bluuebunny/crossref_metadata_2025_split huggingface dataset:
The CD9 Tetraspanin Is Not Required for the Development of Peripheral B Cells or for Humoral Immunity
Authors: Cariappa Annaiah , Shoham Tsipi , Liu Haoyuan , Levy Shoshana , Boucheix Claude , Pillai Shiv 
Published: April 2014

Abstract
The CD9 tetraspanin is known to be expressed at high levels on marginal zone (MZ) B cells, B-1 B cells, and plasma cells, and its expression is believed to be dependent on signals derived via Btk. In CD9 null mice, however, the development and survival of MZ B cells, B-1 B cells, and plasma cells all appear to be unaffected, and humoral immune responses to T-dependent and T-independent Ags are similar to those seen in wild-type littermate controls. In wild-type mice, CD9 levels may serve to distinguish between the presumed MZ precursor B cell population in the spleen and other IgD-expressing transitional B cells that express lower levels of CD21 and CD1d. These results suggest that CD9 is dispensable for B cell development and humoral immunity, but that this protein may serve as an additional marker for the presumed MZ precursor population of splenic B cells.
CD4−8− Dendritic Cells Prime CD4+ T Regulatory 1 Cells to Suppress Antitumor Immunity
Authors: Zhang Xueshu , Huang Hui , Yuan Jinying , Sun Deming , Hou Wu-Shiun , Gordon John , Xiang Jim 
Published: April 2014

Abstract
It is clear that dendritic cells (DCs) are essential for priming of T cell responses against tumors. However, the distinct roles DC subsets play in regulation of T cell responses in vivo are largely undefined. In this study, we investigated the capacity of OVA-presenting CD4−8−, CD4+8−, or CD4−8+ DCs (OVA-pulsed DC (DCOVA)) in stimulation of OVA-specific T cell responses. Our data show that each DC subset stimulated proliferation of allogeneic and autologous OVA-specific CD4+ and CD8+ T cells in vitro, but that the CD4−8− DCs did so only weakly. Both CD4+8− and CD4−8+ DCOVA induced strong tumor-specific CD4+ Th1 responses and fully protective CD8+ CTL-mediated antitumor immunity, whereas CD4−8− DCOVA, which were less mature and secreted substantial TGF-β upon coculture with TCR-transgenic OT II CD4+ T cells, induced the development of IL-10-secreting CD4+ T regulatory 1 (Tr1) cells. Transfer of these Tr1 cells, but not T cells from cocultures of CD4−8− DCOVA and IL-10−/− OT II CD4+ T cells, into CD4−8+ DCOVA-immunized animals abrogated otherwise inevitable development of antitumor immunity. Taken together, CD4−8− DCs stimulate development of IL-10-secreting CD4+ Tr1 cells that mediated immune suppression, whereas both CD4+8− and CD4−8+ DCs effectively primed animals for protective CD8+ CTL-mediated antitumor immunity.
Multiple Cytokines Regulate the NK Gene Complex-Encoded Receptor Repertoire of Mature NK Cells and T Cells
Authors: Gays Frances , Martin Kimberley , Kenefeck Rupert , Aust Jonathan G. , Brooks Colin G. 
Published: April 2014

Abstract
Mature NK cells comprise a highly diverse population of lymphocytes that express different permutations of receptors to facilitate recognition of diseased cells and perhaps pathogens themselves. Many of these receptors, such as those belonging to the NKRP1, NKG2, and Ly49 families are encoded in the NK gene complex (NKC). It is generally thought that these NKC-encoded receptors are acquired by a poorly understood stochastic mechanism, which operates exclusively during NK cell development, and that following maturation the repertoire is fixed. However, we report a series of observations that demonstrates that the mature NK cell repertoire in mice can in fact be radically remodeled by multiple cytokines. Thus, both IL-2 and IL-15 selectively induce the de novo expression of Ly49E on the majority of mature NK cells. By contrast, IL-4 not only blocks this IL-2-induced acquisition of Ly49E, but reduces the proportion of mature NK cells that expresses pre-existing Ly49 receptors and abrogates the expression of NKG2 receptors while leaving the expression of several NKRP1 receptors unaltered. IL-21 also abrogates NKG2 expression on mature NK cells and selectively down-regulates Ly49F. IL-4 and IL-21 additionally cause dramatic and selective alterations in the NKC-encoded receptor repertoire of IL-2-activated T cells but these are quite different to the changes induced on NK cells. Collectively these findings reveal an unexpected aspect of NKC receptor expression that has important implications for our understanding of the function of these receptors and of the genetic mechanisms that control their expression.
Sphingosine-1-Phosphate Mediates Migration of Mature Dendritic Cells
Authors: Czeloth Niklas , Bernhardt Günter , Hofmann Fred , Genth Harald , Förster Reinhold 
Published: April 2014

