bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Adjuvant-Induced Mobilization and Maturation of Gut Dendritic Cells after Oral Administration of Cholera Toxin
Authors: Anjuère Fabienne , Luci Carmelo , Lebens Michael , Rousseau Déborah , Hervouet Catherine , Milon Geneviève , Holmgren Jan , Ardavin Carlos , Czerkinsky Cecil 
Published: April 2014

AbstractAlthough dendritic cells (DCs) regulate immune responses, they exhibit functional heterogeneity depending on their anatomical location. We examined the functional properties of intestinal DCs after oral administration of cholera toxin (CT), the most potent mucosal adjuvant. Two CD11c+ DC subsets were identified both in Peyer’s patches and mesenteric lymph nodes (MLN) based on the expression of CD8α (CD8+ and CD8− DCs, respectively). A third subset of CD11c+CD8int was found exclusively in MLN. Feeding mice with CT induced a rapid and transient mobilization of a new CD11c+CD8− DC subset near the intestinal epithelium. This recruitment was associated with an increased production of the chemokine CCL20 in the small intestine and was followed by a massive accumulation of CD8int DCs in MLN. MLN DCs from CT-treated mice were more potent activators of naive T cells than DCs from control mice and induced a Th2 response. This increase in immunostimulating properties was accounted for by CD8int and CD8− DCs, whereas CD8+ DCs remained insensitive to CT treatment. Consistently, the CD8int and CD8− subsets expressed higher levels of costimulatory molecules than CD8+ and corresponding control DCs. Adoptive transfer experiments showed that these two DC subsets, unlike CD8+ DCs, were able to present Ags orally coadministered with CT in an immunostimulating manner. The ability of CT to mobilize immature DCs in the intestinal epithelium and to promote their emigration and differentiation in draining lymph nodes may explain the exceptional adjuvant properties of this toxin on mucosal immune responses.
Endogenous IL-15 Sustains Recruitment of IL-2Rβ and Common γ and IL-2-Mediated Chemokine Production in Normal and Inflamed Human Gingival Fibroblasts
Authors: Ozawa Akiko , Tada Hiroyuki , Sugawara Yumiko , Uehara Akiko , Sasano Takashi , Shimauchi Hidetoshi , Takada Haruhiko , Sugawara Shunji 
Published: April 2014

AbstractWe recently reported that anti-IL-15 neutralizing mAb has been shown to inhibit production of MCP-1 in response to IL-2 from normal human gingival fibroblasts (HGF), the major constituent of gingival tissue. In the present study, we examined the expression of IL-2R and IL-15R subunits in HGF from normal and inflamed regions and the role of endogenous IL-15 in IL-2-mediated signaling. Normal HGF expressed IL-2Rβ and common γ-chain (γc) but not IL-2Rα or IL-15Rα, whereas inflamed HGF expressed IL-2Rα, IL-15Rα, IL-2Rβ, and γc, as assessed by RT-PCR and flow cytometry. Exogenous IL-2 and IL-15 induced production of MCP-1 but not IL-8 in normal HGF, and induced the production of both chemokines in inflamed HGF. Both HGF constitutively transcribed the 48 aa-IL-15 isoform, and the isoform was not actively secreted but rather existed as a membrane-bound form. Pretreatment with anti-IL-15 neutralizing mAb for 24 h completely inhibited the production of MCP-1 induced by IL-2 and IL-15 and IL-2-induced phosphorylation of Jak 1 and 3 in HGF. The pretreatment and RNA interference targeted to IL-15 mRNA resulted in total inhibition of the IL-2Rβ and γc expression at mRNA and protein levels. Furthermore, excess amounts of IL-2 restored the inhibitory effect of anti-IL-15, inhibition of NF-κB abrogated the expression of IL-2Rβ and γc, and IL-2-induced-nuclear translocation of NF-κB was completely inhibited by the RNA interference in HGF. These results suggest that endogenous membrane-bound IL-15 sustains recruitment of IL-2Rβ and γc through activation of NF-κB in HGF.
T Cell Proliferation by Direct Cross-Talk between OX40 Ligand on Human Mast Cells and OX40 on Human T Cells: Comparison of Gene Expression Profiles between Human Tonsillar and Lung-Cultured Mast Cells
Authors: Kashiwakura Jun-ichi , Yokoi Hidenori , Saito Hirohisa , Okayama Yoshimichi 
Published: April 2014

