bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Role of Programmed Death-Ligand 1 and Programmed Death-Ligand 2 in Regulating the Susceptibility and Chronic Progression of Experimental Autoimmune Encephalomyelitis
Authors: Zhu Bing , Guleria Indira , Khosroshahi Arezou , Chitnis Tanuja , Imitola Jaime , Azuma Miyuki , Yagita Hideo , Sayegh Mohamed H. , Khoury Samia J. 
Published: April 2014

Abstract
Programmed death-1 (PD-1) is a negative costimulatory molecule, and blocking the interaction of PD-1 with its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), enhances autoimmune disease in several animal models. We have studied the role of PD-1 ligands in disease susceptibility and chronic progression in experimental autoimmune encephalomyelitis (EAE). In BALB/c mice immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35–55, PD-L1 but not PD-L2 blockade significantly increased EAE incidence. In B10.S mice immunized with myelin proteolipid protein (PLP) peptide 139–151, both PD-L1 and PD-L2 blockade markedly enhanced EAE severity. In prediabetic NOD mice immunized with PLP48-70, PD-L2 blockade worsened EAE but did not induce diabetes, whereas PD-L1 blockade precipitated diabetes but did not worsen EAE, suggesting different regulatory roles of these two ligands in EAE and diabetes. B6 mice immunized with MOG35-55 developed chronic persistent EAE, and PD-L2 blockade in the chronic phase exacerbated EAE, whereas PD-L1 blockade did not. In contrast, SJL/J mice immunized with PLP139-151 developed chronic relapsing-remitting EAE, and only PD-L1 blockade during remission precipitated EAE relapse. The strain-specific effects of PD-1 ligand blockade did not correlate with the expression of PD-L1 and PD-L2 on dendritic cells and macrophages in lymphoid tissue, or on inflammatory cells in the CNS. However, EAE enhancement is correlated with less prominent Th2 cytokine induction after specific PD-1 ligand blockade. In conclusion, PD-L1 and PD-L2 differentially regulate the susceptibility and chronic progression of EAE in a strain-specific manner.
Overexpression of Cellular Prion Protein Induces an Antioxidant Environment Altering T Cell Development in the Thymus
Authors: Jouvin-Marche Evelyne , Attuil-Audenis Valérie , Aude-Garcia Catherine , Rachidi Walid , Zabel Mark , Podevin-Dimster Valérie , Siret Carole , Huber Christoph , Martinic Marianne , Riondel Jacqueline , Villiers Christian L. , Favier Alain , Naquet Philippe , Cesbron Jean-Yves , Marche Patrice N. 
Published: April 2014

Abstract
Cellular prion protein (PrPC) is an ubiquitously expressed glycoprotein whose roles are still widely discussed, particularly in the field of immunology. Using TgA20- and Tg33-transgenic mice overexpressing PrPC, we investigated the consequences of this overexpression on T cell development. In both models, overexpression of PrPC induces strong alterations at different steps of T cell maturation. On TgA20 mice, we observed that these alterations are cell autonomous and lead to a decrease of αβ T cells and a concomitant increase of γδ T cell numbers. PrPC has been shown to bind and chelate copper and, interestingly, under a copper supplementation diet, TgA20 mice presented a partial restoration of the αβ T cell development, suggesting that PrPC overexpression, by chelating copper, generates an antioxidant context differentially impacting on αβ and γδ T cell lineage.
Primary T Cell Expansion and Differentiation In Vivo Requires Antigen Presentation by B Cells
Authors: Crawford Alison , MacLeod Megan , Schumacher Ton , Corlett Louise , Gray David 
Published: April 2014

