bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different Evolutionary Histories of the Two Classical Class I Genes BF1 and BF2 Illustrate Drift and Selection within the Stable MHC Haplotypes of Chickens
Authors: Shaw Iain , Powell Timothy J. , Marston Denise A. , Baker Ken , van Hateren Andrew , Riegert Patricia , Wiles Michael V. , Milne Sarah , Beck Stephan , Kaufman Jim 
Published: April 2014

Abstract
Compared with the MHC of typical mammals, the chicken MHC (BF/BL region) of the B12 haplotype is smaller, simpler, and rearranged, with two classical class I genes of which only one is highly expressed. In this study, we describe the development of long-distance PCR to amplify some or all of each class I gene separately, allowing us to make the following points. First, six other haplotypes have the same genomic organization as B12, with a poorly expressed (minor) BF1 gene between DMB2 and TAP2 and a well-expressed (major) BF2 gene between TAP2 and C4. Second, the expression of the BF1 gene is crippled in three different ways in these haplotypes: enhancer A deletion (B12, B19), enhancer A divergence and transcription start site deletion (B2, B4, B21), and insertion/rearrangement leading to pseudogenes (B14, B15). Third, the three kinds of alterations in the BF1 gene correspond to dendrograms of the BF1 and poorly expressed class II B (BLB1) genes reflecting mostly neutral changes, while the dendrograms of the BF2 and well-expressed class II (BLB2) genes each have completely different topologies reflecting selection. The common pattern for the poorly expressed genes reflects the fact the BF/BL region undergoes little recombination and allows us to propose a pattern of descent for these chicken MHC haplotypes from a common ancestor. Taken together, these data explain how stable MHC haplotypes predominantly express a single class I molecule, which in turn leads to striking associations of the chicken MHC with resistance to infectious pathogens and response to vaccines.
Coronin Function Is Required for Chemotaxis and Phagocytosis in Human Neutrophils
Authors: Yan Ming , Di Ciano-Oliveira Caterina , Grinstein Sergio , Trimble William S. 
Published: April 2014

Abstract
Coronins are a family of conserved actin-associated proteins that have been implicated in a variety of cellular processes dependent on actin rearrangements. In this study, we show that in primary human neutrophils, coronins-1–4 and -7 are expressed. Coronin-1 accumulates at the leading edge of migrating neutrophils and at the nascent phagosome. Inhibition of coronin function by transduction of a dominant-negative form of the protein leads to inhibition of chemotaxis and a reduction in neutrophil spreading and adhesion. This inhibition appears to correlate with changes in the distribution of F-actin structures within the cell. In addition, phagocytosis is inhibited, but neither secretion nor activation of the NADPH oxidase appears to be affected. Together, these results show that coronins are required for actin-dependent changes in cell morphology that lead to migration and phagocytosis.
The Host Immune Regulator Factor H Interacts via Two Contact Sites with the PspC Protein of Streptococcus pneumoniae and Mediates Adhesion to Host Epithelial Cells
Authors: Hammerschmidt Sven , Agarwal Vaibhav , Kunert Anja , Haelbich Steffi , Skerka Christine , Zipfel Peter F. 
Published: April 2014

Abstract
Pneumococcal surface protein C (PspC) of Streptococcus pneumoniae is a key virulence factor that mediates adhesion to host cells and immune evasion of the host complement. PspC binds the host immune and complement regulator factor H, which is composed of 20 short consensus repeats (SCR). This interaction contributes to pneumococcal virulence. In this study, we identified within the factor H protein two separate PspC binding regions, which were localized to SCR8–11 and SCR19–20, by using recombinant factor H deletion constructs for Western blotting assays and surface plasmon resonance studies. A detailed analysis of binding epitopes in these SCR by peptide spot arrays identified several linear binding regions within the sequences of SCR8–11 and SCR19–20. In addition, the factor H binding site was mapped within the pneumococcal PspC protein to a 121-aa-long stretch positioned in the N terminus (residues 38–158). Factor H attached to the surface of pneumococci via PspC significantly enhanced pneumococcal adherence to host epithelial and endothelial cells. This adhesion was specific and was blocked with a truncated N-terminal factor H-binding fragment of PspC. In conclusion, the acquisition of factor H by pneumococci via PspC occurs via two contact sites located in SCR8–11 and SCR19–20, and factor H attached to the surface of the pneumococcus promotes adhesion to both host epithelial and endothelial cells.
Cross-Regulation of Carbon Monoxide and the Adenosine A2a Receptor in Macrophages
Authors: Haschemi Arvand , Wagner Oswald , Marculescu Rodrig , Wegiel Barbara , Robson Simon C. , Gagliani Nicola , Gallo David , Chen Jiang-Fan , Bach Fritz H. , Otterbein Leo E. 
Published: April 2014

