bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytokines and Cell Surface Molecules Independently Induce CXCR4 Expression on CD4+ CCR7+ Human Memory T Cells
Authors: Jourdan Patrick , Vendrell Jean-Pierre , Huguet Marie-France , Segondy Michel , Bousquet Jean , Pène Jérôme , Yssel Hans 
Published: April 2014

AbstractIn the present study, we show that IL-2, IL-4, IL-7, and IL-15 are able to induce functional CXCR4 surface expression on resting in vitro-generated CD4+ CXCR4− CCR7+ memory T cells. Cytokine-mediated induction of CXCR4 expression was associated with an increase in CXCR4 transcription, enhanced stromal-derived factor-1-induced T cell migration in vitro, and increased susceptibility of these cells to infection with X4 strains of HIV-1. CXCR4 expression could also be induced through an alternative pathway, following coculture of these cells with CD40-activated, autologous, CD34+ progenitor-derived dendritic cells. Although these dendritic cells express transcripts for IL-7 and IL-15, addition of neutralizing anti-IL-7R and IL-15 mAbs did not block induction of CXCR4 expression. Indeed, dendritic cell-mediated up-regulation of CXCR4 expression was found to depend on CD40/CD154 and CD134/CD134L interactions. Whereas activated autologous dendritic cells induced the expression of both CXCR4 and CD25 on a portion of CCR7+ memory T cells, concomitant CD3-mediated activation of these cells further enhanced CD25 expression, but, in contrast, prevented induction of CXCR4 expression. This observation suggests that triggering of the CD134 and CD154 molecules, in contrast to TCR/CD3 complex-mediated stimulation, results in simultaneous T cell activation and CXCR4 expression. Taken together, these results show that common γ-chain-interacting cytokines as well as signals mediated via noncognate interactions between activated dendritic cells and memory T cells are involved in the up-regulation of CXCR4 expression.
An Epithelial Cell Line That Can Stimulate Alloproliferation of Resting CD4+ T Cells, But Not After IFN-γ Stimulation
Authors: Lawson Charlotte , McCormack Ann M. , Moyes David , Yun Sheng , Fabre John W. , Yacoub Magdi , Rose Marlene L. 
Published: April 2014

AbstractIt has previously been shown that IFN-γ-induced up-regulation of HLA class II on the surface of epithelial cells is not sufficient to induce proliferation of allospecific CD4+ T cells in vitro. To further investigate this phenomenon, a human epithelial bladder carcinoma, T24, was induced to constitutively express HLA class II without IFN-γ stimulation, by permanent transfection with the full-length class II transactivator (CIITA) gene. Proliferation of allospecific T cells to transfected and wild-type cells with and without prior activation with saturating levels of IFN-γ for 4 days was examined. IFN-γ-activated T24 did not induce any response from CD4+ T cells. However, T24.CIITA induced significant levels of alloproliferation, which could be abrogated by pretreatment of T24.CIITA with a mAb to LFA-3. Prestimulation of T24.CIITA with saturating levels of IFN-γ for 4 days also prevented allospecific CD4+ T cell proliferation. These findings suggest that epithelial cells may be intrinsically able to process and present alloantigen and provide adequate costimulation. We propose that IFN-γ has a secondary, as yet unidentified, effect that acts to negatively regulate this response, at least in some epithelial cells.
Requirements for the Maintenance of Th1 Immunity In Vivo Following DNA Vaccination: A Potential Immunoregulatory Role for CD8+ T Cells
Authors: Gurunathan Sanjay , Stobie Laura , Prussin Calmin , Sacks David L. , Glaichenhaus Nicolas , Fowell Deborah J. , Locksley Richard M. , Chang John T. , Wu Chang-You , Seder Robert A. 
Published: April 2014