AbstractMast cells (MCs) are the primary effector cells in allergic reactions and have also been found to activate T cells and to reside in close physical proximity to T cells. However, the molecular mechanisms involved in the MC-T cell interaction remain unclear. We hypothesized that human tonsillar MCs, which locate in the interfollicular areas, might interact with T cells. Thus, we first established a culture system of human tonsillar MCs and then compared gene expression profiles of tonsillar MCs with that of lung MCs before and after aggregation of FcεRI by using high-density oligonucleotide probe arrays. Here we show that resting tonsillar MCs, when compared with lung MCs, revealed significantly higher expression levels for CC chemokines (CCL3 and 4), which recruit T cells, and for TNFR superfamilies (OX40 ligand and 4-1BB ligand), which induce proliferation of T cells. After aggregation of FcεRI, not only tonsillar MCs but also lung MCs up-regulated the expression of these molecules. We confirmed that T cell proliferation is induced in direct cross-talk by the MC surface molecule OX40 ligand. These results suggest that human MCs may play important roles in adaptive immunity through the T cell responses.
Allergy Vaccine Engineering: Epitope Modulation of Recombinant Bet v 1 Reduces IgE Binding but Retains Protein Folding Pattern for Induction of Protective Blocking-Antibody Responses
Authors: Holm Jens , Gajhede Michael , Ferreras Mercedes , Henriksen Anette , Ipsen Henrik , Larsen Jørgen N. , Lund Lise , Jacobi Henrik , Millner Anders , Würtzen Peter A. , Spangfort Michael D. 
Published: April 2014

AbstractHuman type 1 immediate allergic response symptoms are caused by mediator release from basophils and mast cells. This event is triggered by allergens aggregating preformed IgE Abs bound to the high-affinity receptor (FcεRI) on these cells. Thus, the allergen/IgE interaction is crucial for the cascade leading to the allergic and anaphylactic response. Two genetically engineered forms of the white birch pollen major allergen Bet v 1 with point mutations directed at molecular surfaces have been characterized. Four and nine point mutations led to a significant reduction of the binding to human serum IgE, suggesting a mutation-induced distortion of IgE-binding B cell epitopes. In addition, the mutated allergens showed a decrease in anaphylactic potential, because histamine release from human basophils was significantly reduced. Retained α-carbon backbone folding pattern of the mutated allergens was indicated by x-ray diffraction analysis and circular dichroism spectroscopy. The rBet v 1 mutants were able to induce proliferation of T cell lines derived from birch pollen allergic patients. The stimulation indices were similar to the indices of nonmutated rBet v 1 and natural Bet v 1 purified from birch pollen. The ability of anti-rBet v 1 mutant specific mouse IgG serum to block binding of human serum IgE to rBet v 1 demonstrates that the engineered rBet v 1 mutants are able to induce Abs reactive with nonmodified Bet v 1. rBet v 1 mutants may constitute vaccine candidates with improved efficacy/safety profiles for safer allergy vaccination.
IgE-Mediated Mast Cell Activation Induces Langerhans Cell Migration In Vivo
Authors: Jawdat Dunia M. , Albert Eric J. , Rowden Geoffrey , Haidl Ian D. , Marshall Jean S. 
Published: April 2014