Abstract
Adenosine and heme oxygenase-1 (HO-1) exert a wide range of anti-inflammatory and immunomodulatory actions, making them crucial regulatory molecules. Despite the diversity in their modes of action, the similarity of biological effects of adenosine and HO-1 led us to hypothesize a possible interrelationship between them. We assessed a potential role for HO-1 in the ability of adenosine or 5′-N-ethylcarboxamidoadenosine (NECA), a stable adenosine analog, to modify the response of LPS-stimulated macrophages. Adenosine and NECA markedly induced HO-1 and blocked LPS-induced TNF-α production via adenosine A2aR-mediated signaling; blocking of HO-1 by RNA interference abrogated the effects of adenosine and NECA on TNF-α. HO-1 overexpression or exposure to carbon monoxide (CO), a product of HO-1 enzymatic activity, resulted in augmented A2aR mRNA and protein levels in RAW264.7 cells and primary macrophages. The induction of A2aR expression by HO-1 or CO resulted in an increase in the sensitivity to the anti-inflammatory effects of adenosine and NECA, which was lost in macrophages isolated from A2aR-deficient mice. Moreover, a decrease in cAMP levels upon NECA stimulation of naive macrophages was counterbalanced by CO exposure to up-regulate A2aR levels. This implies adenosine receptor isoform switch as a selective modification in macrophage phenotype. Taken together, these data suggest the existence of a positive feedback loop among adenosine, HO-1, CO, and the A2aR in the chronological resolution of the inflammatory response.
Interactions between CD47 and Thrombospondin Reduce Inflammation
Authors: Lamy Laurence , Foussat Arnaud , Brown Eric J. , Bornstein Paul , Ticchioni Michel , Bernard Alain 
Published: April 2014

Abstract
CD47 on the surface of T cells was shown in vitro to mediate either T cell activation or, in the presence of high amounts of thrombospondin (TSP), T cell apoptosis. We report here that CD47-deficient mice, as well as TSP-1 or TSP-2-deficient mice, sustain oxazolone-induced inflammation for more than four days, whereas wild-type mice reduce the inflammation within 48 h. We observe that prolonged inflammation in CD47-, TSP-1-, or TSP-2-deficient mice is accompanied by a local deficiency of T cell apoptosis. Finally, we show that upon activation normal T cells increase the expression of the proapoptotic Bcl-2 family member BNIP3 (Bcl-2/adenovirus E1B 19-kDa interacting protein) and undergo CD47-mediated apoptosis. This finding is consistent with our previous demonstration of a physical interaction between BNIP3 and CD47 that inhibits BNIP3 degradation by the proteasome, sensitizing T cells to CD47-induced apoptosis. Overall, these results reveal an important role in vivo for this new CD47/BNIP3 pathway in limiting inflammation by controlling the number of activated T cells.
NAD+ Released during Inflammation Participates in T Cell Homeostasis by Inducing ART2-Mediated Death of Naive T Cells In Vivo
Authors: Adriouch Sahil , Hubert Sandra , Pechberty Severine , Koch-Nolte Friedrich , Haag Friedrich , Seman Michel 
Published: April 2014

AbstractMono ADP-ribosyltransferase 2 (ART2) is an ectoenzyme expressed on mouse T lymphocytes, which catalyze the transfer of ADP-ribose groups from NAD+ onto several target proteins. In vitro, ADP-ribosylation by ART2 activates the P2X7 ATP receptor and is responsible for NAD+-induced T cell death (NICD). Yet, the origin of extracellular NAD+ and the role of NICD in vivo remain elusive. In a model of acute inflammation induced by polyacrylamide beads, we demonstrate release of NAD+ into exudates during the early phase of the inflammatory response. This leads to T cell depletion in the draining lymph nodes from wild-type and, more severely, from mice lacking the CD38 NAD+ glycohydrolase, whereas no effect is observed in ART2-deficient animals. Intravenous injection of NAD+ used to exacerbate NICD in vivo results in fast and dramatic ART2- and P2X7-dependent depletion of CD4+ and CD8+ T lymphocytes, which can affect up to 80% of peripheral T cells in CD38−/− mice. This affects mainly naive T cells as most cells surviving in vivo NAD+ treatment exhibit the phenotype of recently activated/memory cells. Consistently, treatment with NAD+ abolishes primary Ab response to a T-dependent Ag in NICD-susceptible CD38−/− mice but has no effect on the secondary response when given several days after priming. Unexpectedly NAD+ treatment improves the response in their wild-type BALB/c counterparts. We propose that NAD+ released during early inflammation facilitates the expansion of primed T cells, through ART2-driven death of resting cells, thus contributing to the dynamic regulation of T cell homeostasis.
Cutting Edge: Antioxidative Properties of Myeloid Dendritic Cells: Protection of T Cells and NK Cells from Oxygen Radical-Induced Inactivation and Apoptosis
Authors: Thorén Fredrik B. , Betten Åsa , Romero Ana I. , Hellstrand Kristoffer 
Published: April 2014

