bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sialoadhesin Promotes the Inflammatory Response in Experimental Autoimmune Uveoretinitis
Authors: Jiang Hui-Rong , Hwenda Lenias , Makinen Kimmo , Oetke Cornelia , Crocker Paul R. , Forrester John V. 
Published: April 2014

AbstractMacrophages are a prominent component of the effector cell compartment in a number of CD4+ T cell-mediated organ-specific autoimmune diseases. In this study, we investigated the role of the sialic acid binding Ig-like lectin sialoadhesin (Sn, Siglec-1) in a model of interphotoreceptor retinal binding protein peptide-induced experimental autoimmune uveoretinitis in mice with targeted deletion of Sn. Our data show that compared with wild-type mice, experimental autoimmune uveoretinitis is reduced in severity in the initial stages in the Sn knockout (KO) mice. In addition, there is a reduction in the proliferative capacity of T cells from the KO mice draining lymph nodes after immunization with interphotoreceptor retinal binding protein peptides, which is manifest some days before disease onset and persists for the duration of disease. Furthermore, activated T cells from the draining lymph nodes of Sn KO mice secrete lower levels of IFN-γ. The data suggest a role for Sn in “fine tuning” the immune response to autoantigens by modulating T cell priming.
Dendritic Cell-Lysosomal-Associated Membrane Protein (LAMP) and LAMP-1-HIV-1 Gag Chimeras Have Distinct Cellular Trafficking Pathways and Prime T and B Cell Responses to a Diverse Repertoire of Epitopes
Authors: Arruda Luciana B. , Sim Del , Chikhlikar Priya R. , Maciel Milton , Akasaki Kenji , August J. Thomas , Marques Ernesto T. A. 
Published: April 2014

AbstractAg processing is a critical step in defining the repertoire of epitope-specific immune responses. In the present study, HIV-1 p55Gag Ag was synthesized as a DNA plasmid with either lysosomal-associated membrane protein-1 (LAMP/gag) or human dendritic cell-LAMP (DC-LAMP/gag) and used to immunize mice. Analysis of the cellular trafficking of these two chimeras demonstrated that both molecules colocalized with MHC class II molecules but differed in their overall trafficking to endosomal/lysosomal compartments. Following DNA immunization, both chimeras elicited potent Gag-specific T and B cell immune responses in mice but differ markedly in their IL-4 and IgG1/IgG2a responses. The DC-LAMP chimera induced a stronger Th type 1 response. ELISPOT analysis of T cell responses to 122 individual peptides encompassing the entire p55gag sequence (15-aa peptides overlapping by 11 residues) showed that DNA immunization with native gag, LAMP/gag, or DC-LAMP/gag induced responses to identical immunodominant CD4+ and CD8+ peptides. However, LAMP/gag and DC-LAMP/gag plasmids also elicited significant responses to 23 additional cryptic epitopes that were not recognized after immunization with native gag DNA. The three plasmids induced T cell responses to a total of 39 distinct peptide sequences, 13 of which were induced by all three DNA constructs. Individually, DC-LAMP/gag elicited the most diverse response, with a specific T cell response against 35 peptides. In addition, immunization with LAMP/gag and DC-LAMP/gag chimeras also promoted Ab secretion to an increased number of epitopes. These data indicate that LAMP-1 and DC-LAMP Ag chimeras follow different trafficking pathways, induce distinct modulatory immune responses, and are able to present cryptic epitopes.
Preferential Induction of CD4+ T Cell Responses through In Vivo Targeting of Antigen to Dendritic Cell-Associated C-Type Lectin-1
Authors: Carter Robert W. , Thompson Clare , Reid Delyth M. , Wong Simon Y. C. , Tough David F. 
Published: April 2014