AbstractLangerhans cells and mast cells are both resident in large numbers in the skin and act as sentinel cells in host defense. The ability of mast cells to induce Langerhans cell migration from the skin to the draining lymph node in vivo was examined. Genetically mast cell-deficient (W/Wv) mice and control mice were sensitized with IgE Ab in the ear pinna. Seven to 14 days later, mice were challenged with Ag i.v. After a further 18–24 h, epidermal sheets and draining auricular lymph nodes were examined using Langerin/CD207 immunostaining. In mast cell-containing mice, a significant decrease in the number of Langerhans cells was observed at epidermal sites of mast cell activation. A significant increase in total cellularity and accumulation of Langerin-positive dendritic cells was observed in the auricular lymph nodes, draining the sites of IgE-mediated mast cell activation. These changes were not observed in W/Wv mice, but were restored by local mast cell reconstitution. Treatment of mast cell-containing mice with the H2 receptor antagonist cimetidine significantly inhibited the observed IgE/Ag-induced changes in Langerhans cell location. In contrast, Langerhans cell migration in response to LPS challenge was not mast cell dependent. These data directly demonstrate the ability of mast cells to induce dendritic cell migration to lymph nodes following IgE-mediated activation in vivo by a histamine-dependent mechanism.
Increased Natural Killer Cell Activity in Viremic HIV-1 Infection
Authors: Alter Galit , Malenfant Jessica M. , Delabre Rosemary M. , Burgett Nicole C. , Yu Xu G. , Lichterfeld Mathias , Zaunders John , Altfeld Marcus 
Published: April 2014

Abstract
NK cells are a subset of granular lymphocytes that are critical in the innate immune response to infection. These cells are capable of killing infected cells and secreting integral cytokines and chemokines. The role that this subset of cytolytic cells plays in HIV infection is not well understood. In this study, we dissected the function of NK cells in viremic and aviremic HIV-1-infected subjects, as well as HIV-1-negative control individuals. Despite reduced NK cell numbers in subjects with ongoing viral replication, these cells were significantly more active in secreting both IFN-γ and TNF-α than NK cells from aviremic subjects or HIV-1-negative controls. In addition, NK cells in subjects with detectable viral loads expressed significantly higher levels of CD107a, a marker of lysosomal granule exocytosis. The expression of CD107a correlated with NK cell-mediated cytokine secretion and cytolytic activity as well as with the level of viral replication, suggesting that CD107a represents a good marker for the functional activity of NK cells. Finally, killer Ig-related receptor+ NK cells were stable or elevated in viremic subjects, while the numbers of CD3−/CD56+/CD94+ and CD3−/CD56+/CD161+ NK cells were reduced. Taken together, these data demonstrate that viremic HIV-1 infection is associated with a reduction in NK cell numbers and a perturbation of NK cell subsets, but increased overall NK cell activity.
Blockade of IL-18 Receptor Signaling Delays the Onset of Autoimmune Disease in MRL-Fas
lpr Mice
Authors: Kinoshita Koji , Yamagata Toshiaki , Nozaki Yuji , Sugiyama Masafumi , Ikoma Shinya , Funauchi Masanori , Kanamaru Akihisa 
Published: April 2014

Abstract
Autoimmune disease in Fas-deficient MRL-Faslpr mice is dependent on infiltrating autoreactive leukocytes and autoantibodies, and IFN-γ plays an important role in the pathogenesis. As IL-18 is capable of inducing IFN-γ production in T cells, we hypothesized that signaling through IL-18R is involved in the pathogenesis. To investigate the impact of IL-18 in this autoimmune disease, we generated an MRL-Faslpr strain deficient in IL-18Rα. Compared with the wild-type strain, IL-18Rα-deficient MRL-Faslpr mice survived longer and showed a significant reduction in renal pathology, including glomerular IgG deposits, proteinuria, and serum anti-DNA Abs. Intrarenal transcripts encoding IFN-γ, TNF-α, IL-12, and IL-10, which have been linked to nephritis, were all markedly reduced. Skin lesions, lymphadenopathy, and lung pathology characteristic of the MRL-Faslpr mouse disease were diminished in IL-18Rα-deficient MRL-Faslpr mice. Thus, we conclude that IL-18Rα signaling is critical to the pathogenesis of autoimmune disease in MRL-Faslpr mice.
Cutting Edge: Engagement of CD160 by its HLA-C Physiological Ligand Triggers a Unique Cytokine Profile Secretion in the Cytotoxic Peripheral Blood NK Cell Subset
Authors: Barakonyi Aliz , Rabot Magali , Marie-Cardine Anne , Aguerre-Girr Maryse , Polgar Beata , Schiavon Valérie , Bensussan Armand , Le Bouteiller Philippe 
Published: April 2014

