bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-Presentation by Dendritic Cells of Tumor Antigen Expressed in Apoptotic Recombinant Canarypox Virus-Infected Dendritic Cells
Authors: Motta Iris , André Fabrice , Lim Annick , Tartaglia James , Cox William I. , Zitvogel Laurence , Angevin Eric , Kourilsky Philippe 
Published: April 2014

AbstractWe have investigated the possible usefulness of recombinant canarypox virus (ALVAC) encoding the melanoma-associated Ag, Melan-A/MART-1 (MART-1), in cancer immunotherapy, using a dendritic cell (DC)-based approach. ALVAC MART-1-infected DC express, and are able to process and present, the Ag coded by the viral vector. One consistent feature of infection by ALVAC is that these viruses induce apoptosis, and we show cross-presentation of Ag when uninfected DC are cocultured with ALVAC MART-1-infected DC. Uptake of apoptotic virally infected DC by uninfected DC and subsequent expression of tumor Ag in the latter were verified by flow cytometry analysis, image cytometry, and confocal microscopy. Functional activity was monitored in vitro by the stimulation of a MART-1-specific cytotoxic T cell clone. Heightened efficiency in Ag presentation is evidenced in the 2- to 3-fold increase in IFN-γ production by the T cell clone, as compared with the ALVAC-infected DC alone. Cocultures of ALVAC MART-1-infected and uninfected DC are able to induce MART-1-specific T cell immune responses, as assessed by HLA class I/peptide tetramer binding, IFN-γ ELISPOT assays, and cytotoxicity tests. Overall, our data indicate that DC infected with recombinant canarypox viruses may represent an efficient presentation platform for tumor Ags, which can be exploited in clinical studies.
Cutting Edge: Bacterial Flagellin Activates Basolaterally Expressed TLR5 to Induce Epithelial Proinflammatory Gene Expression
Authors: Gewirtz Andrew T. , Navas Tony A. , Lyons Sean , Godowski Paul J. , Madara James L. 
Published: April 2014

Abstract
Flagellin, the structural component of bacterial flagella, is secreted by pathogenic and commensal bacteria. Flagellin activates proinflammatory gene expression in intestinal epithelia. However, only flagellin that contacts basolateral epithelial surfaces is proinflammatory; apical flagellin has no effect. Pathogenic Salmonella, but not commensal Escherichia coli, translocate flagellin across epithelia, thus activating epithelial proinflammatory gene expression. Investigating how epithelia detect flagellin revealed that cell surface expression of Toll-like receptor 5 (TLR5) conferred NF-κB gene expression in response to flagellin. The response depended on both extracellular leucine-rich repeats and intracellular Toll/IL-1R homology region of TLR5 as well as the adaptor protein MyD88. Furthermore, immunolocalization and cell surface-selective biotinylation revealed that TLR5 is expressed exclusively on the basolateral surface of intestinal epithelia, thus providing a molecular basis for the polarity of this innate immune response. Thus, detection of flagellin by basolateral TLR5 mediates epithelial-driven inflammatory responses to Salmonella.
Signaling Through TNF Receptor p55 in TNF-α-Deficient Mice Alters the CXCL13/CCL19/CCL21 Ratio in the Spleen and Induces Maturation and Migration of Anergic B Cells into the B Cell Follicle
Authors: Mandik-Nayak Laura , Huang Guangming , Sheehan Kathleen C. F. , Erikson Jan , Chaplin David D. 
Published: April 2014

Abstract
The organization of secondary lymphoid tissues into distinct T and B cell compartments supports proper regulation of an immune response to foreign Ags. In the splenic white pulp, this compartmentalization is also thought to be important in the maintenance of B cell tolerance. Using lymphotoxin-α-(LT-α)-, TNF-α-, or TNFRp55-deficient mice, all with disrupted splenic architecture, we tested whether normal T/B segregation and/or intact follicular structure are necessary for the maintenance of anti-dsDNA B cell anergy. This study demonstrates that anti-dsDNA B cells remain tolerant in LT-α−/−, TNF-α−/−, and TNFRp55−/− mice; however, TNF-α or a TNF-α-dependent factor is required for their characteristic positioning to the T/B interface. Providing a TNF-α signal in TNF-α−/− mice by systemic administration of an agonist anti-TNFRp55 mAb induces the maturation of the anti-dsDNA B cells and their movement away from the T cell area toward the B cell area. Additionally, the agonist Ab induces changes in the follicular environment, including FDC clustering, up-regulation of the CXC chemokine ligand CXCL13, and down-regulation of the CC chemokine ligands CCL19 and CCL21. Therefore, this study suggests that a balance between B and T cell tropic chemokine signals may be an important mechanism for positioning anergic B cells at the T/B interface of the splenic white pulp.
Regulatory T Cells Induced by 1α,25-Dihydroxyvitamin D3 and Mycophenolate Mofetil Treatment Mediate Transplantation Tolerance
Authors: Gregori Silvia , Casorati Mara , Amuchastegui Susana , Smiroldo Simona , Davalli Alberto M. , Adorini Luciano 
Published: April 2014