Abstract
B cells are well documented as APC; however, their role in supporting and programming the T cell response in vivo is still unclear. Studies using B cell-deficient mice have given rise to contradictory results. We have used mixed BM chimeric mice to define the contribution that B cells make as APC. When the B cell compartment is deficient in MHC class II, while other APC are largely normal, T cell clonal expansion is significantly reduced and the differentiation of T cells into cytokine-secreting effector cells is impaired (in particular, Th2 cells). The development of the memory T cell populations is also decreased. Although MHC class II-mediated presentation by B cells was crucial for an optimal T cell response, neither a B cell-specific lack of CD40 (influencing costimulation) nor lymphotoxin α (influencing lymphoid tissue architecture) had any effect on the T cell response. We conclude that in vivo B cells provide extra and essential Ag presentation capacity over and above that provided by dendritic cells, optimizing expansion and allowing the generation of memory and effector T cells.
Engagement of Glucocorticoid-Induced TNF Receptor Costimulates NKT Cell Activation In Vitro and In Vivo
Authors: Kim Hyun Jung , Kim Hye Young , Kim Byoung Kwon , Kim Sanghee , Chung Doo Hyun 
Published: April 2014

Abstract
Glucocorticoid-induced TNF receptor (GITR) is known to provide costimulatory signals to CD4+CD25− and CD4+CD25+ T cells during immune responses in vivo. However, the functional roles of GITR expressed on NKT cells have not been well characterized. In this study, we have explored the functions of GITR as a costimulatory factor on NKT cells. GITR was found to be constitutively expressed on NKT cells and its expression was enhanced by TCR signals. GITR engagement using DTA-1, an agonistic mAb against GITR, in the presence of TCR signals, augmented IL-2 production, the expression of activation markers, cell cycle progression, and the nuclear translocations of NF-κB p50 and p65. Furthermore, GITR engagement enhanced the production of IL-4, IL-10, IL-13, and IFN-γ by NKT cells and the expression level of phosphorylated p65 in NKT cells in the presence of TCR engagement, indicating that GITR provides costimulatory signals to NKT cells. The costimulatory effects of GITR on NKT cells were comparable to those of CD28 in terms of cytokine production. Moreover, the coinjection of DTA-1 and α-galactosylceramide into B6 mice induced more IL-4 and IFN-γ production than the coinjection of control mAbs and α-galactosylceramide. In addition, the adoptive transfer of DTA-1-pretreated NKT cells into CD1d−/− mice attenuated hypersensitivity pneumonitis more than control IgG pretreated NKT cells in these mice. These findings demonstrate that GITR engagement on NKT cells modulates immune responses in hypersensitivity pneumonitis in vivo. Taken together, our findings suggest that GITR engagement costimulates NKT cells and contributes to the regulation of immune-associated disease processes in vivo.
Complement Receptor 1 and 2 Deficiency Increases Coxsackievirus B3-Induced Myocarditis, Dilated Cardiomyopathy, and Heart Failure by Increasing Macrophages, IL-1β, and Immune Complex Deposition in the Heart
Authors: Fairweather DeLisa , Frisancho-Kiss Sylvia , Njoku Dolores B. , Nyland Jennifer F. , Kaya Ziya , Yusung Susy A. , Davis Sarah E. , Frisancho J. Augusto , Barrett Masheka A. , Rose Noel R. 
Published: April 2014

AbstractComplement and complement receptors (CR) play a central role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of C or CR have been associated with loss of tolerance to self proteins and the development of immune complex-mediated autoimmune diseases such as systemic lupus erythematosus. In this study, we examined the role of CR on coxsackievirus B3 (CVB3)-induced myocarditis using mice deficient in CR1/2. We found that CR1/2 deficiency significantly increased acute CVB3 myocarditis and pericardial fibrosis resulting in early progression to dilated cardiomyopathy and heart failure. The increase in inflammation was not due to increased viral replication, which was not significantly altered in the hearts of CR1/2-deficient mice, but was associated with increased numbers of macrophages, IL-1β levels, and immune complex deposition in the heart. The complement regulatory protein, CR1-related gene/protein Y (Crry), was increased on cardiac macrophage populations, while immature B220low B cells were increased in the spleen of CR1/2-deficient mice during acute CVB3-induced myocarditis. These results show that expression of CR1/2 is not necessary for effective clearance of CVB3 infection, but prevents immune-mediated damage to the heart.
Distinct Subsets of Dendritic Cells Regulate the Pattern of Acute Xenograft Rejection and Susceptibility to Cyclosporine Therapy
Authors: Wang Hao , Arp Jacqueline , Huang Xuyan , Liu Weihua , Ramcharran Siobhan , Jiang Jifu , Garcia Bertha , Kanai Nobuyuki , Min Weiping , O’Connell Peta J. , Zhong Robert 
Published: April 2014