AbstractProtective immunity against Leishmania major generated by DNA encoding the LACK (Leishmania homologue of receptor for activated C kinase) Ag has been shown to be more durable than vaccination with LACK protein plus IL-12. One mechanism to account for this may be the selective ability of DNA vaccination to induce CD8+ IFN-γ-producing T cells. In this regard, we previously reported that depletion of CD8+ T cells in LACK DNA-vaccinated mice abrogated protection when infectious challenge was done 2 wk postvaccination. In this study, we extend these findings to study the mechanism by which CD8+ T cells induced by LACK DNA vaccination mediate both short- and long-term protective immunity against L. major. Mice vaccinated with LACK DNA and depleted of CD8+ T cells at the time of vaccination or infection were unable to control infection when challenge was done 2 or 12 wk postvaccination. Remarkably, it was noted that depletion of CD8+ T cells in LACK DNA-vaccinated mice was associated with a striking decrease in the frequency of LACK-specific CD4+ IFN-γ-producing T cells both before and after infection. Moreover, data are presented to suggest a mechanism by which CD8+ T cells exert this regulatory role. Taken together, these data provide additional insight into how Th1 cells are generated and sustained in vivo and suggest a potentially novel immunoregulatory role for CD8+ T cells following DNA vaccination.
IL-18 Contributes to Host Resistance Against Infection withCryptococcus neoformansin Mice with Defective IL-12 Synthesis Through Induction of IFN-γ Production by NK Cells
Authors: Kawakami Kazuyoshi , Koguchi Yoshinobu , Qureshi Mahboob Hossain , Miyazato Akiko , Yara Satomi , Kinjo Yuki , Iwakura Yoichiro , Takeda Kiyoshi , Akira Shizuo , Kurimoto Masashi , Saito Atsushi 
Published: April 2014

AbstractThe aim of this study was to examine the contribution of IL-18 in host defense against infection caused by Cryptococcus neoformans in mice with defective IL-12 production. Experiments were conducted in mice with a targeted disruption of the gene for IL-12p40 subunit (IL-12p40−/− mice). In these mice, host resistance was impaired, as shown by increased number of organisms in both lungs and brains, compared with control mice. Serum IFN-γ was still detected in these mice at a considerable level (20–30% of that in control mice). The host resistance was moderately impaired in IL-12p40−/− mice compared with IFN-γ−/− mice. Neutralizing anti-IFN-γ mAb further increased the lung burdens of organisms. In addition, treatment with neutralizing anti-IL-18 Ab almost completely abrogated the production of IFN-γ and also impaired the host resistance. Host resistance in IL-12p40−/− IL-18−/− mice was more profoundly impaired than in IL-12p40−/− mice. Administration of IL-12 as well as IL-18 increased the serum levels of IFN-γ and significantly restored the reduced host resistance. Spleen cells obtained from infected IL-12p40−/− mice did not produce any IFN-γ upon restimulation with the same organisms, while those from infected and IL-12-treated mice produced IFN-γ. In contrast, IL-18 did not show such effect. Finally, depletion of NK cells by anti-asialo GM1 Ab mostly abrogated the residual production of IFN-γ in IL-12p40−/− mice. Our results indicate that IL-18 contributes to host resistance to cryptococcal infection through the induction of IFN-γ production by NK cells, but not through the development of Th1 cells, under the condition in which IL-12 synthesis is deficient.
Indispensable Role for TNF-α and IFN-γ at the Effector Phase of Liver Injury Mediated by Th1 Cells Specific to Hepatitis B Virus Surface Antigen
Authors: Ohta Akio , Sekimoto Masashi , Sato Marimo , Koda Toshiaki , Nishimura Shin-ichiro , Iwakura Yoichiro , Sekikawa Kenji , Nishimura Takashi 
Published: April 2014

AbstractWe report the development and characterization of a novel model of severe hepatitis induced against hepatitis B virus surface Ag (HBsAg). HBsAg was successfully targeted into the liver in soluble form. Using this unique property of HBsAg, we established a liver injury model induced by HBsAg-specific Th1 cells. Severe liver injury was induced in C57BL/6 mice by injection of HBsAg together with HBsAg-specific Th1 cells. Histochemical examination demonstrated extensive necroinflammatory hepatic lesions in these animals. Application of this liver injury model to mutant or gene knockout mice enabled us to define the effector mechanisms of Th1 cells in fulminant hepatitis. When Fas-deficient lpr mice were used as recipients, a similar degree of liver injury was induced as in wild-type mice. Moreover, HBsAg-specific Th1 cells obtained from perforin−/− mice could induce severe liver injury in both wild-type and lpr mice. These results indicated that neither Fas ligand nor perforin are essential for Th1-mediated liver injury in this model. Pretreatment with anti-TNF-α mAb prevented liver injury, whereas severe liver injury was induced in TNF-α−/− mice. Moreover, IFN-γ receptor-deficient mice were resistant to Th1-mediated liver injury. Therefore, TNF-α and IFN-γ, which were produced by HBsAg-specific Th1 cells during the effector phase, appeared to be indispensable in the pathogenesis of fulminant hepatitis.
Skin-Specific Caspase-1-Transgenic Mice Show Cutaneous Apoptosis and Pre-Endotoxin Shock Condition with a High Serum Level of IL-18
Authors: Yamanaka Kei-ichi , Tanaka Minoru , Tsutsui Hiroko , Kupper Thomas S. , Asahi Kunihiko , Okamura Haruki , Nakanishi Kenji , Suzuki Misao , Kayagaki Nobuhiko , Black Roy A. , Miller Douglas K. , Nakashima Kunio , Shimizu Masayuki , Mizutani Hitoshi 
Published: April 2014

