bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of MHC Class II-Associated Peptides That Promote the Presentation of Toxic Shock Syndrome Toxin-1 to T Cells
Authors: Hogan Robert J. , VanBeek Josine , Broussard Dana R. , Surman Sherri L. , Woodland David L. 
Published: April 2014

AbstractPrevious studies have shown that the DM-deficient cell line, T2-I-Ab, is very inefficient at presenting toxic shock syndrome toxin 1 (TSST-1) to T cells, suggesting that I-Ab-associated peptides play an essential role in the presentation of this superantigen. Consistent with this, the loading of an I-Ab-binding peptide, staphylococcal enterotoxin B 121–136, onto T2-I-Ab cells enhanced TSST-1 presentation &gt;1000-fold. However, despite extensive screening, no other peptides have been identified that significantly promote TSST-1 presentation. In addition, the peptide effect on TSST-1 presentation has been demonstrated only in the context of the tumor cell line T2-I-Ab. Here we show that peptides that do not promote TSST-1 presentation can be converted into “promoting” peptides by the progressive truncation of C-terminal residues. These studies result in the identification of two peptides derived from IgGV heavy chain and I-Eα proteins that are extremely strong promoters of TSST-1 presentation (47,500- and 12,000-fold, respectively). We have also developed a system to examine the role of MHC class II-associated peptides in superantigen presentation using splenic APC taken directly ex vivo. The data confirmed that the length of the MHC class II-bound peptide plays a critical role in the presentation of TSST-1 by splenic APC and showed that different subpopulations of APC are equally peptide dependent in TSST-1 presentation. Finally, we demonstrated that the presentation of staphylococcal enterotoxin A, like TSST-1, is peptide dependent, whereas staphylococcal enterotoxin B presentation is peptide independent.
Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 on Murine Dendritic Cells Is a Potent Regulator of T Cell Stimulation
Authors: Kammerer Robert , Stober Detlef , Singer Bernhard B. , Öbrink Björn , Reimann Jörg 
Published: April 2014

AbstractDendritic cells (DC) are important APCs that play a key role in the induction of an immune response. The signaling molecules that govern early events in DC activation are not well understood. We therefore investigated whether DC express carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1, also known as BGP or CD66a), a well-characterized signal-regulating cell-cell adhesion molecule that is expressed on granulocytes, monocytes, and activated T cells and B cells. We found that murine DC express in vitro as well as in vivo both major isoforms of CEACAM1, CEACAM1-L (having a long cytoplasmic domain with immunoreceptor tyrosine-based inhibitory motifs) and CEACAM1-S (having a short cytoplasmic domain lacking phosphorylatable tyrosine residues). Ligation of surface-expressed CEACAM1 on DC with the specific mAb AgB10 triggered release of the chemokines macrophage inflammatory protein 1α, macrophage inflammatory protein 2, and monocyte chemoattractant protein 1 and induced migration of granulocytes, monocytes, T cells, and immature DC. Furthermore, the surface expression of the costimulatory molecules CD40, CD54, CD80, and CD86 was increased, indicating that CEACAM1-induced signaling regulates early maturation and activation of dendritic cells. In addition, signaling via CEACAM1 induced release of the cytokines IL-6, IL-12 p40, and IL-12 p70 and facilitated priming of naive MHC II-restricted CD4+ T cells with a Th1-like effector phenotype. Hence, our results show that CEACAM1 is a signal-transducing receptor that can regulate early maturation and activation of DC, thereby facilitating priming and polarization of T cell responses.
Mechanisms of the Antimetastatic Effect in the Liver and of the Hepatocyte Injury Induced by α-Galactosylceramide in Mice
Authors: Nakagawa Ryusuke , Nagafune Ikuko , Tazunoki Yoshiko , Ehara Hiromi , Tomura Hitomi , Iijima Rieko , Motoki Kazuhiro , Kamishohara Masaru , Seki Shuhji 
Published: April 2014

