bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promotion of Skin Graft Tolerance Across MHC Barriers by Mobilization of Dendritic Cells in Donor Hemopoietic Cell Infusions
Authors: Eto Masatoshi , Hackstein Holger , Kaneko Katsuhiko , Nomoto Kikuo , Thomson Angus W. 
Published: April 2014

AbstractFlt3 ligand (FL) dramatically increases the number of immunostimulatory dendritic cells (DC) and their precursors in bone marrow (BM) and secondary lymphoid tissues. Herein we tested the ability of FL-mobilized donor hemopoietic cells to promote induction of skin graft tolerance across full MHC barriers. C57BL/10 (B10; H2b, IE−) mice were given 108 spleen cells (SC) from normal or FL-treated, H-2-mismatched B10.D2 (H2d, IE+) donors i.v. on day 0, 200 mg/kg i.p. cyclophosphamide on day 2, and 107 T cell-depleted BM cells from B10.D2 mice on day 3. B10.D2 skin grafting was performed on day 14. Indefinite allograft survival (100 days) was induced in recipients of FL-SC, but not in mice given normal SC. Tolerance was associated with blood macrochimerism and was confirmed by second-set skin grafting with donor skin 100 days after the first graft. In tolerant mice, peripheral donor-reactive T cells expressing TCR Vβ11 were deleted selectively. Immunocompetence of tolerant FL-SC-treated mice was proven by rapid rejection of third-party skin grafts. To our knowledge this is the first report that mobilization of DC in donor cell infusions can be used to induce skin graft tolerance across MHC barriers, accompanied by specific deletion of donor-reactive T cells.
Immunomodulatory Effects of the Liver: Deletion of Activated CD4+ Effector Cells and Suppression of IFN-γ-Producing Cells After Intravenous Protein Immunization
Authors: Klugewitz Katja , Blumenthal-Barby Friderike , Schrage Arnhild , Knolle Percy A. , Hamann Alf , Crispe Ian Nicholas 
Published: April 2014

AbstractThe liver is tolerogenic in many situations, including as an allograft and during the response to allogeneic MHC expressed on hepatocytes. The majority of data that address this issue focus on endogenous Ags. Little is known about CD4+ T cells and their fate under tolerizing conditions, especially with respect to fully differentiated CD4+ effector T cells. In this study, we used the adoptive transfer of populations of TCR-transgenic CD4+ T cells, skewed toward the Th1 or Th2 phenotype, to test whether either apoptotic or immune deviation mechanisms apply to cytokine-producing CD4+ T cells that enter the liver. After transfer, Th1 and Th2 cells could be detected up to 25 days in lymphoid organs and the liver. Intravenous high dose Ag application resulted in accumulation, proliferation, and subsequent deletion of effector cells within the liver. Th1 cells lost their capacity to produce cytokines, whereas IL-4 expression was sustained within Th2 cells from the liver. However, there was no evidence for a deviation of Th1-programmed cells toward a Th2 (IL-4) or regulatory T cell (IL-10) pattern of cytokine expression. We used isolated populations of liver-derived APCs to test whether the liver had the capacity to impose a bias toward IL-4 expression in T cells. These experiments showed that liver sinusoidal endothelial cells selectively suppress the expansion of IFN-γ-producing cells, yet they promote the outgrowth of IL-4-expressing Th2 cells, creating an immune suppressive milieu within this organ. These data suggest that presentation of Ags in the liver leads to modulation of immune response in terms of quantity and quality.
Stimulation of Th1-Polarizing Cytokines, C-C Chemokines, Maturation of Dendritic Cells, and Adjuvant Function by the Peptide Binding Fragment of Heat Shock Protein 70
Authors: Wang Yufei , Kelly Charles G. , Singh Mahavir , McGowan Edward G. , Carrara Anne-Sophie , Bergmeier Lesley A. , Lehner Thomas 
Published: April 2014