Abstract
We determined whether distinct subclasses of dendritic cells (DC) could polarize cytokine production and regulate the pattern of xenograft rejection. C57BL/6 recipients, transplanted with Lewis rat hearts, exhibited a predominantly CD11c+CD8α+ splenic DC population and an intragraft cytokine profile characteristic of a Th1-dominant response. In contrast, BALB/c recipients of Lewis rat heart xenografts displayed a predominantly CD11c+CD8α− splenic DC population and IL-4 intragraft expression characteristic of a Th2 response. In addition, the CD11c+IL-12+ splenic DC population in C57BL/6 recipients was significantly higher than that in BALB/c recipients. Adoptive transfer of syngeneic CD8α− bone marrow-derived DC shifted a Th1-dominant, slow cell-mediated rejection to a Th2-dominant, aggressive acute vascular rejection (AVR) in C57BL/6 mice. This was associated with a cytokine shift from Th1 to Th2 in these mice. In contrast, transfer of CD8α+ bone marrow-derived DC shifted AVR to cell-mediated rejection in BALB/c mice and significantly prolonged graft survival time from 6.0 ± 0.6 days to 14.2 ± 0.8 days. CD8α+ DC transfer rendered BALB/c mice susceptible to cyclosporine therapy, thereby facilitating long-term graft survival. Furthermore, CD8α+ DC transfer in IL-12-deficient mice reconstituted IL-12 expression, induced Th1 response, and attenuated AVR. Our data suggest that the pattern of acute xenogeneic rejection can be regulated by distinct DC subsets.
Human Dendritic Cell Expression of HLA-DO Is Subset Specific and Regulated by Maturation
Authors: Hornell Tara M. C. , Burster Timo , Jahnsen Frode L. , Pashine Achal , Ochoa Maria T. , Harding James J. , Macaubas Claudia , Lee Andrew W. , Modlin Robert L. , Mellins Elizabeth D. 
Published: April 2014

Abstract
Expression of HLA-DO (DO) in cells that express HLA-DM (DM) results in an altered repertoire of MHC class II/peptide complexes, indicating that DO modulates DM function. Human and murine B cells and thymic epithelial cells express DO, while monocytes/macrophages do not. Monocyte-derived dendritic cells (DC) also have been found to be DO-negative, leading to the assumption that DC do not express DO. In this study, we report that, in fact, certain types of human primary DC express DO. These include Langerhans cells (LC) and some subtypes of circulating blood DC. Specifically, the majority of BDCA-3+ DC, a small subset of uncertain function, are DO+, while smaller proportions of CD11c+, BDCA-1+ (myeloid) DC, at most a minority of CD123+/BDCA-2+ (plasmacytoid) DC, and no detectable CD16+ (myeloid) DC, express DO. Immunohistochemistry of human tonsil sections demonstrates that tonsillar interdigitating DC are also DO+. In a subset of immature LC with higher DO expression, an increased fraction of surface DR molecules carry CLIP peptides, indicating that DO functions as a DM inhibitor in these cells. LC expression of DO is down-regulated by maturation stimuli. DM levels also decrease under these conditions, but the DM:DO ratio generally increases. In the myeloid cell types tested, DO expression correlates with levels of DOβ, but not DOα, implying that modulation of DOβ regulates DO dimer abundance in these cells. The range of APC types shown to express DO suggests a broader role for DO in immune function than previously appreciated.
H2-O Expression in Primary Dendritic Cells
Authors: Chen Xinjian , Reed-Loisel Lisa M. , Karlsson Lars , Jensen Peter E. 
Published: April 2014