AbstractThe role of mouse liver NK1.1 Ag+ T (NKT) cells in the antitumor effect of α-galactosylceramide (α-GalCer) has been unclear. We now show that, whereas α-GalCer increased the serum IFN-γ concentration and alanine aminotransferase activity in NK cell-depleted C57BL/6 (B6) mice and B6-beige/beige mice similarly to its effects in control B6 mice, its enhancement of the antitumor cytotoxicity of liver mononuclear cells (MNCs) was abrogated. Depletion of both NK and NKT cells in B6 mice reduced all these effects of α-GalCer. Injection of Abs to IFN-γ also inhibited the α-GalCer-induced increase in antitumor cytotoxicity of MNCs. α-GalCer induced the expression of Fas ligand on NKT cells in the liver of B6 mice. Whereas α-GalCer did not increase serum alanine aminotransferase activity in B6-lpr/lpr mice and B6-gld/gld mice, it increased the antitumor cytotoxicity of liver MNCs. The α-GalCer-induced increase in survival rate apparent in B6 mice injected intrasplenically with B16 tumor cells was abrogated in beige/beige mice, NK cell-depleted B6 mice, and B6 mice treated with Abs to IFN-γ. Depletion of CD8+ T cells did not affect the α-GalCer-induced antitumor cytotoxicity of liver MNCs but reduced the effect of α-GalCer on the survival of B6 mice. Thus, IFN-γ produced by α-GalCer-activated NKT cells increases both the innate antitumor cytotoxicity of NK cells and the adaptive antitumor response of CD8+ T cells, with consequent inhibition of tumor metastasis to the liver. Moreover, NKT cells mediate α-GalCer-induced hepatocyte injury through Fas-Fas ligand signaling.
The Fetal Liver Counterpart of Adult Common Lymphoid Progenitors Gives Rise to All Lymphoid Lineages, CD45+CD4+CD3− Cells, As Well As Macrophages
Authors: Mebius Reina E. , Miyamoto Toshihiro , Christensen Julie , Domen Jos , Cupedo Tom , Weissman Irving L. , Akashi Koichi 
Published: April 2014

Abstract
We identified an IL-7Rα+Sca-1lowc-Kitlow population in E14 fetal liver, which is the phenotypical analog of common lymphoid progenitors (CLP) in adult bone marrow. After transfer into newborn mice, the IL-7Rα+Sca-1lowc-Kitlow population rapidly differentiated into CD45+CD4+CD3− cells, which are candidate cells for initiating lymph node and Peyer’s patch formation. In addition, this population also gave rise to B, T, NK, and CD8α+ and CD8α− dendritic cells. The fetal liver precursors expressed a significantly lower level of the myeloid-suppressing transcription factor Pax-5, than adult CLP, and retained differentiation activity for macrophages in vitro. We propose that the transition from fetal liver IL-7Rα+Sca-1lowc-Kitlow cells to adult CLP involves a regulated restriction of their developmental potential, controlled, at least in part, by Pax-5 expression.
A Low Affinity TCR Ligand Restores Positive Selection of CD8+ T Cells In Vivo
Authors: Stefanski Heather E. , Mayerova Dita , Jameson Stephen C. , Hogquist Kristin A. 
Published: April 2014