AbstractTo study the pathophysiological roles of overexpressed caspase-1 (CASP1), originally designated as IL-1β-converting enzyme, we generated transgenic mice in which human CASP1 is overexpressed in their keratinocytes. The transgenic mice spontaneously developed recalcitrant dermatitis and skin ulcers, characterized by the presence of massive keratinocyte apoptosis. The skin of the mice contained the active form of human CASP1 and expressed mRNA for caspase-activated DNase, an effector endonuclease responsible for DNA fragmentation. Their skin and sera showed elevated levels of mature IL-18 and IL-1β, but not of IFN-γ. The plasma from these animals induced IFN-γ production by IL-18-responsive NK cells. Administration of heat-killed Propionibacterium acnes, a potent in vivo type 1 cell inducer, caused IFN-γ-mediated lethal liver injury in the transgenic mice, which was completely inhibited by treatment with neutralizing anti-IL-18 Ab. These results indicated that in vivo overexpression of CASP1 caused spontaneous apoptotic tissue injury and rendered mice highly susceptible to exogenous type 1 cell-inducing condition in collaboration with endogenously accumulated proinflammatory cytokines.
Cutting Edge: Cell Autonomous Rather Than Environmental Factors Control Bacterial Superantigen-Induced T Cell Anergy In Vivo
Authors: Attinger Antoine , Acha-Orbea Hans , MacDonald H. Robson 
Published: April 2014

AbstractAnergic T cells display a marked decrease in their ability to produce IL-2 and to proliferate in the presence of an appropriate antigenic signal. Two nonmutually exclusive classes of models have been proposed to explain the persistence of T cell anergy in vivo. While some reports indicate that anergic T cells have intrinsic defects in signaling pathways or transcriptional activities, other studies suggest that anergy is maintained by environmental “suppressor” factors such as cytokines or Abs. To distinguish between these conflicting hypotheses, we employed the well-characterized bacterial superantigen model system to evaluate in vivo the ability of a trace population of adoptively transferred naive or anergized T cells to proliferate in a naive vs anergic environment upon subsequent challenge. Our data clearly demonstrate that bacterial superantigen-induced T cell anergy is cell autonomous and independent of environmental factors.
Requirement of Mature Dendritic Cells for Efficient Activation of Influenza A-Specific Memory CD8+ T Cells
Authors: Larsson Marie , Messmer Davorka , Somersan Selin , Fonteneau Jean-François , Donahoe Sean M. , Lee Marina , Dunbar P. Rod , Cerundolo Vincenzo , Julkunen Ikka , Nixon Douglas F. , Bhardwaj Nina 
Published: April 2014

AbstractIt is critical to identify the developmental stage of dendritic cells (DCs) that is most efficient at inducing CD8+ T cell responses. Immature DCs can be generated from monocytes with GM-CSF and IL-4, while maturation is accomplished by the addition of stimuli such as monocyte-conditioned medium, CD40 ligand, and LPS. We evaluated the ability of human monocytes and immature and mature DCs to induce CD8+ effector responses to influenza virus Ags from resting memory cells. We studied replicating virus, nonreplicating virus, and the HLA-A*0201-restricted influenza matrix protein peptide. Sensitive and quantitative assays were used to measure influenza A-specific immune responses, including MHC class I tetramer binding assays, enzyme-linked immunospot assays for IFN-γ production, and generation of cytotoxic T cells. Mature DCs were demonstrated to be superior to immature DC in eliciting IFN-γ production from CD8+ effector cells. Furthermore, only mature DCs, not immature DCs, could expand and differentiate CTL precursors into cytotoxic effector cells over 7 days. An exception to this was immature DCs infected with live influenza virus, because of the virus’s known maturation effect. Finally, mature DCs pulsed with matrix peptide induced CTLs from highly purified CD8+ T cells without requiring CD4+ T cell help. These differences between DC stages were independent of Ag concentrations or the number of immature DCs. In contrast to DCs, monocytes were markedly inferior or completely ineffective stimulators of T cell immunity. Our data with several qualitatively different assays of the memory CD8+ T cell response suggest that mature cells should be considered as immunotherapeutic adjuvants for Ag delivery.
FDF03, a Novel Inhibitory Receptor of the Immunoglobulin Superfamily, Is Expressed by Human Dendritic and Myeloid Cells
Authors: Fournier Nathalie , Chalus Lionel , Durand Isabelle , Garcia Eric , Pin Jean-Jacques , Churakova Tatyana , Patel Segal , Zlot Constance , Gorman Dan , Zurawski Sandra , Abrams John , Bates Elizabeth E. M. , Garrone Pierre 
Published: April 2014