Abstract1α,25-Dihydroxyvitamin D3, the active form of vitamin D3, and mycophenolate mofetil, a selective inhibitor of T and B cell proliferation, modulate APC function and induce dendritic cells (DCs) with a tolerogenic phenotype. Here we show that a short treatment with these agents induces tolerance to fully mismatched mouse islet allografts that is stable to challenge with donor-type spleen cells and allows acceptance of donor-type vascularized heart grafts. Peritransplant macrophages and DCs from tolerant mice express down-regulated CD40, CD80, and CD86 costimulatory molecules. In addition, DCs from the graft area of tolerant mice secrete, upon stimulation with CD4+ cells, 10-fold lower levels of IL-12 compared with DCs from acutely rejecting mice, and induce a CD4+ T cell response characterized by selective abrogation of IFN-γ production. CD4+ but not CD8+ or class II+ cells from tolerant mice, transferred into naive syngeneic recipients, prevent rejection of donor-type islet grafts. Graft acceptance is associated with impaired development of IFN-γ-producing type 1 CD4+ and CD8+ cells and an increased percentage of CD4+CD25+ regulatory cells expressing CD152 in the spleen and in the transplant-draining lymph node. Transfer of CD4+CD25+ cells from tolerant but not naive mice protects 100% of the syngeneic recipients from islet allograft rejection. These results demonstrate that a short treatment with immunosuppressive agents, such as 1α,25-dihydroxyvitamin D3/mycophenolate mofetil, induces tolerance to islet allografts associated with an increased frequency of CD4+CD25+ regulatory cells that can adoptively transfer transplantation tolerance.
Circulating Human B Cells That Express Surrogate Light Chains Display a Unique Antibody Repertoire
Authors: Meffre Eric , Chiorazzi Michael , Nussenzweig Michel C. 
Published: April 2014

Abstract
Circulating human B cells that coexpress V-preB and conventional L chains (V-preB+L+ B cells) are a recently described subset of B cells that express Abs with features of self-reactivity. Initial analysis of V-preB+L+ B cells was limited to Ig-κ and to the small, underused VH5 family. To determine whether Abs commonly expressed by V-preB+L+ B cells show similar features, we analyzed Ig H chains from three highly expressed VH families, VH1, VH3, and VH4, and Ig-λ. We find that VH1 and VH3 Abs expressed by V-preB+L+ B cells resemble VH5 in that they display increased JH6 use, long CDR3s, and an increased frequency of D-D fusions. Abs in all three of these VH families also show skewed D reading frame use resulting in predominance of hydrophobic amino acids, which are counterselected in conventional B cells. Like Ig-κ genes, the Ig-λ genes in V-preB+L+ B cells show long CDR3s, but they differ from Ig-κ genes in that they display no evidence of receptor editing. We conclude that a large number of H and L chain Abs expressed by V-preB+L+ B cells display features associated with self-reactive Abs.
Catalytic Subunit of Protein Kinase A Is an Interacting Partner of the Inflammation-Responsive Transcription Factor Serum Amyloid A-Activating Factor-1
Authors: Ray Bimal K. , Chen Jing , Ray Alpana 
Published: April 2014

Abstract
Serum amyloid A-activating factor-1 (SAF-1) is a zinc finger transcription factor that is activated by many mediators of inflammation including IL-1, IL-6, and bacterial LPS. However, the mechanism of activation is not fully understood. To identify possible activation partners for SAF-1, we used a yeast two-hybrid system that detected interaction between the catalytic subunit of cyclic AMP-dependent protein kinase (PKA-Cα) and SAF-1. Immunofluorescence and combined immunoprecipitation-Western blot analyses revealed colocalization and interaction between SAF-1 and PKA-Cα. In vivo evidence of SAF-1 and PKA-Cα interaction was further revealed by coimmunoprecipitation of these two proteins in cAMP-activated liver cells. We further show that SAF-1 is phosphorylated in vitro by PKA-Cα and that addition of cAMP markedly induces in vivo phosphorylation of SAF-1 and transcription of SAF-regulated reporter genes. These results showed that SAF1-PKA-Cα interaction is involved in functional activation of SAF-1.
Adoptive Immunotherapy of Experimental Autoimmune Encephalomyelitis Via T Cell Delivery of the IL-12 p40 Subunit
Authors: Costa Gina L. , Sandora Matthew R. , Nakajima Atsuo , Nguyen Eddy V. , Taylor-Edwards Cariel , Slavin Anthony J. , Contag Christopher H. , Fathman C. Garrison , Benson Jacqueline M. 
Published: April 2014

