression of these genes are regulated by a small number of transcription factors including the Rel/NF-κB family. To determine the roles of the Rel/NF-κB family in type I diabetes, we studied multiple low-dose streptozotocin-induced diabetes in mice deficient in either c-Rel or NF-κB1. We found that mice deficient in each of these NF-κB subunits were resistant to streptozotocin-induced diabetes. However, the mechanisms of the disease resistance may differ in different cases. Deficiency in c-Rel selectively reduced Th1, but not Th2 responses, whereas NF-κB1 deficiency had little effect on T cell responses to anti-CD3 stimulation. Death of dendritic cells was accelerated in the absence of NF-κB1, whereas death of macrophages and granulocytes was affected primarily by c-Rel deficiency. Furthermore, Stat-1 expression was significantly reduced in macrophages deficient in NF-κB1, but not c-Rel. These results indicate that both c-Rel and NF-κB1are essential for the development of type I diabetes and that strategies targeting each of these subunits would be effective in preventing the disease.