AbstractIn this study, we describe human FDF03, a novel member of the Ig superfamily expressed as a monomeric 44-kDa transmembrane glycoprotein and containing a single extracellular V-set Ig-like domain. Two potential secreted isoforms were also identified. The gene encoding FDF03 mapped to chromosome 7q22. FDF03 was mostly detected in hemopoietic tissues and was expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes (B, T, and NK cells), indicating an expression restricted to cells of the myelomonocytic lineage. FDF03 was also strongly expressed by monocyte-derived dendritic cells (DC) and preferentially by CD14+/CD1a− DC derived from CD34+ progenitors. Moreover, flow cytometric analysis showed FDF03 expression by CD11c+ blood and tonsil DC, but not by CD11c− DC precursors. The FDF03 cytoplasmic tail contained two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences. When overexpressed in pervanadate-treated U937 cells, FDF03 was tyrosine-phosphorylated and recruited Src homology-2 (SH2) domain-containing protein tyrosine phosphatase (SHP)-2 and to a lesser extent SHP-1. Like engagement of the ITIM-bearing receptor LAIR-1/p40, cross-linking of FDF03 inhibited calcium mobilization in response to CD32/FcγRII aggregation in transfected U937 cells, thus demonstrating that FDF03 can function as an inhibitory receptor. However, in contrast to LAIR-1/p40, cross-linking of FDF03 did not inhibit GM-CSF-induced monocyte differentiation into DC. Thus, FDF03 is a novel ITIM-bearing receptor selectively expressed by cells of myeloid origin, including DC, that may regulate functions other than that of the broadly distributed LAIR-1/p40 molecule.
Redundant and Opposing Functions of Two Tyrosine Kinases, Btk and Lyn, in Mast Cell Activation
Authors: Kawakami Yuko , Kitaura Jiro , Satterthwaite Anne B. , Kato Roberta M. , Asai Koichi , Hartman Stephen E. , Maeda-Yamamoto Mari , Lowell Clifford A. , Rawlings David J. , Witte Owen N. , Kawakami Toshiaki 
Published: April 2014

Abstract
Protein-tyrosine kinases play crucial roles in mast cell activation through the high-affinity IgE receptor (FcεRI). In this study, we have made the following observations on growth properties and FcεRI-mediated signal transduction of primary cultured mast cells from Btk-, Lyn-, and Btk/Lyn-deficient mice. First, Lyn deficiency partially reversed the survival effect of Btk deficiency. Second, FcεRI-induced degranulation and leukotriene release were almost abrogated in Btk/Lyn doubly deficient mast cells while singly deficient cells exhibited normal responses. Tyrosine phosphorylation of cellular proteins including phospholipases C-γ1 and C-γ2 was reduced in Btk/Lyn-deficient mast cells. Accordingly, FcεRI-induced elevation of intracellular Ca2+ concentrations and activation of protein kinase Cs were blunted in the doubly deficient cells. Third, in contrast, Btk and Lyn demonstrated opposing roles in cytokine secretion and mitogen-activated protein kinase activation. Lyn-deficient cells exhibited enhanced secretion of TNF-α and IL-2 apparently through the prolonged activation of extracellular signal-related kinases and c-Jun N-terminal kinase. Potentially accounting for this phenomenon and robust degranulation in Lyn-deficient cells, the activities of protein kinase Cα and protein kinase CβII, low at basal levels, were enhanced in these cells. Fourth, cytokine secretion was severely reduced and c-Jun N-terminal kinase activation was completely abrogated in Btk/Lyn-deficient mast cells. The data together demonstrate that Btk and Lyn are involved in mast cell signaling pathways in distinctly different ways, emphasizing that multiple signal outcomes must be evaluated to fully understand the functional interactions of individual signaling components.
Follicular Dendritic Cells Carry MHC Class II-Expressing Microvesicles at Their Surface
Authors: Denzer Kristin , van Eijk Marco , Kleijmeer Monique J. , Jakobson Eva , de Groot Cornelis , J. Geuze Hans 
Published: April 2014