AbstractThe peptide binding C-terminal portion of heat shock protein (HSP)70 (aa 359–610) stimulates human monocytes to produce IL-12, TNF-α, NO, and C-C chemokines. The N-terminal, ATPase portion (HSP701–358) failed to stimulate any of these cytokines or chemokines. Both native and the truncated HSP70359–610 stimulation of chemokine production is mediated by the CD40 costimulatory molecule. Maturation of dendritic cells was induced by stimulation with native HSP70, was not seen with the N-terminal HSP701–358, but was enhanced with HSP70359–610, as demonstrated by up-regulation of CD83, CCR7, CD86, CD80, and HLA class II. In vivo studies in macaques showed that immunization with HSP70359–610 enhances the production of IL-12 and RANTES. Immunization with peptide-bound HSP70359–610 in mice induced higher serum IgG2a and IgG3 Abs than the native HSP70-bound peptide. This study suggests that the C-terminal, peptide-binding portion of HSP70 is responsible for stimulating Th1-polarizing cytokines, C-C chemokines, and an adjuvant function.
TheDermatophagoides pteronyssinusGroup 2 Allergen Contains a Universally Immunogenic T Cell Epitope
Authors: Wu Bo , Elst Luc Vander , Carlier Vincent , Jacquemin Marc G. , Saint-Remy Jean-Marie R. 
Published: April 2014

AbstractThe use of T cell epitope-containing peptides for the induction of anergy in allergen sensitization is limited by genetic restriction that could be circumvented by using universally immunogenic epitopes. We attempted to identify such epitopes on Dermatophagoides pteronyssinus group 2 allergen (Der p 2), a major allergen of D. pteronyssinus T cells from BALB/c (H-2d), C57BL/6 (H-2b), C3H (H-2k), and SJL (H-2s) mice that were immunized with rDer p 2, recognized an immunodominant region encompassing residues 21–35. A synthetic 21–35 peptide (p21–35) induced strong dose-dependent in vitro T cell proliferation with cells of the four mouse strains and required processing for MHC class II presentation. Substitution of Ile28 with Ala resulted in reduction of T cell proliferation in each strain. Ile28 could represent an important MHC class II anchoring residue for T cell response to p21–35. An immunodominant T cell epitope of Der p 2 therefore behaves as a universal epitope and could be a suitable candidate for T cell anergy induction.
T Cell Response to Preproinsulin I and II in the Nonobese Diabetic Mouse
Authors: Halbout Philippe , Briand Jean-Paul , Bécourt Chantal , Muller Sylviane , Boitard Christian 
Published: April 2014

AbstractImmunization against insulin, insulin B chain, or B chain peptide B9–23 (preproinsulin peptide II33–47) prevents diabetes in the nonobese diabetic (NOD) mouse. Whether or not peptide II33–47 is the only proinsulin determinant recognized by CD4 T cells remains unclear. Using two peptide libraries spanning the entire sequence of preproinsulin I and preproinsulin II, respectively, we identified T cells specific for four proinsulin epitopes within the islet cell infiltrate of prediabetic female NOD mice. These epitopes were among immunogenic epitopes to which a T cell response was detected after immunization of NOD mice with individual peptides in CFA. Immunogenic epitopes were found on both isoforms of insulin, especially proinsulin II, which is the isoform expressed in the thymus. The autoimmune response to proinsulin represented only part of the immune response to islet cells within the islet cell infiltrate in 15-wk-old NOD mice. This is the first systematic study of preproinsulin T cell epitopes in the NOD mouse model.
Role of Disulfide Bonds in Regulating Antigen Processing and Epitope Selection
Authors: Li Ping , Haque M. Azizul , Blum Janice S. 
Published: April 2014