AbstractTargeting of Ags and therapeutics to dendritic cells (DCs) has immense potential for immunotherapy and vaccination. Because DCs are heterogeneous, optimal targeting strategies will require knowledge about functional specialization among DC subpopulations and identification of molecules for targeting appropriate DCs. We characterized the expression of a fungal recognition receptor, DC-associated C-type lectin-1 (Dectin-1), on mouse DC subpopulations and investigated the ability of an anti-Dectin-1 Ab to deliver Ag for the stimulation of immune responses. Dectin-1 was shown to be expressed on CD8α−CD4−CD11b+ DCs found in spleen and lymph nodes and dermal DCs present in skin and s.c. lymph nodes. Injection of Ag-anti-Dectin-1 conjugates induced CD4+ and CD8+ T cell and Ab responses at low doses where free Ag failed to elicit a response. Notably, qualitatively different immune responses were generated by targeting Ag to Dectin-1 vs CD205, a molecule expressed on CD8α+CD4−CD11b− DCs, dermal DCs, and Langerhans cells. Unlike anti-Dectin-1, anti-CD205 conjugates failed to elicit an Ab response. Moreover, when conjugates were injected i.v., anti-Dectin-1 stimulated a much stronger CD4+ T cell response and a much weaker CD8+ T cell response than anti-CD205. The results reveal Dectin-1 as a potential targeting molecule for immunization and have implications for the specialization of DC subpopulations.
The Th2 Lymphoproliferation Developing inLatY136FMutant Mice Triggers Polyclonal B Cell Activation and Systemic Autoimmunity
Authors: Genton Céline , Wang Ying , Izui Shozo , Malissen Bernard , Delsol Georges , Fournié Gilbert J. , Malissen Marie , Acha-Orbea Hans 
Published: April 2014

AbstractLat Y136F knock-in mice harbor a point mutation in Tyr136 of the linker for activation of T cells and show accumulation of Th2 effector cells and IgG1 and IgE hypergammaglobulinemia. B cell activation is not a direct effect of the mutation on B cells since in the absence of T cells, mutant B cells do not show an activated phenotype. After adoptive transfer of linker for activation of T cell mutant T cells into wild-type, T cell-deficient recipients, recipient B cells become activated. We show in vivo and in vitro that the LatY136F mutation promotes T cell-dependent B cell activation leading to germinal center, memory, and plasma cell formation even in an MHC class II-independent manner. All the plasma and memory B cell populations found in physiological T cell-dependent B cell responses are found. Characterization of the abundant plasmablasts found in secondary lymphoid organs of LatY136F mice revealed the presence of a previously uncharacterized CD93-expressing subpopulation, whose presence was confirmed in wild-type mice after immunization. In LatY136F mice, B cell activation was polyclonal and not Ag-driven because the increase in serum IgG1 and IgE concentrations involved Abs and autoantibodies with different specificities equally. Although the noncomplement-fixing IgG1 and IgE are the only isotypes significantly increased in LatY136F serum, we observed early-onset systemic autoimmunity with nephritis showing IgE autoantibody deposits and severe proteinuria. These results show that Th2 cells developing in LatY136F mice can trigger polyclonal B cell activation and thereby lead to systemic autoimmune disease.
Constitutively Active β-Catenin Promotes Expansion of Multipotent Hematopoietic Progenitors in Culture
Authors: Baba Yoshihiro , Yokota Takafumi , Spits Hergen , Garrett Karla P. , Hayashi Shin-Ichi , Kincade Paul W. 
Published: April 2014

AbstractThis study was designed to investigate one component of the Wnt/β-catenin signaling pathway that has been implicated in stem cell self-renewal. Retroviral-mediated introduction of stable β-catenin to primitive murine bone marrow cells allowed the expansion of multipotential c-KitlowSca-1low/−CD19− CD11b/Mac-1−Flk-2−CD43+AA4.1+NK1.1−CD3−CD11c−Gr-1−CD45R/B220+ cells in the presence of stromal cells and cytokines. They generated myeloid, T, and B lineage lymphoid cells in culture, but had no T lymphopoietic potential when transplanted. Stem cell factor and IL-6 were found to be minimal requirements for long-term, stromal-free propagation, and a β-catenin-transduced cell line was maintained for 5 mo with these defined conditions. Although multipotential and responsive to many normal stimuli in culture, it was unable to engraft several types of irradiated recipients. These findings support previous studies that have implicated the canonical Wnt pathway signaling in regulation of multipotent progenitors. In addition, we demonstrate how it may be experimentally manipulated to generate valuable cell lines.
TRAIL-Mediated Apoptosis in HIV-1-Infected Macrophages Is Dependent on the Inhibition of Akt-1 Phosphorylation
Authors: Huang Yunlong , Erdmann Nathan , Peng Hui , Herek Shelley , Davis John S. , Luo Xu , Ikezu Tsuneya , Zheng Jialin 
Published: April 2014

AbstractHIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.
Antigen Chemically Coupled to the Surface of Liposomes Are Cross-Presented to CD8+ T Cells and Induce Potent Antitumor Immunity
Authors: Taneichi Maiko , Ishida Hideaki , Kajino Kiichi , Ogasawara Kazumasa , Tanaka Yuriko , Kasai Michiyuki , Mori Masahito , Nishida Mitsuhiro , Yamamura Hiroyuki , Mizuguchi Junichiro , Uchida Tetsuya 
Published: April 2014

AbstractWe have previously demonstrated that liposomes with differential lipid components display differential adjuvant effects when Ags are chemically coupled to their surfaces. In the present study, Ag presentation of liposome-coupled OVA was investigated in vitro, and it was found that OVA coupled to liposomes made using unsaturated fatty acid was presented to both CD4+ and CD8+ T cells, whereas OVA coupled to liposomes made using saturated fatty acid was presented only to CD4+ T cells. Confocal laser scanning microscopic analysis demonstrated that a portion of the OVA coupled to liposomes made using unsaturated, but not saturated fatty acid, received processing beyond the MHC class II compartment, suggesting that the degradation of OVA might occur in the cytosol, and that the peptides generated in this manner would be presented to CD8+ T cells via MHC class I. The ability to induce cross-presentation of an Ag coupled to liposomes consisting of unsaturated fatty acid was further confirmed by in vivo induction of CTL and by the induction of tumor eradication in mice; E.G7 tumors in mice that received combined inoculation with OVA257–264-liposome conjugates, CpG, and anti-IL-10 mAbs were completely eradicated. In those mice, the frequency of CD8+ T cells reactive with OVA257–264 peptides in the context of H-2Kb was significantly increased. These results suggested that, by choosing lipid components for liposomes, surface-coupled liposomal Ags might be applicable for the development of tumor vaccines to present tumor Ags to APCs and induce antitumor responses.
Homeostatic Lymphoid Chemokines Synergize with Adhesion Ligands to Trigger T and B Lymphocyte Chemokinesis
Authors: Stachowiak Agnieszka N. , Wang Yana , Huang Yen-Chen , Irvine Darrell J. 
Published: April 2014

AbstractHomeostatic chemokines such as CCL19, CCL21, and CXCL13 are known to elicit chemotaxis from naive T and B cells and play a critical role in lymphocyte homing to appropriate zones within secondary lymphoid organs (SLO). Here we tested whether CCL21 and CXCL13 modulate murine lymphocyte motility in the absence of concentration gradients, using videomicroscopy to directly observe the migration of single cells. CCL21 treatment of T cells induced rapid polarization and sustained random migration with average speeds of 5.16 ± 2.08 μm/min; B cell migration (average velocity 4.10 ± 1.58 μm/min) was similarly induced by CXCL13. Migration required the presence of both chemokine and adhesion ligands and was sustained for &gt;24 h. Furthermore, in in vitro assays modeling the relative infrequency of Ag-specific T cell-dendritic cell (DC) encounters during primary immune responses, we found that CCL21 addition to T-DC cocultures accelerated the kinetics of CD69 up-regulation and enhanced by 2-fold the proliferation of Ag-specific T cells in a manner dependent on G-protein-coupled receptor signaling in T cells. These results suggest that homeostatic chemokines could substantially impact the dynamics and priming of lymphocytes within SLO even in the absence of significant concentration gradients.
ICOS-Induced B7h Shedding on B Cells Is Inhibited by TLR7/8 and TLR9
Authors: Logue Eric C. , Bakkour Sonia , Murphy Michael M. , Nolla Hector , Sha William C. 
Published: April 2014

