bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen Release Kinetics in the Phagosome Are Critical to Cross-Presentation Efficiency
Authors: Howland Shanshan W. , Wittrup K. Dane 
Published: April 2014

Abstract
Cross-presentation of exogenous Ags in MHC class I molecules by dendritic cells is the underlying basis for many developing immunotherapies and vaccines. In the phagosome-to-cytosol pathway, Ags in phagocytosed particles must become freely soluble before being exported to the cytosol, but the kinetics of this process has yet to be fully appreciated. We demonstrate with a yeast vaccine model that the rate of Ag release in the phagosome directly affects cross-presentation efficiency, with an apparent time limit of ∼25 min postphagocytosis for Ag release to be productive. Ag expressed on the yeast surface is cross-presented much more efficiently than Ag trapped in the yeast cytosol by the cell wall. The cross-presentation efficiency of yeast surface-displayed Ag can be increased by the insertion of linkers susceptible to cleavage in the early phagosome. Ags indirectly attached to yeast through Ab fragments are less efficiently cross-presented when the Ab dissociation rate is extremely slow.
Direct Action of Type I IFN on NK Cells Is Required for Their Activation in Response to Vaccinia Viral Infection In Vivo
Authors: Martinez Jennifer , Huang Xiaopei , Yang Yiping 
Published: April 2014

Abstract
Type I IFN plays an important role in the activation of NK cells. However, the mechanism underlying type I IFN-dependent NK cell activation remains largely unknown. A recent report suggested that type I IFN acted on accessory dendritic cells, leading to IL-15 production, and that subsequent trans-presentation of IL-15 was required for NK cell activation upon stimulation with synthetic TLR ligands. It is not clear how type I IFN regulates NK cell activation in response to live pathogens. Using a murine model of infection with vaccinia virus (VV), we previously demonstrated a critical role for type I IFN in the innate immune control of VV infection. In this study, we first showed that type I IFN did not directly protect L929 cells from VV infection in vitro and that type I IFN-dependent innate immune control of VV infection in vivo was mediated by activated NK cells. We further demonstrated that direct action of type I IFN on NK cells, but not on dendritic cells, is required for the activation of NK cells in response to VV infection both in vitro and in vivo, leading to efficient VV clearance. Our findings may help design effective strategies for the control of poxviral infections in vivo.
Regulation of T Cell Homeostasis by the Transmembrane Adaptor Protein SIT
Authors: Posevitz Vilmos , Arndt Boerge , Krieger Tina , Warnecke Nicole , Schraven Burkhart , Simeoni Luca 
Published: April 2014

Abstract
The transmembrane adaptor protein SIT is a negative regulator of TCR-mediated signaling. However, little is known about the functional role of SIT in mature T cells. In this study, we show that mice deficient for SIT display a decreased number of naive CD8+ T cells and a progressive accumulation of memory-like (CD44high) CD8+ T lymphocytes that resemble cells undergoing homeostatic proliferation. Indeed, when transferred into lymphopenic hosts, SIT−/− naive CD8+ T cells undergo enhanced homeostatic proliferation and express a higher level of CD44 in comparison to wild-type T cells. By using class-I-restricted TCR transgenic models with different ligand affinity/avidity, we show that lymphopenia-induced homeostatic proliferation is more pronounced in cells carrying low-affinity TCRs. Strikingly, the loss of SIT induces homeostatic proliferation of HY TCR transgenic cells, which are normally unable to proliferate in lymphopenic mice. Collectively, these data demonstrate that SIT negatively regulates T cell homeostasis. Finally, we show that SIT-deficient T cells develop a mechanism analogous to sensory adaptation as they up-regulate CD5, down-regulate the coreceptor, and display impaired TCR-mediated ZAP-70 activation.
EBV Latent Membrane Proteins (LMPs) 1 and 2 as Immunotherapeutic Targets: LMP-Specific CD4+ Cytotoxic T Cell Recognition of EBV-Transformed B Cell Lines
Authors: Haigh Tracey A. , Lin Xiaorong , Jia Hui , Hui Edwin P. , Chan Anthony T. C. , Rickinson Alan B. , Taylor Graham S. 
Published: April 2014