Abstract
Follicular dendritic cells (FDCs) present in lymphoid follicles play a critical role in germinal center reactions. They trap native Ags in the form of immune complexes providing a source for continuous stimulation of specific B lymphocytes. FDCs have been reported to express MHC class II molecules, suggesting an additional role in the presentation of not only native, but also processed Ag in the form of peptide-loaded MHC class II. Adoptive bone marrow transfer experiments have shown that MHC class II molecules are only passively acquired. Up to now the origin of these MHC class II molecules was not clear. Here we show by cryoimmunogold electron microscopy that MHC class II molecules are not present at the plasma membrane of FDCs. In contrast, microvesicles attached to the FDC surface contain MHC class II and other surface proteins not expressed by FDCs themselves. The size and marker profiles of these microvesicles resemble exosomes. Exosomes, which are secreted internal vesicles from multivesicular endosomes, have been shown earlier to stimulate proliferation of specific T lymphocytes in vitro, but their target in vivo remained a matter of speculation. We demonstrate here that isolated exosomes in vitro bind specifically to FDCs and not to other cell types, suggesting that FDCs might be a physiological target for exosomes.
TNF Receptor Family Member BCMA (B Cell Maturation) Associates with TNF Receptor-Associated Factor (TRAF) 1, TRAF2, and TRAF3 and Activates NF-κB, Elk-1, c-Jun N-Terminal Kinase, and p38 Mitogen-Activated Protein Kinase
Authors: Hatzoglou Anastassia , Roussel Jérôme , Bourgeade Marie-Françoise , Rogier Edith , Madry Christine , Inoue Junichiro , Devergne Odile , Tsapis Andreas 
Published: April 2014

Abstract
BCMA (B cell maturation) is a nonglycosylated integral membrane type I protein that is preferentially expressed in mature B lymphocytes. Previously, we reported in a human malignant myeloma cell line that BCMA is not primarily present on the cell surface but lies in a perinuclear structure that partially overlaps the Golgi apparatus. We now show that in transiently or stably transfected cells, BCMA is located on the cell surface, as well as in a perinulear Golgi-like structure. We also show that overexpression of BCMA in 293 cells activates NF-κB, Elk-1, the c-Jun N-terminal kinase, and the p38 mitogen-activated protein kinase. Coimmunoprecipitation experiments performed in transfected cells showed that BCMA associates with TNFR-associated factor (TRAF) 1, TRAF2, and TRAF3 adaptor proteins. Analysis of deletion mutants of the intracytoplasmic tail of BCMA showed that the 25-aa protein segment, from position 119 to 143, conserved between mouse and human BCMA, is essential for its association with the TRAFs and the activation of NF-κB, Elk-1, and c-Jun N-terminal kinase. BCMA belongs structurally to the TNFR family. Its unique TNFR motif corresponds to a variant motif present in the fourth repeat of the TNFRI molecule. This study confirms that BCMA is a functional member of the TNFR superfamily. Furthermore, as BCMA is lacking a “death domain” and its overexpression activates NF-κB and c-Jun N-terminal kinase, we can reasonably hypothesize that upon binding of its corresponding ligand BCMA transduces signals for cell survival and proliferation.
Insulin-Like Growth Factor 1 Promotes Cord Blood T Cell Maturation and Inhibits Its Spontaneous and Phytohemagglutinin-Induced Apoptosis Through Different Mechanisms
Authors: Tu Wenwei , Cheung Pik-To , Lau Yu-Lung 
Published: April 2014

AbstractFunctional immaturity of neonatal T cells is related to their immature phenotype, with the majority of neonatal T cells of naive (CD45RA+) T cells. The progression of T cells from naive cells to effector cells is dependent on the survival of Ag-specific T cells and their resistance to apoptosis. In this study, we showed for the first time that insulin-like growth factor 1 (IGF-1) converted cord blood CD45RA+ T cells to CD45RO+ T cells and inhibited cord blood T cell apoptosis. We found cord blood T cells stimulated with PHA would result in gradual loss of CD45RA and gain of CD45RO expression. IGF-1 further increased the loss of CD45RA and enhanced CD45RO expression in PHA-stimulated cord blood T cells. In addition, IGF-1 prevented cord blood T cells from spontaneous apoptosis through a mechanism other than Fas/FasL. In PHA-activated cord blood T cells, IGF-1 prevented both naive (CD45RA+) and memory/mature (CD45RO+) T cells from apoptosis. Moreover, cord blood T cells cultured with IGF-1 and PHA had a higher resistance to anti-Fas-induced apoptosis as compared with PHA-activated cord blood T cells. IGF-1 also significantly inhibited PHA-induced Fas expression on cord blood T cells. These results demonstrate that IGF-1 promotes the maturation and maintains the survival of cord blood T cells. Its antiapoptotic effect in PHA-activated cord blood T cells may be mediated through the down-regulation of Fas expression.