Abstract
Dendritic cells (DCs) communicate with nonadaptive and adaptive lymphocytes on multiple levels. Efficient DC-lymphocyte interactions require that lymphocytes remain viable and functional also under conditions of oxidative stress, such as in microbial infection or in the malignant microenvironment. For this study, we exposed human T and NK cells to oxidants delivered either by autologous phagocytes or in the form of exogenous hydrogen peroxide. In accordance with earlier studies, these lymphocytes became dysfunctional and subsequently apoptotic. The presence of myeloid DCs efficiently rescued T cells (CD4+ and CD8+) and NK cells from oxidant-induced inactivation and apoptosis. The mechanism of the myeloid DC-mediated lymphocyte protection was, at least in part, explained by the capacity of the myeloid DCs to neutralize extracellular oxygen radicals, which, in turn, was reversible upon coincubation with a catalase inhibitor. Our results are suggestive of a novel aspect of DC-lymphocyte interaction that may have implications for lymphocyte function in inflamed tissue.
Role of Phosphatidylinositol-3 Kinase in Transcriptional Regulation of TLR-Induced IL-12 and IL-10 by Fcγ Receptor Ligation in Murine Macrophages
Authors: Polumuri Swamy Kumar , Toshchakov Vladimir Y. , Vogel Stefanie N. 
Published: April 2014

Abstract
Ligation of FcγR concurrent with LPS stimulation of murine macrophages results in decreased IL-12 and increased IL-10 production. Because PI3K deficiency has been associated with increased IL-12, we hypothesized that PI3K was central to the anti-inflammatory effect of FcγR ligation on TLR-induced IL-12. FcγR ligation of macrophages increased pAKT, a correlate of PI3K activity, above levels induced by TLR4 or TLR2 agonists. This increase was blocked by PI3K inhibitors, wortmannin or LY294002, as was the effect of FcγR ligation on TLR-induced IL-12 and IL-10. LPS-induced binding of NF-κB to the IL-12 p40 promoter NF-κB-binding site was not affected by FcγR ligation at 1 h; however, by 4 h, NF-κB binding was markedly inhibited, confirmed in situ by chromatin immunoprecipitation analysis. This effect was wortmannin sensitive. Although TLR-induced IκBα degradation was not affected by FcγR ligation, IκBα accumulated in the nuclei of cells treated with LPS and FcγR ligation for 4 h, and was blocked by PI3K inhibitors. LPS-induced IFN regulatory factor-8/IFN consensus sequence-binding protein mRNA, and an IFN regulatory factor-8-dependent gene, Nos2, were inhibited by concurrent FcγR ligation, and this was also reversed by wortmannin. Thus, FcγR ligation modulates LPS-induced IL-12 via multiple PI3K-sensitive pathways that affect production, accumulation, and binding of key DNA-binding proteins required for IL-12 induction.
IL-5-Induced Hypereosinophilia Suppresses the Antigen-Induced Immune Response via a TGF-β-Dependent Mechanism
Authors: Nakagome Kazuyuki , Dohi Makoto , Okunishi Katsuhide , Tanaka Ryoichi , Kouro Taku , Kano Mitsunobu R. , Miyazono Kohei , Miyazaki Jun-ichi , Takatsu Kiyoshi , Yamamoto Kazuhiko 
Published: April 2014