Abstract
Knowledge of the events governing Ag processing and epitope selection within APC is key to the development of novel immunotherapeutic strategies for infectious diseases, cancer, and autoimmunity. The influence of disulfides and Ag reduction on the hierarchy of epitope presentation via MHC class II molecules was investigated through studies of a self Ag, IgG κ. HLA-DR4+ B cells preferentially present an immunodominant IgG-derived epitope, κI, relative to a subdominant κII peptide. κI contains a cysteine masked within the native Ag via an intrachain disulfide, the latter of which is reduced during Ag processing. Mutagenesis of this cysteine as well as others within κ minimally perturbed the abundance and overall conformation of IgG. Yet, disruptions in disulfide bonding within this Ag influenced the selective display of class II-restricted dominant and subdominant T cell epitopes. Presentation of the κI epitope from both native and variant IgG was dependent upon cellular expression of IFN-γ-inducible lysosomal thiol reductase. These studies indicate that disulfide bonds regulate Ag processing both locally and at distant sites, thus influencing epitope selection within the class II pathway.
TCR-Independent CD30 Signaling Selectively Induces IL-13 Production Via a TNF Receptor-Associated Factor/p38 Mitogen-Activated Protein Kinase-Dependent Mechanism
Authors: Harlin Helena , Podack Eckhard , Boothby Mark , Alegre Maria-Luisa 
Published: April 2014

AbstractInitiation of T lymphocyte responses to most Ags requires concurrent stimulation through the TCR and costimulatory receptors such as CD28. Following initial activation, secondary receptors are up-regulated that can costimulate T cells in concert with TCR engagement. One such receptor is the TNFR family member CD30. In this study, we report that unlike CD28, ligation of CD30 on normal effector T cells induces IL-13 production in the absence of concurrent TCR engagement. TCR-independent CD30-mediated IL-13 release correlated with activation of c-Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), and NF-κB, and was completely inhibited by the expression of a TNFR-associated factor 2 (TRAF2) dominant-negative transgene (TRAF2.DN-Tg), but not by that of an I-κBα dominant-negative transgene. In parallel, expression of the TRAF2.DN-Tg selectively prevented the induction of c-Jun N-terminal kinase and p38 MAPK, but not that of NF-κB. Furthermore, IL-13 production was reduced in a dose-dependent manner by the p38 MAPK inhibitor SB203580. Together, these results suggest that TCR-independent CD30-mediated production of IL-13 is triggered by association of CD30 with TRAF family members and subsequent activation of p38 MAPK. Inasmuch as IL-13 can promote airway inflammation and cancer progression, production of IL-13 in a TCR-independent manner has important pathological implications in vivo.
The Human IL-2 Gene Promoter Can Assemble a Positioned Nucleosome That Becomes Remodeled Upon T Cell Activation
Authors: Attema Joanne L. , Reeves Raymond , Murray Vincent , Levichkin Ilya , Temple Mark D. , Tremethick David J. , Shannon M. Frances 
Published: April 2014

AbstractControlled production of the cytokine IL-2 plays a key role in the mammalian immune system. Expression from the gene is tightly regulated with no detectable expression in resting T cells and a strong induction following T cell activation. The IL-2 proximal promoter (+1 to −300) contains many well-defined transcriptional activation elements that respond to T cell stimulation. To determine the role of chromatin structure in the regulation of interleukin-2 gene transcription, nucleosome assembly across the IL-2 promoter region was examined using in vitro chromatin reconstitution assays. The IL-2 promoter assembles a nucleosome that is both translationally and rotationally positioned, spanning some of the major functional control elements. The binding of transcription factors to these elements, with the exception of the architectural protein HMGA1, was occluded by the presence of the nucleosome. Analysis of the chromatin architecture of the IL-2 gene in Jurkat T cells provided evidence for the presence of a similarly positioned nucleosome in vivo. The region encompassed by this nucleosome becomes remodeled following activation of Jurkat T cells. These observations suggest that the presence of a positioned nucleosome across the IL-2 proximal promoter may play an important role in maintaining an inactive gene in resting T cells and that remodeling of this nucleosome is important for gene activation.
High Frequency of Matrix Attachment Regions and Cut-Like Protein x/CCAAT-Displacement Protein and B Cell Regulator of IgH Transcription Binding Sites Flanking Ig V Region Genes
Authors: Goebel Peter , Montalbano Alina , Ayers Neil , Kompfner Elizabeth , Dickinson Liliane , Webb Carol F. , Feeney Ann J. 
Published: April 2014