Abstract
CD4+ T cells are believed to play a central role in the initiation and perpetuation of autoimmune diseases such as multiple sclerosis. In the murine model for multiple sclerosis, experimental autoimmune encephalomyelitis, pathogenic T cells exhibit a Th1-like phenotype characterized by heightened expression of proinflammatory cytokines. Systemic administration of “regulatory” cytokines, which serve to counter Th1 effects, has been shown to ameliorate autoimmune responses. However, the inherent problems of nonspecific toxicity limit the usefulness of systemic cytokine delivery as a potential therapy. Therefore, we used the site-specific trafficking properties of autoantigen-reactive CD4+ T cells to develop an adoptive immunotherapy protocol that provided local delivery of a Th1 cytokine antagonist, the p40 subunit of IL-12. In vitro analysis demonstrated that IL-12 p40 suppressed IFN-γ production in developing and effector Th1 populations, indicating its potential to modulate Th1-promoted inflammation. We have previously demonstrated that transduction of myelin basic protein-specific CD4+ T cells with pGC retroviral vectors can result in efficient and stable transgene expression. Therefore, we adoptively transferred myelin basic protein-specific CD4+ T cells transduced to express IL-12 p40 into mice immunized to develop experimental autoimmune encephalomyelitis and demonstrated a significant reduction in clinical disease. In vivo tracking of bioluminescent lymphocytes, transduced to express luciferase, using low-light imaging cameras demonstrated that transduced CD4+ T cells trafficked to the central nervous system, where histological analysis confirmed long-term transgene expression. These studies have demonstrated that retrovirally transduced autoantigen-specific CD4+ T cells inhibited inflammation and promoted immunotherapy of autoimmune disorders.
Glomerulonephritis Induced by Recombinant Collagen IVα3 Chain Noncollagen Domain 1 Is Not Associated with Glomerular Basement Membrane Antibody: A Potential T Cell-Mediated Mechanism
Authors: Wu Jean , Hicks John , Ou Ching-nan , Singleton David , Borillo Jason , Lou Ya-Huan 
Published: April 2014

Abstract
Glomerulonephritis is believed to result commonly from Ab-mediated glomerular injury. However, Ab-associated mechanisms alone cannot explain many cases of human glomerulonephritis. We developed a rat model of human anti-glomerular basement membrane (GBM) disease to investigate T cell and Ab response, and their associations with the disease. A single immunization of highly denatured recombinant mouse collagen IVα3 chain noncollagen domain 1 (rCol4α3NC1) induced severe glomerulonephritis in 100% of Wistar Kyoto rats, 33% of which died of this disease around day 35 postimmunization. The renal pathology demonstrated widespread glomerular damage and a mononuclear cell infiltration within the interstitial tissue. T cells from immunized rats responded not only to rCol4α3NC1, but also to isolated rat GBM. Sera Abs to rCol4α3NC1 were detectable in 100% of the rats, but only 20% of the rats had low levels of Ab to isolated rat GBM by Western blot, and none by immunofluorescence. Furthermore, IgG/M binding to or C3 deposition on endogenous GBM in immunized rats were not detected in most of the experimental rats, and showed no statistical correlation with disease severity. Additionally, no electronic dense deposition in the glomeruli was detected in all rats. Those data revealed a disassociation between the disease and anti-GBM Ab. T cell-mediated mechanisms, which are currently under our investigation, may be responsible for the glomerular disease.
A Pivotal Role of Rho GTPase in the Regulation of Morphology and Function of Dendritic Cells
Authors: Kobayashi Michihiro , Azuma Eiichi , Ido Masaru , Hirayama Masahiro , Jiang Qi , Iwamoto Shotaro , Kumamoto Tadashi , Yamamoto Hatsumi , Sakurai Minoru , Komada Yoshihiro 
Published: April 2014