AbstractThe T cell repertoire is shaped by the processes of positive and negative selection. During development, the TCR binds self peptide-MHC complexes in the thymus, and the kinetics of this interaction are thought to determine the thymocyte’s fate. For development of CD8+ T cells, the data supporting such a model have been obtained using fetal thymic organ culture. To confirm the fidelity of this model in vivo, we studied development of OT-I TCR-transgenic mice that expressed different individual Kb binding peptides in thymic epithelial cells under the control of the human keratin 14 promoter. We used a system that allowed TAP-independent expression of the peptide-MHC complex, such that the ability of given peptides to restore positive selection in TAPo mice could be assessed. We found that transgenic expression of a TCR antagonist peptide (E1) in vivo efficiently restored positive selection of OT-I T cells in TAPo mice. An unrelated transgenic peptide (SIY) did not restore selection of OT-I T cells, nor did the E1-transgenic peptide restore selection of an unrelated receptor (2C), showing that positive selection is peptide specific in vivo, as observed in organ cultures. Neither E1 nor SIY transgenes increased the polyclonal CD8 T cell repertoire size in non-TCR-transgenic animals, arguing that single class I binding peptides do not detectably affect the size of the CD8 T cell repertoire when expressed at low levels. We also observed that OT-I T cells selected in TAPo-E1 mice were functional in their response to Ag; however, there was a lag in this response, suggesting that the affinity of the TCR interaction with MHC-self peptide can result in fine-tuning of the T cell response.
Clustering of Peptide-Loaded MHC Class I Molecules for Endoplasmic Reticulum Export Imaged by Fluorescence Resonance Energy Transfer
Authors: Pentcheva Tsvetelina , Edidin Michael 
Published: April 2014

Abstract
Fluorescence resonance energy transfer between cyan fluorescent protein- and yellow fluorescent protein-tagged MHC class I molecules reports on their spatial organization during assembly and export from the endoplasmic reticulum (ER). A fraction of MHC class I molecules is clustered in the ER at steady state. Contrary to expectations from biochemical models, this fraction is not bound to the TAP. Instead, it appears that MHC class I molecules cluster after peptide loading. This clustering points toward a novel step involved in the selective export of peptide-loaded MHC class I molecules from the ER. Consistent with this model, we detected clusters of wild-type HLA-A2 molecules and of mutant A2-T134K molecules that cannot bind TAP, but HLA-A2 did not detectably cluster with A2-T134K at steady state. Lactacystin treatment disrupted the HLA-A2 clusters, but had no effect on the A2-T134K clusters. However, when cells were fed peptides with high affinity for HLA-A2, mixed clusters containing both HLA-A2 and A2-T134K were detected.
A Novel Pathway Regulating Lipopolysaccharide-Induced Shock by ST2/T1 Via Inhibition of Toll-Like Receptor 4 Expression
Authors: Sweet Matthew J. , Leung Bernard P. , Kang Daiwu , Sogaard Morten , Schulz Kerstin , Trajkovic Vladimir , Campbell Carol C. , Xu Damo , Liew Foo Y. 
Published: April 2014

AbstractST2/ST2L, a member of the IL-1R gene family, is expressed by fibroblasts, mast cells, and Th2, but not Th1, cells. It exists in both membrane-bound (ST2L) and soluble forms (ST2). Although ST2L has immunoregulatory properties, its ligand, cellular targets, and mode of action remain unclear. Using a soluble ST2-human IgG fusion protein, we demonstrated that ST2 bound to primary bone marrow-derived macrophages (BMM) and that this binding was enhanced by treatment with LPS. The sST2 treatment of BMMs inhibited production of the LPS-induced proinflammatory cytokines IL-6, IL-12, and TNF-α but did not alter IL-10 or NO production. Treatment of BMMs with sST2 down-regulated expression of Toll-like receptors-4 and -1 but induced nuclear translocation of NF-κB. Administration of sST2 in vivo after LPS challenge significantly reduced LPS-mediated mortality and serum levels of IL-6, IL-12, and TNF-α. Conversely, blockade of endogenous ST2 through administration of anti-ST2 Ab exacerbated the toxic effects of LPS. Thus, ST2 has anti-inflammatory properties that act directly on macrophages. We demonstrate here a novel regulatory pathway for LPS-induced shock via the ST2-Toll-like receptor 4 route. This may be of considerable therapeutic potential for reducing the severity and pathology of inflammatory diseases.
An Alternative Form of IL-18 in Human Blood Plasma: Complex Formation with IgM Defined by Monoclonal Antibodies
Authors: Shida Kyoko , Shiratori Ikuo , Matsumoto Misak , Fukumori Yasuo , Matsuhisa Akio , Kikkawa Satomi , Tsuji Shoutaro , Okamura Haruki , Toyoshima Kumao , Seya Tsukasa 
Published: April 2014