Abstract
The EBV-latent membrane proteins (LMPs) 1 and 2 are among only three viral proteins expressed in EBV-associated Hodgkin’s lymphoma and nasopharyngeal carcinoma. Since these tumors are HLA class I and class II-positive, the LMPs could serve as both CD8+ and CD4+ T cell targets. In contrast to CD8 responses, very little is known about CD4 responses to LMPs. In this study, we describe CD4+ T cell clones defining four LMP1- and three LMP2-derived peptide epitopes and their restricting alleles. All clones produced Th1-like cytokines in response to peptide and most killed peptide-loaded target cells by perforin-mediated lysis. Although clones to different epitopes showed different functional avidities in peptide titration assays, avidity per se was a poor predictor of the ability to recognize naturally infected B lymphoblastoid cell lines (LCLs) expressing LMPs at physiologic levels. Some epitopes, particularly within LMP1, consistently mediated strong LCL recognition detectable in cytokine release, cytotoxicity, and outgrowth inhibition assays. Using cyclosporin A to selectively block cytokine release, we found that CD4+ T cell cytotoxicity is the key effector of LCL outgrowth control. We therefore infer that cytotoxic CD4+ T cells to a subset of LMP epitopes could have therapeutic potential against LMP-expressing tumors.
An Essential Role of Sialylated O-Linked Sugar Chains in the Recognition of Mouse CD99 by Paired Ig-Like Type 2 Receptor (PILR)
Authors: Wang Jing , Shiratori Ikuo , Satoh Takeshi , Lanier Lewis L. , Arase Hisash 
Published: April 2014

Abstract
The paired Ig-like type 2 receptor (PILR), which comprises both inhibitory and activating isoforms, is well conserved among most mammalians. The inhibitory PILRα possesses an ITIM in its cytoplasmic domain, whereas the activating PILRβ does not have an ITIM but transduces activating signals by associating with the ITAM-bearing DAP12 adapter molecule. Both mouse PILRα and PILRβ recognize mouse CD99, which is broadly expressed on various cells, including lymphocytes, and is involved in the regulation of immune responses. We herein report that sialylated O-linked sugar chains on CD99 are essential for the recognition by PILR. Mutations of one of two O-glycosylation sites on CD99 significantly reduced recognition of CD99 by the activating PILRβ, whereas recognition by the inhibitory PILRα was not affected. In contrast, mutations of both O-glycosylation sites on CD99 completely abrogated the recognition by both PILRα and PILRβ. PILR did not recognize CD99 treated with neuraminidase, and CD99 expressed on cells transfected with core 2 β-1,6-N-acetylglucosaminyltransferase was not recognized by PILR. NK cells expressing endogenous activating PILRβ receptors mediated cytotoxicity against cells expressing wild-type CD99 but not cells expressing mutant CD99 that lacked O-glycosylation sites. These findings indicate that sialylated O-linked sugar structures on CD99 play an important role in the recognition of PILR.
Puromycin-Sensitive Aminopeptidase Limits MHC Class I Presentation in Dendritic Cells but Does Not Affect CD8 T Cell Responses during Viral Infections
Authors: Towne Charles F. , York Ian A. , Neijssen Joost , Karow Margaret L. , Murphy Andrew J. , Valenzuela David M. , Yancopoulos George D. , Neefjes Jacques J. , Rock Kenneth L. 
Published: April 2014

Abstract
Previous experiments using enzyme inhibitors, cell lysates, and purified enzyme have suggested that puromycin-sensitive aminopeptidase (PSA) plays a role in creating and destroying MHC class I-presented peptides although its precise contribution to these processes is unknown. To examine the importance of this enzyme in MHC class I Ag presentation, we have generated PSA-deficient mice and cell lines from these animals. PSA-deficient mice are smaller and do not reproduce as well as wild type mice. In addition, dendritic cells from PSA-deficient mice display more MHC class I molecules on the cell surface, suggesting that PSA normally limits Ag presentation by destroying certain peptides in these key APCs. Surprisingly, MHC class I levels are not altered on other PSA-deficient cells and the processing and presentation of peptide precursors in PSA-deficient fibroblasts is normal. Moreover, PSA-deficient mice have normal numbers of T cells in the periphery, and respond as well as wild type mice to eight epitopes from three viruses. These data indicate that PSA may play a role in limiting MHC class I Ag presentation in dendritic cells in vivo but that it is not essential for generating most MHC class I-presented peptides or for stimulating CTL responses to several Ags.
Identification of Pax5 Target Genes in Early B Cell Differentiation
Authors: Pridans Clare , Holmes Melissa L. , Polli Matthew , Wettenhall James M. , Dakic Aleksandar , Corcoran Lynn M. , Smyth Gordon K. , Nutt Stephen L. 
Published: April 2014