AbstractDendritic cell (DC) is the most potent activator of CD4+ T cells and has unique dendrites and veils. To explore the function of Rho in DC, exoenzyme C3 from Clostridium botulinum was used as a specific inhibitor of Rho. Treatment of DC with C3 (DC/C3) resulted in profound morphological changes by losing dendrites and emerging of shrunk membrane processes that were in parallel with marked reduction of polymerized actin in the marginal area. Inactivation of Rho-associated coiled coil-containing kinase (p160ROCK) by a specific ROCK inhibitor Y-27632 also led to disappearance of dendrites of DC with retaining large membrane expansions. In scanning electron microscopy, untreated DCs interacted with CD4+ T cells more efficiently than DC/C3. Conjugate formation assay showed that the number of DCs associated with CD4+ T cells was 2-fold higher in untreated DCs than that of DC/C3. Alloantigen-presenting capacity of DC/C3 was significantly suppressed in a dose-dependent manner. Because C3 treatment did not affect the surface expression of HLA, costimulatory, and adhesion molecules of DC, we examined cytokine production of DC and naive CD4+ T cells to further elucidate the inhibitory mechanism of MLR. Unexpectedly, DC/C3 increased IL-12 production after LPS stimulation. Naive CD4+ T cells cocultured with DC/C3 produced the increased percentage of IFN-γ-producing cells, whereas the percentage of IL-2-producing T cells was decreased. These results demonstrate that Rho GTPase in DC controls both characteristic shape and immunogenic capacity.
Cytotoxic Activity of Human Dendritic Cells Is Differentially Regulated by Double-Stranded RNA and CD40 Ligand
Authors: Vidalain Pierre-Olivier , Azocar Olga , Yagita Hideo , Rabourdin-Combe Chantal , Servet-Delprat Christine 
Published: April 2014

Abstract
The main function of dendritic cells (DCs) is to induce adaptive immune response through Ag presentation and specific T lymphocyte activation. However, IFN-α- or IFN-γ-stimulated CD11c+ blood DCs and IFN-β-stimulated monocyte-derived DCs were recently reported to express functional TNF-related apoptosis-inducing ligand (TRAIL), suggesting that DCs may become cytotoxic effector cells of innate immunity upon appropriate stimulation. In this study, we investigate whether dsRNA and CD40 ligand (CD40L), that were characterized as potent inducers of DC maturation, could also stimulate or modulate DC cytotoxicity toward tumoral cells. We observed that dsRNA, but not CD40L, is a potent inducer of TRAIL expression in human monocyte-derived DCs. As revealed by cytotoxicity assays, DCs acquire the ability to kill tumoral cells via the TRAIL pathway when treated with dsRNA. More precisely, dsRNA is shown to induce IFN-β synthesis that consecutively mediates TRAIL expression by the DCs. In contrast, we demonstrate that TRAIL expression in dsRNA- or IFN-α-treated DCs is potently inhibited after CD40L stimulation. Unexpectedly, CD40L-activated DCs still developed cytotoxicity toward tumoral cells. This latter appeared to be partly mediated by TNF-α induction and a yet unidentified pathway. Altogether, these results demonstrate that dsRNA and CD40L, that were originally characterized as maturation signals for DCs, also stimulate their cytotoxicity that is mediated through TRAIL-dependent or -independent mechanisms.
Lipopolysaccharide-Induced Increase of Prostaglandin E2 Is Mediated by Inducible Nitric Oxide Synthase Activation of the Constitutive Cyclooxygenase and Induction of Membrane-Associated Prostaglandin E Synthase
Authors: Devaux Yvan , Seguin Carole , Grosjean Sandrine , de Talancé Nicole , Camaeti Viviane , Burlet Arlette , Zannad Faiez , Meistelman Claude , Mertes Paul-Michel , Longrois Dan 
Published: April 2014

AbstractNO produced by the inducible NO synthase (NOS2) and prostanoids generated by the cyclooxygenase (COX) isoforms and terminal prostanoid synthases are major components of the host innate immune and inflammatory response. Evidence exists that pharmacological manipulation of one pathway could result in cross-modulation of the other, but the sense, amplitude, and relevance of these interactions are controversial, especially in vivo. Administration of 6 mg/kg LPS to rats i.p. resulted 6 h later in induction of NOS2 and the membrane-associated PGE synthase (mPGES) expression, and decreased constitutive COX (COX-1) expression. Low level inducible COX (COX-2) mRNA with absent COX-2 protein expression was observed. The NOS2 inhibitor aminoguanidine (50 and 100 mg/kg i.p.) dose dependently decreased both NO and prostanoid production. The LPS-induced increase in PGE2 concentration was mediated by NOS2-derived NO-dependent activation of COX-1 pathway and by induction of mPGES. Despite absent COX-2 protein, SC-236, a putative COX-2-specific inhibitor, decreased mPGES RNA expression and PGE2 concentration. Ketoprofen, a nonspecific COX inhibitor, and SC-236 had no effect on the NOS2 pathway. Our results suggest that in a model of systemic inflammation characterized by the absence of COX-2 protein expression, NOS2-derived NO activates COX-1 pathway, and inhibitors of COX isoforms have no effect on NOS2 or NOS3 (endothelial NOS) pathways. These results could explain, at least in part, the deleterious effects of NOS2 inhibitors in some experimental and clinical settings, and could imply that there is a major conceptual limitation to the use of NOS2 inhibitors during systemic inflammation.
Loss of IFN-γ Production by Invariant NK T Cells in Advanced Cancer
Authors: Muhammad Ali Tahir Syed , Cheng Olivia , Shaulov Angela , Koezuka Yasuhiko , Bubley Glenn J. , Wilson S. Brian , Balk Steven P. , Exley Mark A. 
Published: April 2014