AbstractMonoclonal Abs 21 and 132 were raised against human functionally inactive rIL-18, and plasma IL-18 levels were determined by the sandwich ELISA established with these mAbs. Plasma IL-18, designated type 2, was detected by this ELISA, and the levels found were not consistent with those obtained with the commercially available kit for determination of functionally active IL-18 (type 1). Type 1 was detected in all volunteers, whereas type 2 was detected in ∼30% of healthy subjects, and the levels of type 2 in their blood plasma were high (25–100 ng/ml) compared with those of type 1 (0.05–0.3 ng/ml). We purified IL-18 type 2 from blood plasma of volunteers with high IL-18 type 2 concentrations, and its Mr was determined to be 800 kDa by SDS-PAGE and molecular sieve HPLC. The purified 800-kDa protein, either caspase-1-treated or untreated, expressed no or marginal IL-18 function in terms of potentiation of NK-mediated cytolysis and IFN-γ induction, and it barely bound IL-18R-positive cells. N-terminal amino acid analysis indicated that the purified protein was IgM containing a minimal amount of IL-18 proform and its fragment. Again, the purified IgM from IL-18 type2-positive volunteers exhibited cross-reaction with mAb 21 against IL-18. This band was not detected with 125-2H, an mAb against functionally active IL-18. Hence, human IgM carries functionally inactive IL-18 forming a disulfide-bridged complex, and this IL-18 moiety is from 10- to 100-fold higher than the conventional type 1 IL-18 in blood circulation in ∼30% normal subjects.
Association of ERp57 with Mouse MHC Class I Molecules Is Tapasin Dependent and Mimics That of Calreticulin and not Calnexin
Authors: Harris Michael R. , Lybarger Lonnie , Yu Yik Y. L. , Myers Nancy B. , Hansen Ted H. 
Published: April 2014

AbstractBefore peptide binding in the endoplasmic reticulum, the class I heavy (H) chain-β2-microglobulin complexes are detected in association with TAP and two chaperones, TPN and CRT. Recent studies have shown that the thiol-dependent reductase, ERp57, is also present in this peptide-loading complex. However, it remains controversial whether the association of ERp57 with MHC class I molecules precedes their combined association with the peptide-loading complex or whether ERp57 only associates with class I molecules in the presence of TPN. Resolution of this controversy could help determine the role of ERp57 in class I folding and/or assembly. To define the mouse class I H chain structures involved in interaction with ERp57, we tested chaperone association of Ld mutations at residues 134 and 227/229 (previously implicated in TAP association), residues 86/88 (which ablate an N-linked glycan), and residue 101 (which disrupts a disulfide bond). The association of ERp57 with each of these mutant H chains showed a complete concordance with CRT, TAP, and TPN but not with calnexin. Furthermore, ERp57 failed to associate with H chain in TPN-deficient .220 cells. These combined data demonstrate that, during the assembly of the peptide-loading complex, the association of ERp57 with mouse class I is TPN dependent and parallels that of CRT and not calnexin.
Flexibility in MHC and TCR Recognition: Degenerate Specificity at the T Cell Level in the Recognition of Promiscuous Th Epitopes Exhibiting No Primary Sequence Homology
Authors: Joshi Sunil K. , Suresh Padma R. , Chauhan Virander S. 
Published: April 2014