AbstractA major component in controlling V(D)J recombination is differential accessibility through localized changes in chromatin structure. Attachment of DNA to the nuclear matrix via matrix attachment region (MAR) sequences, and interaction with MAR-binding proteins have been shown to alter chromatin conformation, promote histone acetylation, and influence gene transcription. In this study, the flanking regions of several human and mouse Ig VH and Ig Vκ genes were analyzed extensively for the presence of MARs by in vitro matrix-binding assay, and for interaction with the MAR-binding proteins cut-like protein x/CCAAT-displacement protein (Cux/CDP), B cell regulator of IgH transcription (Bright), and special AT-rich sequence-binding protein (SATB1) by EMSA. Cux/CDP and SATB1 are associated with repression, while Bright is an activator of Ig transcription. Binding sites were identified in the vicinity of all analyzed Ig V genes, and were also found flanking TCR Vβ genes. We also show that the binding sites of the different factors do not always occur at MAR sequences. MAR sequences were also found within the Ig V loci at a much higher frequency than throughout the rest of the genome. Overall, the frequency and location of binding sites relative to the coding regions, and the strength of DNA-protein interaction showed much heterogeneity. Thus, variations in factor binding and MAR activity could potentially influence the extent of localized accessibility to V(D)J recombination and thus could play a role in unequal rearrangement of individual V genes. These sites could also contribute to effective transcription of Ig genes in mature and/or activated B cells, bringing both the promoter as well as the enhancer regions into close proximity at the nuclear matrix.
TheIgHLocus of the Channel Catfish,Ictalurus punctatus, Contains Multiple Constant Region Gene Sequences: Different Genes Encode Heavy Chains of Membrane and Secreted IgD
Authors: Bengtén Eva , Quiniou Sylvie M.-A. , Stuge Tor B. , Katagiri Takayuki , Miller Norman W. , Clem L. William , Warr Gregory W. , Wilson Melanie 
Published: April 2014

AbstractThe δ-chain of catfish IgD was initially characterized as a unique chimeric molecule containing a rearranged VDJ spliced to Cμ1, seven C domain-encoding exons (δ1–δ7), and a transmembrane tail. The presence of cDNA forms showing splicing of δ7 to an exon encoding a secretory tail was interpreted to indicate that membrane (δm) and secreted (δs) forms were likely expressed from a single gene by alternative RNA processing. Subsequent cloning and sequence analyses have unexpectedly revealed the presence of three δ C region genes, each linked to a μ gene or pseudogene. The first (IGHD1) is located 1.6 kb 3′ of the functional Cμ (IGHM1). The second (IGHD3) is positioned immediately downstream of a pseudo Cμ (IGHM3P), ∼725 kb 5′ of IGHM1. These two δ genes are highly similar in sequence and each contains a tandem duplication of δ2-δ3-δ4. However, IGHD1 has a terminal exon encoding the transmembrane region, whereas IGHD3 has a single terminal exon encoding a secreted tail. The occurrence of IGHD3 immediately downstream of a μ pseudogene indicates that the putative δs product may not be expressed as a chimeric μδ molecule. Western blots and protein sequencing data indicate that an IGHD3-encoded protein is expressed in catfish serum. Thus, catfish δm transcripts appear to originate from IGHD1, whereas δs transcripts originate from IGHD3 rather than, as previously inferred, from a single expressed δ gene. The third δ (IGHD2) is associated with a pseudo Cμ (IGHM2P); its presence is inferred by Southern blot analyses.
RGS13 Regulates Germinal Center B Lymphocytes Responsiveness to CXC Chemokine Ligand (CXCL)12 and CXCL13
Authors: Shi Geng-Xian , Harrison Kathleen , Wilson Gaye Lynn , Moratz Chantal , Kehrl John H. 
Published: April 2014