Abstract
The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression while simultaneously activating the B cell gene expression program. In this study we have performed a global gene expression screen of wild-type and Pax5-deficient pro-B cells in an attempt to identify the crucial Pax5 targets in early B lymphopoiesis. These studies have identified 109 Pax5 targets comprising 61% activated and 39% repressed genes. Interestingly, Pax5 directly regulates the genes encoding a number of transcription factors that are required at the pre-B cell stage of differentiation, including Irf8, Spib, and Ikzf3 (Aiolos), suggesting that a key function of Pax5 is to activate secondary transcription factors that further reinforce the B cell program. Pax5 is also required for the expression of many genes known to be involved in adhesion and signaling, indicating that Pax5 modulates the homing and or migration properties of B cell progenitors. Finally, Pax5 also represses a cohort of genes that are involved in multiple biological processes, many of which are not typically associated with B cells. These include the repression of the adhesion molecule Embigin, which is expressed in bone marrow progenitors, T cells, and myeloid cells but is specifically repressed by Pax5 in B cells.
Healthy Human Subjects Have CD4+ T Cells Directed against H5N1 Influenza Virus
Authors: Roti Michelle , Yang Junbao , Berger DeAnna , Huston Laurie , James Eddie A. , Kwok William W. 
Published: April 2014

Abstract
It is commonly perceived that the human immune system is naive to the newly emerged H5N1 virus. In contrast, most adults have been exposed to influenza A H1N1 and H3N2 viruses through vaccination or infection. Adults born before 1968 have likely been exposed to H2N2 viruses. We hypothesized that CD4+ T cells generated in response to H1N1, H3N2, and H2N2 influenza A viruses also recognize H5N1 epitopes. Tetramer-guided epitope mapping and Ag-specific class II tetramers were used to identify H5N1-specific T cell epitopes and detect H5N1-specific T cell responses. Fifteen of 15 healthy subjects tested had robust CD4+ T cell responses against matrix protein, nucleoprotein, and neuraminidase of the influenza A/Viet Nam/1203/2004 (H5N1) virus. These results are not surprising, because the matrix protein and nucleoprotein of influenza A viruses are conserved while the neuraminidase of the H5N1 virus is of the same subtype as that of the circulating H1N1 influenza strain. However, H5N1 hemagglutinin-reactive CD4+ T cells were also detected in 14 of 14 subjects examined despite the fact that hemagglutinin is less conserved. Most were cross-reactive to H1, H2, or H3 hemagglutinin epitopes. H5N1-reactive T cells were also detected ex vivo, exhibited a memory phenotype, and were capable of secreting IFN-γ, TNF-α, IL-5, and IL-13. These data demonstrate the presence of H5N1 cross-reactive T cells in healthy Caucasian subjects, implying that exposure to influenza A H1N1, H3N2, or H2N2 viruses through either vaccination or infection may provide partial immunity to the H5N1 virus.
Naturally Occurring IgM Anti-Leukocyte Autoantibodies (IgM-ALA) Inhibit T Cell Activation and Chemotaxis
Authors: Lobo Peter I. , Schlegel Kailo H. , Spencer Clinton E. , Okusa Mark D. , Chisholm Christopher , Mchedlishvili Nino , Park Andrew , Christ Constance , Burtner Christopher 
Published: April 2014

Abstract
The physiological relevance of naturally occurring IgM-ALA remains to be elucidated. These autoantibodies are present from birth and increase in diverse inflammatory states that are both infectious and noninfectious. Clinical observations showing significantly less acute allograft rejections in recipients having high IgM-ALA levels, led us to investigate whether IgM-ALA could have a functional role in attenuating T cell mediated inflammatory responses. In pursuit of this hypothesis, we did studies using IgM purified from the serum of normal individuals, patients with end stage renal disease, and HIV-1 infection. All preparations of IgM immunoprecipitated certain receptors e.g., CD3, CD4, CCR5, and CXCR4 from whole cell lysates but failed to immunoprecipitate IL-2R and HLA Ags. In physiological doses IgM down-regulated CD4, CD2 and CD86 but not CD8 and CD28, inhibited T cell proliferation, decreased production of certain proinflammatory cytokines e.g., TNF-α, IL-13 and IL-2, but not IFN- γ, IL-1β, GM-CSF, IL-6 and IL-8 and inhibited leukocyte chemotaxis. These inhibitory effects were more pronounced when using IgM from patients with high levels of IgM-ALA and these inhibitory effects were significantly reduced after using IgM preabsorbed with leukocytes. IgM-ALA binding to leukocytes was found to be highly specific, as &lt;10% of IgM secreting B cell clones had IgM-ALA specificity with some clones having specificity for either T cells or monocytes. These findings support the concept that IgM-ALA provides an innate mechanism to regulate T cell mediated inflammatory responses.
Down-Regulation of MHC II in Mesenchymal Stem Cells at High IFN-γ Can Be Partly Explained by Cytoplasmic Retention of CIITA
Authors: Tang Katherine C. , Trzaska Katarzyna A. , Smirnov Sergey V. , Kotenko Sergei V. , Schwander Stephan K. , Ellner Jerrold J. , Rameshwar Pranela 
Published: April 2014