Abstract
We report in this study that B7h, the ligand for the ICOS costimulatory receptor, is rapidly shed from mouse B cells following either ICOS binding or BCR engagement. Shedding occurs through proteolytic cleavage that releases the extracellular ICOS-binding region of B7h. Prior exposure of B7h-expressing APCs to ICOS-expressing cells inhibits their subsequent ability to costimulate IFN-γ and IL-4 production from CD4+ T cells. Shedding is regulated as TLR7/8 and TLR9 ligands inhibit B7h shedding. A shedding-resistant B7h mutant elicits greater costimulation of IFN-γ production from CD4+ T cells than does wild-type B7h. These data define shedding of B7h as a novel mechanism for controlling costimulatory signaling by B7-CD28 family members that is regulated on B cells by TLR signaling.
Activation of NFAT Signal In Vivo Leads to Osteopenia Associated with Increased Osteoclastogenesis and Bone-Resorbing Activity
Authors: Ikeda Fumiyo , Nishimura Riko , Matsubara Takuma , Hata Kenji , Reddy Sakamuri V. , Yoneda Toshiyuki 
Published: April 2014

Abstract
The transcription factor family member NFAT plays an important role in the regulation of osteoclast differentiation. However, the role of NFAT in osteoclasts in vivo is still not fully understood. Thus, we generated transgenic mice in which constitutively active-NFAT1/NFATc2 (CA-NFAT1) is specifically expressed in the osteoclast lineage, using the tartrate-resistant acid phosphatase gene promoter. Both x-ray and histological analyses demonstrated an osteopenic bone phenotype in the CA-NFAT1 transgenic mice, whereas the number of tartrate-resistant acid phosphatase-positive osteoclasts was markedly higher in the long bones of these mice. Furthermore, the bone-resorbing activity of mature osteoclasts derived from the transgenic mice was much higher than that of wild-type mice. Interestingly, the introduction of CA-NFAT1 into osteoclasts or RAW264 cells increased the expression and activity of c-Src and stimulated actin ring formation. In contrast, CA-NFAT1 or GFP-tagged VIVIT peptide, a specific inhibitor of NFAT, did not affect the survival of mature osteoclasts. Collectively, our data indicate that NFAT controls bone resorption in vivo by stimulating the differentiation and functioning of osteoclasts but not their survival.
A Pathogenic Role for CD8+ T Cells in a Spontaneous Model of Demyelinating Disease
Authors: Brisebois Marcel , Zehntner Simone P. , Estrada José , Owens Trevor , Fournier Sylvie 
Published: April 2014

AbstractTransgenic (Tg) mice that overexpress the costimulatory ligand B7.2/CD86 on microglia spontaneously develop a T cell-mediated demyelinating disease. Characterization of the inflammatory infiltrates in the nervous tissue revealed a predominance of CD8+ T cells, suggesting a prominent role of this T cell subset in the pathology. In this study, we show that the same neurological disease occurred in Tg mice deficient in the generation of CD4+ T cells, with an earlier time of onset. Analysis of the CD8+ T cell repertoire at early stage of disease revealed the presence of selected clonal expansions in the CNS but not in peripheral lymphoid organs. We further show that Tg animals deficient in IFN-γ receptor expression were completely resistant to disease development. Microglia activation that is an early event in disease development is IFN-γ dependent and thus appears as a key element in disease pathogenesis. Collectively, our data indicate that the spontaneous demyelinating disease in this animal model occurs as a consequence of an inflammatory response initiated through the activation of CNS-specific CD8+ T cells by Tg expression of B7.2 within the target organ. Thus, autoreactive CD8+ T cells can contribute directly to the pathogenesis of neuroinflammatory diseases such as multiple sclerosis.
Identification of PP1α as a Caspase-9 Regulator in IL-2 Deprivation-Induced Apoptosis
Authors: Dessauge Frédéric , Cayla Xavier , Albar Juan Pablo , Fleischer Aarne , Ghadiri Ata , Duhamel Marianne , Rebollo Angelita 
Published: April 2014

Abstract
One of the mechanisms that regulate cell death is the reversible phosphorylation of proteins. ERK/MAPK phosphorylates caspase-9 at Thr125, and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr125 dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1α (PP1α) associates with phosphorylated caspase-9. IL-2 deprivation induces PP1α dephosphorylation, which leads to its activation and, as a consequence, dephosphorylation and activation of caspase-9 and subsequent dissociation of both molecules. In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1α is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation. Moreover, PP1α associates with caspase-9 in vitro and in vivo, suggesting that it is the phosphatase responsible for caspase-9 dephosphorylation and activation. Finally, we describe two novel phosphatase-binding sites different from the previously described PP1α consensus motifs, and we demonstrate that these novel sites mediate the interaction of PP1α with caspase-9.
Diverse Immunoglobulin Light Chain Organizations in Fish Retain Potential to Revise B Cell Receptor Specificities
Authors: Hsu Ellen , Criscitiello Michael F. 
Published: April 2014