Abstract
Normal lymphoid tissue development and function depend upon directed cell migration. Providing guideposts for cell movement and positioning within lymphoid tissues, chemokines signal through cell surface receptors that couple to heterotrimeric G proteins, which are in turn subject to regulation by regulator of G protein signaling (RGS) proteins. In this study, we report that germinal center B lymphocytes and thymic epithelial cells strongly express one of the RGS family members, RGS13. Located between Rgs1 and Rgs2, Rgs13 spans 42 kb on mouse chromosome 1. Rgs13 encodes a 157-aa protein that shares 82% amino acid identity with its 159-aa human counterpart. In situ hybridization with sense and antisense probes localized Rgs13 expression to the germinal center regions of mouse spleens and Peyer’s patches and to the thymus medulla. Affinity-purified RGS13 Abs detected RGS13-expressing cells in the light zone of the germinal center. RGS13 interacted with both Giα and Gqα and strongly impaired signaling through Gi-linked signaling pathways, including signaling through the chemokine receptors CXCR4 and CXCR5. Prolonged CD40 signaling up-regulated RGS13 expression in human tonsil B lymphocytes. These results plus previous studies of RGS1 indicate the germinal center B cells use two RGS proteins, RGS1 and RGS13, to regulate their responsiveness to chemokines.
IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression
Authors: Joshi Vishwas D. , Kalvakolanu Dhananjaya V. , Hasday Jeffrey D. , Hebel Richard J. , Cross Alan S. 
Published: April 2014

AbstractLPS enhanced antibacterial host defenses (ABHD) when given at low (75 μg) doses (16 of 19 mice survived 3× LD50 Escherichia coli vs 3 of 19 LPS-naive mice; p = 0.0001), but induced lethal inflammation at high (500 μg) doses (5 of 5 died). Differences in the cytokine profiles induced by these LPS doses may provide insight into the mechanism(s) of transition from beneficial to lethal LPS responses. The 75 μg LPS induced 5.9 ± 0.9 ng/ml serum IL-18 at 8 h, which decreased to 2.3 ± 0.4 ng/ml by 24 h, whereas 500 μg LPS induced 11.1 ± 1.6 ng/ml serum IL-18 levels at 8 h, which increased until death. Compared with 75 μg, higher but sublethal (150 μg) doses of LPS induced greater serum IL-18 levels and less effectively induced ABHD (3 of 8 survived). Reduction of serum IL-18 with neutralizing Ab improved the ABHD induced by 150 μg, but reduced that produced by 75 μg LPS, suggesting an optimal range of serum IL-18 level was essential for efficient ABHD. Increased expression of caspase-1 mRNA in response to the higher IL-18 levels induced at the 150 and 500 μg, but not at the 75 μg doses of LPS may represent a positive feedback regulatory loop leading to sustained serum IL-18 levels. We conclude that the regulation of serum IL-18 expression is critical to the outcome of innate immune responses to LPS.
The Bacterial Superantigen Streptococcal Mitogenic Exotoxin Z Is the Major Immunoactive Agent ofStreptococcus pyogenes
Authors: Unnikrishnan Meera , Altmann Daniel M. , Proft Thomas , Wahid Faisal , Cohen Jonathan , Fraser John D. , Sriskandan Shiranee 
Published: April 2014