Abstract
Mesenchymal stem cells (MSCs) are located in postnatal bone marrow, show plasticity, are linked to various bone marrow disorders, exhibit phagocytosis, exert Ag-presenting properties (APC), and are immune suppressive. Unlike professional APCs, MSCs respond bimodally to IFN-γ in MHC-II expression, with expression at 10 U/ml and baseline, and down-regulation at 100 U/ml. The effects at high IFN-γ could not be explained by down-regulation of its receptor, IFN-γRI. In this study, we report on the mechanisms by which IFN-γ regulates MHC-II expression in MSCs. Gel shift assay and Western blot analyses showed dose-dependent increases in activated STAT-1, indicating responsiveness by IFN-γRI. Western blots showed decreased intracellular MHC-II, which could not be explained by decreased transcription of the master regulator CIITA, based on RT-PCR and in situ immunofluorescence. Reporter gene assays with PIII and PIV CIITA promoters indicate constitutive expression of PIII in MSCs and a switch to PIV by IFN-γ, indicating the presence of factors for effect promoter responses. We explained decreased MHC-II at the level of transcription because CIITA protein was observed in the cytosol and not in nuclei at high IFN-γ level. The proline/serine/threonine region of CIITA showed significant decrease in phosphorylation at high IFN-γ levels. An understanding of the bimodal effects could provide insights on bone marrow homeostasis, which could be extrapolated to MSC dysfunction in hematological disorders.
The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4+ T Cell Effector Function in a Murine Model of Inflammatory Bowel Disease
Authors: Fukata Masayuki , Breglio Keith , Chen Anli , Vamadevan Arunan S. , Goo Tyralee , Hsu David , Conduah Daisy , Xu Ruliang , Abreu Maria T. 
Published: April 2014

Abstract
Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4+CD45Rbhigh T cells and/or CD4+CD45RblowCD25+ regulatory T cells were isolated and adoptively transferred to RAG1−/− mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [3H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4+CD45Rbhigh T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88−/− CD4+ T cells showed decreased proliferation compared with WT CD4+ T cells both in vivo and in vitro. CD4+CD45Rbhigh T cells from MyD88−/− mice did not induce wasting disease when transferred into RAG1−/− recipients. Lamina propria CD4+ T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88−/− cells than mice receiving WT cells. In vitro, MyD88−/− T cells were blunted in their ability to secrete IL-17 but not IFN-γ. Absence of MyD88 in CD4+CD45Rbhigh cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease.
Dual Roles of Immunoregulatory Cytokine TGF-β in the Pathogenesis of Autoimmunity-Mediated Organ Damage
Authors: Saxena Vijay , Lienesch Douglas W. , Zhou Min , Bommireddy Ramireddy , Azhar Mohamad , Doetschman Thomas , Singh Ram Raj 
Published: April 2014

AbstractAmple evidence suggests a role of TGF-β in preventing autoimmunity. Multiorgan inflammatory disease, spontaneous activation of self-reactive T cells, and autoantibody production are hallmarks of autoimmune diseases, such as lupus. These features are reminiscent of the immunopathology manifest in TGF-β1-deficient mice. In this study, we show that lupus-prone (New Zealand Black and White)F1 mice have reduced expression of TGF-β1 in lymphoid tissues, and TGF-β1 or TGF-β1-producing T cells suppress autoantibody production. In contrast, the expression of TGF-β1 protein and mRNA and TGF-β signaling proteins (TGF-β receptor type II and phosphorylated SMAD3) increases in the target organs, i.e., kidneys, of these mice as they age and develop progressive organ damage. In fact, the levels of TGF-β1 in kidney tissue and urine correlate with the extent of chronic lesions that represent local tissue fibrosis. In vivo TGF-β blockade by treatment of these mice with an anti-TGF-β Ab selectively inhibits chronic fibrotic lesions without affecting autoantibody production and the inflammatory component of tissue injury. Thus, TGF-β plays a dual, seemingly paradoxical, role in the development of organ damage in multiorgan autoimmune diseases. According to our working model, reduced TGF-β in immune cells predisposes to immune dysregulation and autoantibody production, which causes tissue inflammation that triggers the production of anti-inflammatory cytokines such as TGF-β in target organs to counter inflammation. Enhanced TGF-β in target organs, in turn, can lead to dysregulated tissue repair, progressive fibrogenesis, and eventual end-organ damage.
Differential Contribution of Three Activating IgG Fc Receptors (FcγRI, FcγRIII, and FcγRIV) to IgG2a- and IgG2b-Induced Autoimmune Hemolytic Anemia in Mice
Authors: Baudino Lucie , Nimmerjahn Falk , Azeredo da Silveira Samareh , Martinez-Soria Eduardo , Saito Takashi , Carroll Michael , Ravetch Jeffrey V. , Verbeek J. Sjef , Izui Shozo 
Published: April 2014