Abstract
Invariant NK T cells express certain NK cell receptors and an invariant TCRα chain specific for the MHC class I-like CD1d protein. These invariant NK T cells can regulate diverse immune responses in mice, including antitumor responses, through mechanisms including rapid production of IL-4 and IFN-γ, but their physiological functions remain uncertain. Invariant NK T cells were markedly decreased in peripheral blood from advanced prostate cancer patients, and their ex vivo expansion with a CD1d-presented lipid Ag (α-galactosylceramide) was diminished compared with healthy donors. Invariant NK T cells from healthy donors produced high levels of both IFN-γ and IL-4. In contrast, whereas invariant NK T cells from prostate cancer patients also produced IL-4, they had diminished IFN-γ production and a striking decrease in their IFN-γ:IL-4 ratio. The IFN-γ deficit was specific to the invariant NK T cells, as bulk T cells from prostate cancer patients produced normal levels of IFN-γ and IL-4. These findings support an immunoregulatory function for invariant NK T cells in humans mediated by differential production of Th1 vs Th2 cytokines. They further indicate that antitumor responses may be suppressed by the marked Th2 bias of invariant NK T cells in advanced cancer patients.
Peptide Antigen Priming of Naive, But Not Memory, CD8 T Cells Requires a Third Signal That Can Be Provided by IL-12
Authors: Schmidt Clint S. , Mescher Matthew F. 
Published: April 2014

AbstractChallenge with peptide Ag in the absence of adjuvant results in tolerance of CD8 T cells specific for the Ag. In contrast, administration of IL-12 along with peptide results in massive clonal expansion, development of effector function, and establishment of a long-lived memory population. Using adoptive transfer of TCR-transgenic CD8 T cells, this effect of IL-12 is shown to be independent of CD4 T cells and to require costimulation provided by CD28 and possibly LFA-1. IL-12 supports responses when IL-12Rβ1-deficient mice are used as recipients for the adoptively transferred CD8 T cells, demonstrating that the IL-12 is acting directly on the T cells rather than on host APC. These results provide strong support for a three-signal model for in vivo activation of naive CD8 T cells by peptide Ag, in which the presence or absence of the third signal determines whether tolerance or activation occurs. In contrast, memory CD8 T cells are effectively activated by peptide Ag in the absence of IL-12 or adjuvant.
Regulatory Effects of Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) on B Cell Function
Authors: Senaldi Giorgio , Stolina Marina , Guo Jane , Faggioni Raffaella , McCabe Susan , Kaufman Stephen A. , Van Gwyneth , Xu Weilong , Fletcher Frederick A. , Boone Thomas , Chang Ming-Shi , Sarmiento Ulla , Cattley Russell C. 
Published: April 2014

Abstract
We describe regulatory effects that a novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3; also reported as cardiotrophin-like cytokine) has on B cell function. NNT-1/BSF-3 stimulates B cell proliferation and Ig production in vitro. NNT-1/BSF-3-transgenic mice, engineered to express NNT-1/BSF-3 in the liver under control of the apolipoprotein E promoter, show B cell hyperplasia with particular expansion of the mature follicular B cell subset in the spleen and the prominent presence of plasma cells. NNT-1/BSF-3-transgenic mice show high serum levels of IgM, IgE, IgG2b, IgG3, anti-dsDNA Abs, and serum amyloid A. NNT-1/BSF-3-transgenic mice also show non-amyloid mesangial deposits that contain IgM, IgG, and C3 and are characterized by a distinctive ultrastructure similar to that of immunotactoid glomerulopathy. NNT-1/BSF-3-transgenic mice produce high amounts of Ag-specific IgM, IgA, and IgE and low amounts of IgG2a and IgG3. Normal mice treated with NNT-1/BSF-3 also produce high amounts of Ag-specific IgE. NNT-1/BSF-3 regulates immunity by stimulating B cell function and Ab production, with preference for Th2 over Th1 Ig types.