AbstractRecognition of peptide Ags by T cells through the TCR can be highly specific. In this report we show the degeneracy of Ag recognition at both MHC and TCR levels. We present evidence that unrelated promiscuous Th cell epitopes from various protein sources exhibit sufficient structural homology, despite minimal structural identity, to elicit cross-reactive proliferative responses at the bulk T cell level. This epitopic mimicry was also observed when peptide (CS.T3378–395 and TT830–844)-specific CD4+ T cell lines and T cell hybridoma clones were used in proliferation and Ag presentation assays. A scrambled CS.T3378–395 peptide did not show any proliferation, indicating that the specificity of the cross-reactive responses may be linked with the primary structure of the peptides. Blocking of CS.T3378–395-specific CD4+ T cell proliferation by anti-MHC class II mAb showed that recognition of promiscuous T cell epitopes is largely in association with MHC class II molecules. These findings suggest that promiscuous Th epitopes may be useful in designing peptide-based vaccine constructs. At the same time these results show that at the T cell level there may be a great deal of immunological cross-reactivity between heterologous pathogens, and because of this the host’s response to a pathogen may be modified by its previous experience with other unrelated pathogens.
Immunological and Biochemical Characterization of Streptococcal Pyrogenic Exotoxins I and J (SPE-I and SPE-J) from Streptococcus pyogenes
Authors: Proft Thomas , Arcus Vickery L. , Handley Vanessa , Baker Edward N. , Fraser John D. 
Published: April 2014

Abstract
Recently, we described the identification of novel streptococcal superantigens (SAgs) by mining the Streptococcus pyogenes M1 genome database at Oklahoma University. Here, we report the cloning, expression, and functional analysis of streptococcal pyrogenic exotoxin (SPE)-J and another novel SAg (SPE-I). SPE-I is most closely related to SPE-H and staphylococcal enterotoxin I, whereas SPE-J is most closely related to SPE-C. Recombinant forms of SPE-I and SPE-J were mitogenic for PBL, both reaching half maximum responses at 0.1 pg/ml. Evidence from binding studies and cell aggregation assays using a human B-lymphoblastoid cell line (LG-2) suggests that both toxins exclusively bind to the polymorphic MHC class II β-chain in a zinc-dependent mode but not to the generic MHC class II α-chain. The results from analysis by light scattering indicate that SPE-J exists as a dimer in solution above concentrations of 4.0 mg/ml. Moreover, SPE-J induced a rapid homotypic aggregation of LG-2 cells, suggesting that this toxin might cross-link MHC class II molecules on the cell surface by building tetramers of the type HLA-DRβ–SPE-J–SPE-J–HLA-DRβ. SPE-I preferably stimulates T cells bearing the Vβ18.1 TCR, which is not targeted by any other known SAg. SPE-J almost exclusively stimulates Vβ2.1 T cells, a Vβ that is targeted by several other streptococcal SAgs, suggesting a specific role for this T cell subpopulation in immune defense. Despite a primary sequence diversity of 51%, SPE-J is functionally indistinguishable from SPE-C and might play a role in streptococcal disease, which has previously been addressed to SPE-C.
Serum Amyloid P Component Binds to Fcγ Receptors and Opsonizes Particles for Phagocytosis
Authors: Bharadwaj Dwaipayan , Mold Carolyn , Markham Eric , Du Clos Terry W. 
Published: April 2014