AbstractThe gene encoding streptococcal mitogenic exotoxin Z (SMEZ) was disrupted in Streptococcus pyogenes. Despite the presence of other superantigen genes, mitogenic responses in human and murine HLA-DQ transgenic cells were abrogated when cells were stimulated with supernatant from the smez− mutant compared with the parent strain. Remarkably, disruption of smez led to a complete inability to elicit cytokine production (TNF-α, lymphotoxin-α, IFN-γ, IL-1 and -8) from human cells, when cocultured with streptococcal supernatants. The potent effects of SMEZ were apparent even though transcription and expression of SMEZ were barely detectable. Human Vβ8+ T cell proliferation in response to S. pyogenes was SMEZ-dependent. Cells from HLA-DQ8 transgenic mice were 3 logs more sensitive to SMEZ-13 than cells from HLA-DR1 transgenic or wild-type mice. In the mouse, SMEZ targeted the human Vβ8+ TCR homologue, murine Vβ11, at the expense of other TCR T cell subsets. Expression of SMEZ did not affect bacterial clearance or survival from peritoneal streptococcal infection in HLA-DQ8 mice, though effects of SMEZ on pharyngeal infection are unknown. Infection did lead to a rise in Vβ11+ T cells in the spleen which was partly reversed by disruption of the smez gene. Most strikingly, a clear rise in murine Vβ4+ cells was seen in mice infected with the smez− mutant S. pyogenes strain, indicating a potential role for SMEZ as a repressor of cognate anti-streptococcal responses.
Inhibition of NF-κB Activity by a Membrane-Transducing Mutant of IκBα
Authors: Kabouridis Panagiotis S. , Hasan Maemunah , Newson Justine , Gilroy Derek W. , Lawrence Toby 
Published: April 2014

AbstractThe transcription factor NF-κB is regulated by the IκB family of proteins. The nonphosphorylatable, nondegradable superrepressor IκBα (srIκBα) mutant is a potent inhibitor of NF-κB activity when expressed in cells. We generated a form of srIκBα in which its N terminus is fused to the protein transduction domain of HIV TAT (TAT-srIκBα). Purified TAT-srIκBα protein rapidly and efficiently entered HeLa or Jurkat T cells. TAT-srIκBα, when exogenously added to HeLa cells, inhibited in a dose-dependent manner TNF-α- or IL-1β-induced NF-κB activation and binding of NF-κB to its consensus DNA sequence. TAT-srIκBα was coimmunoprecipitated with the p65 subunit of NF-κB, and this interaction was resistant to stimulation with IL-1β. Therefore, TAT-srIκBα-mediated inhibition could result from its nonreversible binding and sequestration of endogenous NF-κB. In contrast, exogenously added TAT-srIκBα did not inhibit IL-1β-induced activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase, or p38 mitogen-activated protein kinases or the phosphorylation and degradation of endogenous IκBα. These results identify a novel way for direct regulation of NF-κB activity in diverse cell types that may be useful for therapeutic purposes.
Complement Activates the c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase in Glomerular Epithelial Cells
Authors: Peng Hongwei , Takano Tomoko , Papillon Joan , Bijian Krikor , Khadir Abdelkrim , Cybulsky Andrey V. 
Published: April 2014

AbstractIn the rat passive Heymann nephritis model of membranous nephropathy, complement C5b-9 induces sublethal glomerular epithelial cell (GEC) injury and proteinuria. C5b-9 activates cytosolic phospholipase A2 (cPLA2), and products of cPLA2-mediated phospholipid hydrolysis modulate GEC injury and proteinuria. In the present study, we demonstrate that C5b-9 activates c-Jun N-terminal kinase (JNK) in cultured rat GECs and that JNK activity is increased in glomeruli isolated from proteinuric rats with passive Heymann nephritis, as compared with control rats. Stable overexpression of cPLA2 in GECs amplified complement-induced release of arachidonic acid (AA) and JNK activity, as compared with neo (control) GECs. Activation of JNK was not affected by indomethacin. Incubation of GECs with complement stimulated production of superoxide, and pretreatment with the antioxidants, N-acetylcysteine, glutathione, and α-tocopherol as well as with diphenylene iodonium, an inhibitor of the NADPH oxidase, inhibited complement-induced JNK activation. Conversely, H2O2 activated JNK, whereas exogenously added AA stimulated both superoxide production and JNK activity. Overexpression of a dominant-inhibitory JNK mutant or treatment with diphenylene iodonium exacerbated complement-dependent GEC injury. Thus, activation of cPLA2 and release of AA facilitate complement-induced JNK activation. AA may activate the NADPH oxidase, leading to production of reactive oxygen species, which in turn mediate the activation of JNK. The functional role of JNK activation is to limit or protect GECs from complement attack.