Abstract
CD160 is an Ig-like activating NK cell receptor expressed on the majority of circulating NK cells. This population corresponds to the nonproliferating, highly cytolytic, CD56dimCD16+ subset. CD160 engagement by HLA-C molecules mediates cytotoxic function. In this study, we report that upon specific activation by the physiological ligand HLA-C, or Ab cross-linking, CD160+ peripheral blood NK cells produce IFN-γ, TNF-α, and IL-6. This unique CD160-mediated cytokine production differs from the one observed after CD16 engagement whose expression is also restricted to the CD56dim cytotoxic NK cell subset. As already reported for the CD160-mediated cytotoxic effector function, CD160-mediated cytokine production by peripheral blood-NK cells is negatively controlled by the killer Ig-like receptor CD158b. Thus, the CD160 receptor represents a unique triggering surface molecule expressed by cytotoxic NK cells that participates in the inflammatory response and determines the type of subsequent specific immunity.
Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-6
Authors: Ozaki Katsutoshi , Spolski Rosanne , Ettinger Rachel , Kim Hyoung-Pyo , Wang Gang , Qi Chen-Feng , Hwu Patrick , Shaffer Daniel J. , Akilesh Shreeram , Roopenian Derry C. , Morse Herbert C. , Lipsky Peter E. , Leonard Warren J. 
Published: April 2014

Abstract
IL-21 is a type I cytokine whose receptor is expressed on T, B, and NK cells. Within the B cell lineage, IL-21 regulates IgG1 production and cooperates with IL-4 for the production of multiple Ab classes in vivo. Using IL-21-transgenic mice and hydrodynamics-based gene delivery of IL-21 plasmid DNA into wild-type mice as well as in vitro studies, we demonstrate that although IL-21 induces death of resting B cells, it promotes differentiation of B cells into postswitch and plasma cells. Thus, IL-21 differentially influences B cell fate depending on the signaling context, explaining how IL-21 can be proapoptotic for B cells in vitro yet critical for Ag-specific Ig production in vivo. Moreover, we demonstrate that IL-21 unexpectedly induces expression of both Blimp-1 and Bcl-6, indicating mechanisms as to how IL-21 can serve as a complex regulator of B cell maturation and terminal differentiation. Finally, BXSB-Yaa mice, which develop a systemic lupus erythematosus-like disease, have greatly elevated IL-21, suggesting a role for IL-21 in the development of autoimmune disease.
CD28 and Lipid Rafts Coordinate Recruitment of Lck to the Immunological Synapse of Human T Lymphocytes
Authors: Tavano Regina , Gri Giorgia , Molon Barbara , Marinari Barbara , Rudd Christopher E. , Tuosto Loretta , Viola Antonella 
Published: April 2014