AbstractH2-O is a nonpolymorphic class II molecule whose biological role remains to be determined. H2-O modulates H2-M function, and it has been generally believed to be expressed only in B lymphocytes and thymic medullary epithelial cells, but not in dendritic cells (DCs). In this study, we report identification of H2-O expression in primary murine DCs. Similar to B cells, H2-O is associated with H2-M in DCs, and its expression is differentially regulated in DC subsets as well as during cell maturation and activation. Primary bone marrow DCs and plasmacytoid DCs in the spleen and lymph nodes express MHC class II and H2-M, but not the inhibitor H2-O. In contrast, myeloid DCs in secondary lymphoid organs express both H2-M and H2-O. In CD8αα+ DCs, the ratio of H2-O to H2-M is higher than in CD8αα− DCs. In DCs generated from GM-CSF- and IL-4-conditioned bone marrow cultures, H2-O expression is not detected regardless of the maturation status of the cells. Administration of LPS induces in vivo activation of myeloid DCs, and this activation is associated with down-regulation of H2-O expression. Primary splenic DCs from H2-O−/− and H2-O+/+ mice present exogenous protein Ags to T cell hybridomas similarly well, but H2-O−/− DCs induce stronger allogeneic CD4 T cell response than the H2-O+/+ DCs in mixed leukocyte reactions. Our results suggest that H2-O has a broader role than previously appreciated in regulating Ag presentation.
IL-4 and IL-13 Form a Negative Feedback Circuit with Surfactant Protein-D in the Allergic Airway Response
Authors: Haczku Angela , Cao Yang , Vass Geza , Kierstein Sonja , Nath Puneeta , Atochina-Vasserman Elena N. , Scanlon Seth T. , Li Lily , Griswold Don E. , Chung K. Fan , Poulain Francis R. , Hawgood Samuel , Beers Michael F. , Crouch Erika C. 
Published: April 2014

Abstract
The innate immune molecule surfactant protein-D (SP-D) plays an important regulatory role in the allergic airway response. In this study, we demonstrate that mice sensitized and challenged with either Aspergillus fumigatus (Af) or OVA have increased SP-D levels in their lung. SP-D mRNA and protein levels in the lung also increased in response to either rIL-4 or rIL-13 treatment. Type II alveolar epithelial cell expression of IL-4Rs in mice sensitized and challenged with Af, and in vitro induction of SP-D mRNA and protein by IL-4 and IL-13, but not IFN-γ, suggested a direct role of IL-4R-mediated events. The regulatory function of IL-4 and IL-13 was further supported in STAT-6-deficient mice as well as in IL-4/IL-13 double knockout mice that failed to increase SP-D production upon allergen challenge. Interestingly, addition of rSP-D significantly inhibited Af-driven Th2 cell activation in vitro whereas mice lacking SP-D had increased numbers of CD4+ cells with elevated IL-13 and thymus- and activation-regulated chemokine levels in the lung and showed exaggerated production of IgE and IgG1 following allergic sensitization. We propose that allergen exposure induces elevation in SP-D protein levels in an IL-4/IL-13-dependent manner, which in turn, prevents further activation of sensitized T cells. This negative feedback regulatory circuit could be essential in protecting the airways from inflammatory damage after allergen inhalation.
Fms-Like Tyrosine Kinase 3 Ligand Recruits Plasmacytoid Dendritic Cells to the Brain
Authors: Curtin James F. , King Gwendalyn D. , Barcia Carlos , Liu Chunyan , Hubert François X. , Guillonneau Carole , Josien Régis , Anegon Ignacio , Lowenstein Pedro R. , Castro Maria G. 
Published: April 2014