Abstract
Murine phagocytes express three different activating IgG FcγR: FcγRI is specific for IgG2a; FcγRIII for IgG1, IgG2a, and IgG2b; and FcγRIV for IgG2a and IgG2b. Although the role of FcγRIII in IgG1 and IgG2a anti-RBC-induced autoimmune hemolytic anemia (AIHA) is well documented, the contribution of FcγRI and FcγRIV to the development of IgG2a- and IgG2b-induced anemia has not yet been defined. In the present study, using mice deficient in FcγRI, FcγRIII, and C3, in combination with an FcγRIV-blocking mAb, we assessed the respective roles of these three FcγR in the development of mild and severe AIHA induced by two different doses (50 and 200 μg) of the IgG2a and IgG2b subclasses of the 34-3C anti-RBC monoclonal autoantibody. We observed that the development of mild anemia induced by a low dose of 34-3C IgG2a autoantibody was highly dependent on FcγRIII, while FcγRI and FcγRIV additionally contributed to the development of severe anemia induced by a high dose of this subclass. In contrast, the development of both mild and severe anemia induced by 34-3C IgG2b was dependent on FcγRIII and FcγRIV. Our results indicate differential roles of the three activating FcγR in IgG2a- and IgG2b-mediated AIHA.
Cutting Edge: A cis-Acting DNA Element Targets AID-Mediated Sequence Diversification to the Chicken Ig Light Chain Gene Locus
Authors: Kothapalli Nagarama , Norton Darrell D. , Fugmann Sebastian D. 
Published: April 2014

Abstract
Somatic hypermutation and gene conversion are two closely related processes that increase the diversity of the primary Ig repertoire. Both processes are initiated by the activation-induced cytidine deaminase that converts cytosine residues to uracils in a transcription-dependent manner; these lesions are subsequently fixed in the genome by direct replication and error-prone DNA repair. Two alternative mechanisms were proposed to explain why this mutagenic activity is targeted almost exclusively to Ig loci: 1) specific cis-acting DNA sequences; or 2) very high levels of Ig gene transcription. In this study we now identify a novel 3′ regulatory region in the chicken Ig light chain gene containing not only a classical transcriptional enhancer but also cis-acting DNA elements essential for targeting activation-induced cytidine deaminase-mediated sequence diversification to this locus.
Cutting Edge: Innate Immune Response Triggered by Influenza A Virus Is Negatively Regulated by SOCS1 and SOCS3 through a RIG-I/IFNAR1-Dependent Pathway
Authors: Pothlichet Julien , Chignard Michel , Si-Tahar Mustapha 
Published: April 2014

AbstractInfluenza A virus (IAV) triggers a contagious respiratory disease that produces considerable lethality. Although this lethality is likely due to an excessive host inflammatory response, the negative feedback mechanisms aimed at regulating such a response are unknown. In this study, we investigated the role of the eight “suppressor of cytokine signaling” (SOCS) regulatory proteins in IAV-triggered cytokine expression in human respiratory epithelial cells. SOCS1 to SOCS7, but not cytokine-inducible Src homology 2-containing protein (CIS), are constitutively expressed in these cells and only SOCS1 and SOCS3 expressions are up-regulated upon IAV challenge. Using distinct approaches affecting the expression and/or the function of the IFNαβ receptor (IFNAR)1, the viral sensors TLR3 and retinoic acid-inducible gene I (RIG-I) as well as the mitochondrial antiviral signaling protein (MAVS, a RIG-I signaling intermediate), we demonstrated that SOCS1 and SOCS3 up-regulation requires a TLR3-independent, RIG-I/MAVS/IFNAR1-dependent pathway. Importantly, by using vectors overexpressing SOCS1 and SOCS3 we revealed that while both molecules inhibit antiviral responses, they differentially modulate inflammatory signaling pathways.