AbstractIn T lymphocytes, the Src family kinase Lck associates lipid rafts and accumulates at the immunological synapse (IS) during T cell stimulation by APCs. Using CD4- or CD28-deficient murine T cells, it was suggested that recruitment of Lck to the IS depends on CD4, whereas CD28 sustains Lck activation. However, in human resting T cells, CD28 is responsible for promoting recruitment of lipid rafts to the IS by an unknown mechanism. Thus, we performed a series of experiments to determine 1) whether Lck is recruited to the IS through lipid rafts; and 2) whether Lck recruitment to the IS of human resting T cells depends on CD4 or on CD28 engagement. We found that CD28, but not CD4, stimulation induced recruitment of Lck into detergent-resistant domains as well as its accumulation at the IS. We also found that Lck recruitment to the IS depends on the CD28 COOH-terminal PxxPP motif. Thus, the CD28-3A mutant, generated by substituting the prolines in positions 208, 211, and 212 with alanines, failed to induce Lck and lipid raft accumulation at the synapse. These results indicate that CD28 signaling orchestrates both Lck and lipid raft recruitment to the IS to amplify T cell activation.
β-Defensin-2 Expression Is Regulated by TLR Signaling in Intestinal Epithelial Cells
Authors: Vora Puja , Youdim Adrienne , Thomas Lisa S. , Fukata Masayuki , Tesfay Samuel Y. , Lukasek Katie , Michelsen Kathrin S. , Wada Akihiro , Hirayama Toshiya , Arditi Moshe , Abreu Maria T. 
Published: April 2014

Abstract
The intestinal epithelium serves as a barrier to the intestinal flora. In response to pathogens, intestinal epithelial cells (IEC) secrete proinflammatory cytokines. To aid in defense against bacteria, IEC also secrete antimicrobial peptides, termed defensins. The aim of our studies was to understand the role of TLR signaling in regulation of β-defensin expression by IEC. The effect of LPS and peptidoglycan on β-defensin-2 expression was examined in IEC lines constitutively or transgenically expressing TLRs. Regulation of β-defensin-2 was assessed using promoter-reporter constructs of the human β-defensin-2 gene. LPS and peptidoglycan stimulated β-defensin-2 promoter activation in a TLR4- and TLR2-dependent manner, respectively. A mutation in the NF-κB or AP-1 site within the β-defensin-2 promoter abrogated this response. In addition, inhibition of Jun kinase prevents up-regulation of β-defensin-2 protein expression in response to LPS. IEC respond to pathogen-associated molecular patterns with expression of the antimicrobial peptide β-defensin-2. This mechanism may protect the intestinal epithelium from pathogen invasion and from potential invaders among the commensal flora.
Transgenic Expression of CTLA-4 Controls Lymphoproliferation in IL-2-Deficient Mice
Authors: Hwang Kwang Woo , Sweatt William B. , Mashayekhi Mona , Palucki David A. , Sattar Hussain , Chuang Ellen , Alegre Maria-Luisa 
Published: April 2014

Abstract
IL-2-deficient mice develop a lymphoproliferative and autoimmune disease characterized by autoimmune hemolytic anemia (AHA) and inflammatory bowel disease. We have previously reported that IL-2 is necessary for optimal up-regulation of CTLA-4, an inducible negative regulator of T cell activation. In this study, we have tested the hypothesis that reduced expression of CTLA-4 in IL-2-deficient T cells contributes to the pathogenesis of disease in IL-2-deficient mice. Expression of CTLA-4 as a transgene completely prevented lymphoaccumulation and AHA in IL-2-deficient mice. The normalization of T cell numbers was due to inhibition of expansion of conventional CD4+CD25− T cells rather than to rescue of the numbers or function of CD4+CD25+ regulatory T cells, suggesting that CTLA-4 expression on conventional T cells plays a role in maintaining normal T cell homeostasis. In addition, the inhibitory effect of the CTLA-4 transgene on T cell expansion was at least in part independent of CD28 expression. Our results suggest that deficient CTLA-4 expression on conventional T cells contributes to the pathophysiology of the lymphoproliferative disease and AHA in IL-2-deficient mice. Thus, restoring CTLA-4 expression in T cells may be an attractive strategy to control clinical autoimmune diseases in which CTLA-4 expression is reduced.
The Regulated Expression of a Diverse Set of Genes during Thymocyte Positive Selection In Vivo
Authors: Mick Verity E. , Starr Timothy K. , McCaughtry Tom M. , McNeil Lisa K. , Hogquist Kristin A. 
Published: April 2014