Abstract
The lack of professional afferent APCs in naive brain parenchyma contributes to the systemic immune ignorance to Ags localized exclusively within the brain. Dendritic cells (DCs) appear within the brain as a consequence of inflammation, but no molecular mechanisms accounting for this influx have been described. In this study we demonstrate that Fms-like tyrosine kinase 3 ligand (Flt3L) recruits plasmacytoid DCs (pDCs; &gt;50-fold; p &lt; 0.001) to the brain parenchyma. These pDCs expressed IFN-α, the hallmark cytokine produced by pDCs, indicating recruitment and activation in situ of bona fide pDCs within the brain parenchyma. Flt3L did not increase the numbers of conventional DCs, macrophages, or B, T, NK, NKT, or microglial cells within the brain. Our data demonstrate that Flt3L reconstitutes a crucial afferent component of the immune response, namely, professional APCs within the brain parenchyma, and this could counteract the intrinsic systemic immune ignorance to Ags localized exclusively within the brain.
Modulation of Dendritic Cell Trafficking to and from the Airways
Authors: Jakubzick Claudia , Tacke Frank , Llodra Jaime , van Rooijen Nico , Randolph Gwendalyn J. 
Published: April 2014

Abstract
We investigated the fate of latex (LX) particles that were introduced into mice intranasally. Macrophages acquired the vast majority of particles and outnumbered LX particle-bearing airway dendritic cells (DCs) by at least two orders of magnitude. Yet alveolar macrophages were refractory to migration to the draining lymph node (DLN), and all transport to the DLN could be ascribed to the few LX+ airway DCs. Upon macrophage depletion, markedly greater numbers of DCs were recruited into the alveolar space. Consequently, the number of DCs that carried particles to the DLN was boosted by 20-fold. Thus, a so far overlooked aspect of macrophage-mediated suppression of airway DC function stems from the modulation of DC recruitment into the airway. This increase in DC recruitment permitted the development of a robust assay to quantify the subsequent migration of DCs to the DLN. Therefore, we determined whether lung DCs use the same molecules that skin DCs use during migration to DLNs. Like skin DCs, lung DCs used CCR7 ligands and CCR8 for emigration to DLN, but the leukotriene C4 transporter multidrug resistance-related protein 1 did not mediate lung DC migration as it does in skin, indicating that pathways governing DC migration from different tissues partially differ in molecular regulation.
Placenta-Derived Soluble MHC Class I Chain-Related Molecules Down-Regulate NKG2D Receptor on Peripheral Blood Mononuclear Cells during Human Pregnancy: A Possible Novel Immune Escape Mechanism for Fetal Survival
Authors: Mincheva-Nilsson Lucia , Nagaeva Olga , Chen Ting , Stendahl Ulf , Antsiferova Julia , Mogren Ingrid , Hernestål Jenny , Baranov Vladimir 
Published: April 2014

Abstract
Mammalian pregnancy is an intriguing immunological phenomenon where the semiallogeneic fetus is not rejected. Tolerance toward the fetus involves a number of mechanisms associated with modifications of the immune status of the mother. In this study, we strongly suggest a novel mechanism for fetal evasion of maternal immune attack, based on the engagement and down-regulation of the activating NK cell receptor NKG2D on PBMC by soluble MHC class I chain-related proteins A and B (collectively termed MIC). A similar immune escape pathway was previously described in tumors. We found that MIC mRNA was constitutively expressed by human placenta and could be up-regulated upon heat shock treatment. Our immunomorphologic studies showed that the MIC expression in placenta was restricted to the syncytiotrophoblast. Immunoelectron microscopy revealed a dual MIC expression in the syncytiotrophoblast: on the apical and basal cell membrane and in cytoplasmic vacuoles as MIC-loaded microvesicles/exosomes. Soluble MIC molecules were present at elevated levels in maternal blood throughout normal pregnancy and were released by placental explants in vitro. Simultaneously, the cell surface NKG2D expression on maternal PBMC was down-regulated compared with nonpregnant controls. The soluble MIC molecules in pregnancy serum were able to interact with NKG2D and down-regulate the receptor on PBMC from healthy donors, with the consequent inhibition of the NKG2D-dependent cytotoxic response. These findings suggest a new physiological mechanism of silencing the maternal immune system that promotes fetal allograft immune escape and supports the view of the placenta as an immunoregulatory organ.
Molecular Mechanisms Underlying FOXP3 Induction in Human T Cells
Authors: Mantel Pierre-Yves , Ouaked Nadia , Rückert Beate , Karagiannidis Christian , Welz Roland , Blaser Kurt , Schmidt-Weber Carsten B. 
Published: April 2014