AbstractSerum amyloid P component (SAP) is a member of the pentraxin family of proteins. These proteins are characterized by cyclic pentameric structure, calcium-dependent ligand binding, and frequent regulation as acute-phase serum proteins. SAP is the serum precursor of the P component of amyloid. It binds to a broad group of molecules, including autoantigens, through a pattern recognition binding site. The related pentraxin, C-reactive protein (CRP), is a strong acute-phase reactant in man and an opsonin. We previously determined that the binding of CRP to leukocytes occurs through Fc receptors for IgG (FcγR). We now report that SAP also binds to FcγR and opsonizes particles for phagocytosis by human polymorphonuclear leukocytes (PMN). Specific, saturable binding of SAP to FcγRI, FcγRIIa, and FcγRIIIb expressed on transfected COS cells was detected using SAP-biotin and PE-streptavidin. Zymosan was used to test the functional consequences of SAP and CRP binding to FcγR. Both SAP and CRP bound to zymosan and enhanced its uptake by PMN. This enhanced phagocytosis was abrogated by treatment of PMN with wortmannin, a phosphatidylinositol-3 kinase inhibitor, or with piceatannol, a Syk inhibitor, consistent with uptake through FcγR. Treatment of PMN with phosphatidylinositol-specific phospholipase C to remove FcγRIIIb also decreased phagocytosis of SAP-opsonized zymosan, but not CRP-opsonized zymosan. These results suggest that SAP may function in host defense. In addition, as SAP binds to chromatin, a major immunogen in systemic lupus erythematosus, it may provide a clearance mechanism for this Ag through FcγR bearing cells.
Peroxisome Proliferator-Activated Receptor γ-Retinoid X Receptor Agonists Increase CD36-Dependent Phagocytosis ofPlasmodium falciparum-Parasitized Erythrocytes and Decrease Malaria-Induced TNF-α Secretion by Monocytes/Macrophages
Authors: Serghides Lena , Kain Kevin C. 
Published: April 2014

AbstractSevere and fatal malaria is associated with the failure of host defenses to control parasite replication, excessive secretion of proinflammatory cytokines such as TNF-α, and sequestration of parasitized erythrocytes (PEs) in vital organs. The identification of CD36 as a major sequestration receptor has led to the assumption that it contributes to the pathophysiology of severe malaria and has prompted the development of antiadherence therapies to disrupt the CD36-PE interaction. This concept has been challenged by unexpected evidence that individuals deficient in CD36 are more susceptible to severe and cerebral malaria. In this study, we demonstrate that CD36 is the major receptor mediating nonopsonic phagocytosis of PEs by macrophages, a clearance mechanism of potential importance in nonimmune hosts at the greatest risk of severe malaria. CD36-mediated uptake of PEs occurs via a novel pathway that does not involve thrombospondin, the vitronectin receptor, or phosphatidylserine recognition. Furthermore, we show that proliferator-activated receptor γ-retinoid X receptor agonists induce an increase in CD36-mediated phagocytosis and a decrease in parasite-induced TNF-α secretion. Specific up-regulation of monocyte/macrophage CD36 may represent a novel therapeutic strategy to prevent or treat severe malaria.
A Retroviral-Derived Immunosuppressive Peptide Activates Mitogen-Activated Protein Kinases
Authors: Takahashi Akio , Day Noorbibi K. , Luangwedchakarn Voravich , Good Robert A. , Haraguchi Soichi 
Published: April 2014

Abstract
The highly conserved region within the retroviral transmembrane envelope proteins has been implicated in a number of retrovirus-associated mechanisms of immunosuppression. CKS-17, a synthetic peptide representing the prototypic sequence of the immunosuppressive domain, has been found to suppress numerous immune functions, disregulate cytokines, and elevate intracellular cAMP. In this report we show that using a human monocytic cell line THP-1, CKS-17 activates mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase 1 and 2 (ERK1/2). Kinetic studies show that CKS-17 induces an acute increase of ERK1/2 activity followed by a rapid decrease and then a second sustained increase of ERK1/2. CKS-17 also activates MAP kinase/ERK kinase (MEK) with a similar induction pattern. Mutant THP-1 cells isolated in our laboratory, in which CKS-17 exclusively fails to activate cAMP, did not show the transient decrease of CKS-17-induced ERK1/2 phosphorylation. Pretreatment of THP-1 cells or mutant THP-1 cells with cAMP analog or forskolin followed by treatment with CKS-17 showed no activation of MEK or ERK1/2. These results indicate that CKS-17 activates the MEK/ERK cascade and that there is a cross-talk between CKS-17-mediated MEK/ERK cascade and cAMP in that the MEK/ERK cascade is negatively regulated by cAMP. These data present a novel molecular mechanism(s) by this highly conserved retroviral immunosuppressive component.