Abstract
Although eosinophils play an essential role in allergic inflammation, their role has recently been under controversy. Epidemic studies suggest that hypereosinophilia induced by parasite infection could suppress subsequent Ag sensitization, although the mechanism has not been fully clarified. In this study, we investigated whether eosinophils could suppress the Ag-specific immune response in the airway. BALB/c mice were sensitized and airway challenged with OVA. Systemic hypereosinophilia was induced by delivery of an IL-5-producing plasmid. IL-5 gene delivery suppressed the Ag-specific proliferation and cytokine production of CD4+ T cells in the spleen. IL-5 gene delivery before OVA sensitization significantly suppressed airway eosinophilia and hyperresponsiveness provoked by subsequent OVA airway challenge, while delivery during the OVA challenge did not suppress them. This IL-5-induced immune suppression was abolished in eosinophil-ablated mice, suggesting an essential role of eosinophils. IL-5 treatment increased the production of TGF-β1 in the spleen, and we demonstrated that the main cellular source of TGF-β1 production was eosinophils, using eosinophil-ablated mice and depletion study. TGF-β1, but not IL-5 itself, suppressed the Ag-specific immune response of CD4+ T cells in vitro. Furthermore, IL-5 treatment enhanced phosphorylation of Smad2 in CD4+ T cells. Finally, a TGF-β type I receptor kinase inhibitor restored this IL-5-induced immune suppression both in vitro and in vivo. These results suggest that IL-5-induced hypereosinophilia could suppress sensitization to Ag via a TGF-β-dependent mechanism, thus suppressed allergic airway inflammation. Therefore, hypereosinophilia could reveal an immunosuppressive effect in the early stage of Ag-induced immune response.
IL-10 Controls Ultraviolet-Induced Carcinogenesis in Mice
Authors: Loser Karin , Apelt Jenny , Voskort Maik , Mohaupt Mariette , Balkow Sandra , Schwarz Thomas , Grabbe Stephan , Beissert Stefan 
Published: April 2014

Abstract
UV radiation-induced immunosuppression contributes significantly to the development of UV-induced skin cancer by inhibiting protective immune responses. IL-10 has been shown to be a key mediator of UV-induced immunosuppression. To investigate the role of IL-10 during photocarcinogenesis, groups of IL-10+/+, IL-10+/−, and IL-10−/− mice were chronically irradiated with UV. IL-10+/+ and IL-10+/− mice developed skin cancer to similar extents, whereas IL-10−/− mice were protected against the induction of skin malignancies by UV. Because UV is able to induce regulatory T cells, which play a role in the suppression of protective immunity, UV-induced regulatory T cell function was analyzed. Splenic regulatory T cells from UV-irradiated IL-10−/− mice were unable to confer immunosuppression upon transfer into naive recipients. UV-induced CD4+CD25+ T cells from IL-10−/− mice showed impaired suppressor function when cocultured with conventional CD4+CD25− T cells. CD4+CD25− T cells from IL-10−/− mice produced increased amounts of IFN-γ and enhanced numbers of CD4+TIM-3+ T cells were detectable within UV-induced tumors in IL-10−/− mice, suggesting strong Th1-drived immunity. Mice treated with CD8+ T cells from UV-irradiated IL-10−/− mice rejected a UV tumor challenge significantly faster, and augmented numbers of granzyme A+ cells were detected within injected UV tumors in IL-10−/− animals, suggesting marked antitumoral CTL responses. Together, these findings indicate that IL-10 is critically involved in antitumoral immunity during photocarcinogenesis. Moreover, these results point out the crucial role of Th1 responses and UV-induced regulatory T cell function in the protection against UV-induced tumor development.
Gliadin Regulates the NK-Dendritic Cell Cross-Talk by HLA-E Surface Stabilization
Authors: Terrazzano Giuseppe , Sica Michela , Gianfrani Carmen , Mazzarella Giuseppe , Maurano Francesco , De Giulio Beatrice , de Saint-Mezard Sophie , Zanzi Delia , Maiuri Luigi , Londei Marco , Jabri Bana , Troncone Riccardo , Auricchio Salvatore , Zappacosta Serafino , Carbone Ennio 
Published: April 2014

Abstract
We analyzed the autologous NK cell interaction with gliadin-presenting dendritic cells. Gliadin is the known Ag priming the celiac disease (CD) pathogenesis. We demonstrate that gliadin prevents immature dendritic cells (iDCs) elimination by NK cells. Furthermore, cooperation between human NK cells-iDCs and T cells increases IFN-γ production of anti-gliadin immune response. Gliadin fractions were analyzed for their capability to stabilize HLA-E molecules. The α and ω fractions conferred the protection from NK cell lysis to iDCs and increased their HLA-E expression. Gliadin pancreatic enzyme digest and a peptide derived from gliadin α increased HLA-E levels on murine RMA-S/HLA-E-transfected cells. Analysis of HLA-E expression in the small intestinal mucosa of gluten-containing diet celiac patients and organ culture experiments confirmed the in vitro data.
CTL-Associated Antigen-4 Ligation Induces Rapid T Cell Polarization That Depends on Phosphatidylinositol 3-Kinase, Vav-1, Cdc42, and Myosin Light Chain Kinase
Authors: Wei Bin , da Rocha Dias Silvy , Wang Hongyan , Rudd Christopher E. 
Published: April 2014