AbstractA signal initiated by the newly formed Ag receptor is integrated with microenvironmental cues during T cell development to ensure positive selection of CD4+CD8+ progenitors into functionally mature CD4+ or CD8+ T lymphocytes. During this transition, a survival program is initiated, TCR gene recombination ceases, cells migrate into a new thymic microenvironment, the responsiveness of the Ag receptor is tuned, and the cells commit to a specific T lineage. To determine potential regulators of these processes, we used mRNA microarray analysis to compare gene expression changes in CD4+CD8+ thymocytes from TCR transgenic mice that have received a TCR selection signal with those that had not received a signal. We found 129 genes with expression that changed significantly during positive selection, the majority of which were not previously appreciated. A large number of these changes were confirmed by real-time PCR or flow cytometry. We have combined our findings with gene changes reported in the literature to provide a comprehensive report of the genes regulated during positive selection, and we attempted to assign these genes to positive selection process categories.
B7-H3 Enhances Tumor Immunity In Vivo by Costimulating Rapid Clonal Expansion of Antigen-Specific CD8+ Cytolytic T Cells
Authors: Luo Liqun , Chapoval Andrei I. , Flies Dallas B. , Zhu Gefeng , Hirano Fumiya , Wang Shengdian , Lau Julie S. , Dong Haidong , Tamada Koji , Flies Andrew S. , Liu Yang , Chen Lieping 
Published: April 2014

Abstract
B7-H3 is a B7 family molecule with T cell costimulatory function in vitro. The in vivo role of B7-H3 in the stimulation of tumor immunity is unclear. We report here that expression of B7-H3 by transfection of the mouse P815 tumor line enhances its immunogenicity, leading to the regression of tumors and amplification of a tumor-specific CD8+ CTL response in syngeneic mice. Tumor cells engineered to express B7-H3 elicit a rapid clonal expansion of P1A tumor Ag-specific CD8+ CTL in lymphoid organs in vivo and acquire the ability to directly stimulate T cell growth, division, and development of cytolytic activity in vitro. Our results thus establish a role for B7-H3 in the costimulation of T cell immune responses in vivo.
Specificity-Based Negative Selection of Autoreactive B Cells during Memory Formation
Authors: Guay Heath M. , Panarey Laura , Reed Amy J. , Caton Andrew J. 
Published: April 2014

Abstract
Autoreactive B cells are not completely purged from the primary B cell repertoire, and whether they can be prevented from maturation into memory B cells has been uncertain. We show here that a population of B cells that dominates primary immune responses of BALB/c mice to influenza virus A/PR/8/34 hemagglutinin (HA) are negatively selected in transgenic mice expressing PR8 HA as an abundant membrane-bound Ag (HACII mice). However, a separate population of B cells that contains precursors of memory B cells is activated by PR8 virus immunization and is subsequently negatively selected during the formation of the memory response. Negative selection of PR8 HA-specific B cells altered the specificity of the memory B cell response to a mutant virus containing a single amino acid substitution in a B cell epitope. Strikingly, this skewed reactivity resulted from an increase in the formation of memory B cells directed to non-self-epitopes on the mutant virus, which increased 8-fold in HACII mice relative to nontransgenic mice and precisely compensated for the absence of autoreactive PR8 HA-specific memory B cells. Negative selection of PR8 HA-specific B cells was a dominant process, since B cells from HACII mice could induce negative selection of PR8 HA-specific B cells from BALB/c mice. Lastly, HA-specific memory responses were unaffected by self-tolerance in another lineage of HA-transgenic mice (HA104 mice), indicating that the amount and/or cell type in which self-Ags are expressed can determine their ability to prevent autoreactive memory B cell formation.