AbstractWe have characterized the genomic organization of the three zebrafish L chain isotypes and found they all differed from those reported in other teleost fishes. Two of the zebrafish L chain isotypes are encoded by two loci, each carrying multiple V gene segments. To understand the derivation of these L chain genes and their organizations, we performed phylogenetic analyses and show that IgL organization can diverge considerably among closely related species. Except in zebrafish, the teleost fish IgL each contain only two to four recombinogenic components (one to three V, one J) and exist in multiple copies. BCR heterogeneity can be generated, but this arrangement apparently provides neither combinatorial diversification nor an opportunity for the secondary rearrangements that, in mammals, take place during receptor editing, a process crucial to the promotion of tolerance in developing lymphocytes. Examination of the zebrafish IgL recombination possibilities gave insight into how the suppression of self-reactivity by receptor editing might be managed, including in miniloci. We suggest that, despite the diverse IgL organizations in early and higher vertebrates, two elements essential to generating the Ab repertoire are retained: the numerous genes/loci for ligand-binding diversification and the potential for correcting unwanted specificities that arise.
TCR-α CDR3 Loop Audition Regulates Positive Selection
Authors: Ferreira Cristina , Furmanski Anna , Millrain Maggie , Bartok Istvan , Guillaume Philippe , Lees Rosemary , Simpson Elizabeth , MacDonald H. Robson , Dyson Julian 
Published: April 2014

Abstract
How positive selection molds the T cell repertoire has been difficult to examine. In this study, we use TCR-β-transgenic mice in which MHC shapes TCR-α use. Differential AV segment use is directly related to the constraints placed on the composition of the CDR3 loops. Where these constraints are low, efficient selection of αβ pairs follows. This mode of selection preferentially uses favored AV-AJ rearrangements and promotes diversity. Increased constraint on the α CDR3 loops leads to inefficient selection associated with uncommon recombination events and limited diversity. Further, the two modes of selection favor alternate sets of AJ segments. We discuss the relevance of these findings to the imprint of self-MHC restriction and peripheral T cell activation.
Identification and Characterization of a FcR Homolog in an Ectothermic Vertebrate, the Channel Catfish (Ictalurus punctatus)
Authors: Stafford James L. , Wilson Melanie , Nayak Deepak , Quiniou Sylvie M. , Clem L. W. , Miller Norman W. , Bengtén Eva 
Published: April 2014

AbstractAn FcR homolog (IpFcRI), representing the first such receptor from an ectothermic vertebrate, has been identified in the channel catfish (Ictalurus punctatus). Mining of the catfish expressed sequence tag databases using mammalian FcR sequences for CD16, CD32, and CD64 resulted in the identification of a teleost Ig-binding receptor. IpFcRI is encoded by a single-copy gene containing three Ig C2-like domains, but lacking a transmembrane segment and cytoplasmic tail. The encoded Ig domains of IpFcRI are phylogenetically and structurally related to mammalian FcR and the presence of a putative Fc-binding region appears to be conserved. IpFcRI-related genomic sequences are also present in both pufferfish and rainbow trout, indicating the likely presence of a soluble FcR in other fish species. Northern blot and qualitative PCR analyses demonstrated that IpFcRI is primarily expressed in IgM-negative leukocytes derived from the lymphoid kidney tissues and PBL. Significantly lower levels of IpFcRI expression were detected in catfish clonal leukocyte cell lines. Using the native leader, IpFcRI was secreted when transfected into insect cells and importantly the native IpFcRI glycoprotein was detected in catfish plasma using a polyclonal Ab. Recombinant IpFcRI binds catfish IgM as assessed by both coimmunoprecipation and cell transfection studies and it is presumed that it functions as a secreted FcR akin to the soluble FcR found in mammals. The identification of an FcR homolog in an ectothermic vertebrate is an important first step toward understanding the evolutionary history and functional importance of vertebrate Ig-binding receptors.