Abstract
CTLA-4 can negatively regulate cytokine production and proliferation, increase motility, and override the TCR-induced stop-signal needed for stable T cell-APC conjugation. Despite this, little is known regarding whether CTLA-4 can alter T cell morphology and the nature of the signaling events that could account for this event. In this study, we demonstrate that anti-CTLA-4 and CD3/CTLA-4 induce rapid T cell polarization (i.e., within 15–30 min) with increases in lamellipodia, filopodia, and uropod formation. This was observed with anti-CTLA-4 and CD80-Ig ligation of CTLA-4, but not with anti-CD3 alone, or anti-CD3/CD28 coligation. Polarization required PI3K, the guanine nucleotide exchange factor Vav1, the GTP-binding protein Cdc42, as well as myosin L chain kinase. By contrast, a key downstream target of PI3K, protein kinase B, as well as Rho kinase and RhoA, were not needed. Our results demonstrate that CTLA-4 is a potent activator T cell polarization needed for motility, and this process involves specific set of signaling proteins that might contribute to coreceptor regulation of T cell function.
Cutting Edge: T Cells Respond to Lipopolysaccharide Innately via TLR4 Signaling
Authors: Zanin-Zhorov Alexandra , Tal-Lapidot Guy , Cahalon Liora , Cohen-Sfady Michal , Pevsner-Fischer Meirav , Lider Ofer , Cohen Irun R. 
Published: April 2014

Abstract
LPS, a molecule produced by Gram-negative bacteria, is known to activate both innate immune cells such as macrophages and adaptive immune B cells via TLR4 signaling. Although TLR4 is also expressed on T cells, LPS was observed not to affect T cell proliferation or cytokine secretion. We now report, however, that LPS can induce human T cells to adhere to fibronectin via TLR4 signaling. This response to LPS was confirmed in mouse T cells; functional TLR4 and MyD88 were required, but T cells from TLR2 knockout mice could respond to LPS. The human T cell response to LPS depended on protein kinase C signaling and involved the phosphorylation of the proline-rich tyrosine kinase (Pyk-2) and p38. LPS also up-regulated the T cell expression of suppressor of cytokine signaling 3, which led to inhibition of T cell chemotaxis toward the chemokine stromal cell-derived factor 1α (CXCL12). Thus, LPS, through TLR4 signaling, can affect T cell behavior in inflammation.
Localization and Characterization of the Mannose-Binding Lectin (MBL)-Associated-Serine Protease-2 Binding Site in Rat Ficolin-A: Equivalent Binding Sites within the Collagenous Domains of MBLs and Ficolins
Authors: Girija Umakhanth Venkatraman , Dodds Alister W. , Roscher Silke , Reid Kenneth B. M. , Wallis Russell 
Published: April 2014

Abstract
Ficolins and mannose-binding lectins (MBLs) are the first components of the lectin branch of the complement system. They comprise N-terminal collagen-like domains and C-terminal pathogen-recognition domains (fibrinogen-like domains in ficolins and C-type carbohydrate-recognition domains in MBLs), which target surface-exposed N-acetyl groups or mannose-like sugars on microbial cell walls. Binding leads to activation of MBL-associated serine protease-2 (MASP-2) to initiate complement activation and pathogen neutralization. Recent studies have shown that MASP-2 binds to a short segment of the collagen-like domain of MBL. However, the interaction between ficolins and MASP-2 is relatively poorly understood. In this study, we show that the MASP-2 binding site on rat ficolin-A is also located within the collagen-like domain and encompasses a conserved motif that is present in both MBLs and ficolins. Characterization of this motif using site-directed mutagenesis reveals that a lysine residue in the X position of the Gly-X-Y collagen repeat, Lys56 in ficolin-A, which is present in all ficolins and MBLs known to activate complement, is essential for MASP-2 binding. Adjacent residues also make important contributions to binding as well as to MASP activation probably by stabilizing the local collagen helix. Equivalent binding sites and comparable activation kinetics of MASP-2 suggest that complement activation by ficolins and MBLs proceeds by analogous mechanisms.