Abstract
FOXP3 is playing an essential role for T regulatory cells and is involved in the molecular mechanisms controlling immune tolerance. Although the biological relevance of this transcription factor is well documented, the pathways responsible for its induction are still unclear. The current study reveals structure and function of the human FOXP3 promoter, revealing essential molecular mechanisms of its induction. The FOXP3 promoter was defined by RACE, cloned, and functionally analyzed using reporter-gene constructs in primary human T cells. The analysis revealed the basal, T cell-specific promoter with a TATA and CAAT box 6000 bp upstream the translation start site. The basal promoter contains six NF-AT and AP-1 binding sites, which are positively regulating the trans activation of the FOXP3 promoter after triggering of the TCR. The chromatin region containing the FOXP3 promoter was bound by NF-ATc2 under these conditions. Furthermore, FOXP3 expression was observed following TCR engagement. Promoter activity, mRNA, and protein expression of T cells were suppressed by addition of cyclosporin A. Taken together, this study reveals the structure of the human FOXP3 promoter and provides new insights in mechanisms of addressing T regulatory cell-inducing signals useful for promoting immune tolerance. Furthermore, the study identifies essential, positive regulators of the FOXP3 gene and highlights cyclosporin A as an inhibitor of FOXP3 expression contrasting other immunosuppressants such as steroids or rapamycin.
Signaling through Mutants of the IgA Receptor CD89 and Consequences for Fc Receptor γ-Chain Interaction
Authors: Bakema Jantine E. , de Haij Simone , den Hartog-Jager Constance F. , Bakker Johanna , Vidarsson Gestur , van Egmond Marjolein , van de Winkel Jan G. J. , Leusen Jeanette H. W. 
Published: April 2014

AbstractThe prototypic receptor for IgA (FcαRI, CD89) is expressed on myeloid cells and can trigger phagocytosis, tumor cell lysis, and release of inflammatory mediators. The functions of FcαRI and activating receptors for IgG (FcγRI and FcγRIII) are dependent on the FcR γ-chain dimer. This study increases our understanding of the molecular basis of the FcαRI-FcR γ-chain transmembrane interaction, which is distinct from that of other activatory FcRs. FcαRI is unique in its interaction with the common FcR γ-chain, because it is based on a positively charged residue at position 209, which associates with a negatively charged amino acid of FcR γ-chain. We explored the importance of the position of this positive charge within human FcαRI for FcR γ-chain association and FcαRI functioning with the use of site-directed mutagenesis. In an FcαRI R209L/A213H mutant, which represents a vertical relocation of the positive charge, proximal and distal FcR γ-chain-dependent functions, such as calcium flux, MAPK phosphorylation, and IL-2 release, were similar to those of wild-type FcαRI. A lateral transfer of the positive charge, however, completely abrogated FcR γ-chain-dependent functions in an FcαRI R209L/M210R mutant. By coimmunoprecipitation, we have demonstrated the loss of a physical interaction between FcR γ-chain and FcαRI M210R mutant, thus explaining the loss of FcR γ-chain-dependent functions. In conclusion, not only the presence of a basic residue in the transmembrane region of FcαRI, but also the orientation of FcαRI toward the FcR γ-chain dimer is essential for FcR γ-chain association. This suggests the involvement of additional amino acids in the FcαRI-FcR γ-chain interaction.