Abstract
Sphingosine-1-phosphate (S1P) represents a potent modulator of diverse cellular activities, including lymphocyte trafficking and maintenance of lymphocyte homeostasis. The five known receptors for S1P (S1P1–5) belong to the family of G protein-coupled receptors. Upon binding S1P, they act downstream via heterotrimeric G proteins on members of the small GTPase family (Cdc42/Rac/Rho), evoking a S1P receptor-dependent activation pattern of Cdc42, Rac, and Rho, respectively. This, in turn, triggers cytoskeletal rearrangements determining cellular morphology and movement. In this study we investigated the effects of S1P on murine dendritic cells (DC). Mature DC, but not immature in vitro differentiated DC, were found to migrate to S1P, a phenomenon that correlated to the up-regulation of S1P1 and S1P3 in maturing DC. The same pattern of S1P receptor regulation could be observed in vivo on skin DC after their activation and migration into the lymph node. The migration-inducing effect of S1P could be severely hampered by application of the S1P analogon FTY720 in vitro and in vivo. A similar, yet more pronounced, block was observed upon preventing Cdc42/Rac and/or Rho activation by specific inhibitors. These results suggest that S1P-mediated signaling plays a pivotal role in the life cycle of DC.
Galectin-9 Induces Maturation of Human Monocyte-Derived Dendritic Cells
Authors: Dai Shu-Yan , Nakagawa Ryusuke , Itoh Aiko , Murakami Hiromoto , Kashio Yumiko , Abe Hiroko , Katoh Shigeki , Kontani Keiichi , Kihara Minoru , Zhang Shu-Lan , Hata Toshiyuki , Nakamura Takanori , Yamauchi Akira , Hirashima Mitsuomi 
Published: April 2014

Abstract
Maturation of dendritic cells (DCs) is critical for initiation of immune responses and is regulated by various stimulatory signals. We assessed the role of galectin (Gal)-9 in DC maturation. Culture of immature DCs with exogenous Gal-9 markedly increased the surface expression of CD40, CD54, CD80, CD83, CD86, and HLA-DR in a dose-dependent manner, although Gal-9 had no or little effect on differentiation of human monocytes into immature DCs. Gal-9-treated DCs secreted IL-12 but not IL-10, and they elicited the production of Th1 cytokines (IFN-γ and IL-2) but not that of the Th2 cytokines (IL-4 and IL-5) by allogeneic CD4+ T cells. These effects of Gal-9 on immature DCs were not essentially dependent on its lectin properties, given that they were inhibited only slightly by lactose. We further found that a Gal-9 mutant that lacks β-galactoside binding activity reproduced the above activities and that an anti-Gal-9 mAb suppressed them. Gal-9 induced phosphorylation of the MAPK p38 and ERK1/2 in DCs, and an inhibitor of p38 signaling, but not inhibitors of signaling by either ERK1/2 or PI3K, blocked Gal-9-induced up-regulation of costimulatory molecule expression and IL-12 production. These findings suggest that Gal-9 plays a role not only in innate immunity but also in acquired immunity by inducing DC maturation and promoting Th1 immune responses.
Activation of Vascular Endothelial Growth Factor Receptor-2 in Bone Marrow Leads to Accumulation of Myeloid Cells: Role of Granulocyte-Macrophage Colony-Stimulating Factor
Authors: Larrivée Bruno , Pollet Ingrid , Karsan Aly 
Published: April 2014

Abstract
Vascular endothelial growth factor (VEGF) is a secreted cytokine that plays a major role in the formation and maintenance of the hemopoietic and vascular compartments. VEGF and its receptors, VEGFR-1 and VEGFR-2, have been found to be expressed on subsets of normal and malignant hemopoietic cells, but the role of the individual receptors in hemopoiesis requires further study. Using a VEGFR-2 fusion protein that can be dimerized with a synthetic drug, we were able to specifically examine the effects of VEGFR-2 signaling in hemopoietic cells in vivo. Mice transplanted with bone marrow transduced with this inducible VEGFR-2 fusion protein demonstrated expansion of myeloid cells (Gr-1+, CD11b+). Levels of myeloid progenitors were also increased following VEGFR-2 activation, through autocrine and paracrine mechanisms, as measured by clonogenic progenitor assays. VEGFR-2 activation induced expression of GM-CSF and increased serum levels in vivo. Abrogation of GM-CSF activity, either with neutralizing Abs or by using GM-CSF-null hemopoietic cells, inhibited VEGFR-2-mediated myeloid progenitor activity. Our findings indicate that VEGF signaling through VEGFR-2 promotes myelopoiesis through GM-CSF-dependent and -independent mechanisms.
Natural Recovery and Protection from Autoimmune Encephalomyelitis: Contribution of CD4+CD25+ Regulatory Cells within the Central Nervous System
Authors: McGeachy Mandy J. , Stephens Leigh A. , Anderton Stephen M. 
Published: April 2014

Abstract
Immune regulation of autoimmune disease can function at two sites: at the secondary lymphoid organs or in the target organ itself. In this study, we investigated the natural resolution of autoimmune pathology within the CNS using murine experimental autoimmune encephalomyelitis (EAE). Recovery correlates with the accumulation of IL-10-producing CD4+CD25+ T cells within the CNS. These CD4+CD25+ cells represent as many as one in three of CD4+ cells in the CNS during recovery, they are FoxP3+ and express other markers associated with regulatory cells (CTLA-4, GITR, and αEβ7), and they have regulatory function ex vivo. Depletion of CD25+ cells inhibits the natural recovery from EAE. Also, depletion of CD25+ cells after recovery removes the resistance to reinduction of EAE observed in this model. Furthermore, passive transfer of CNS-derived CD4+CD25+ cells in low numbers provides protection from EAE in recipient mice. These are the first data demonstrating the direct involvement of CD4+CD25+ regulatory T cells in the natural resolution of autoimmune disease within the target organ.
Conditional Fas-Associated Death Domain Protein (FADD):GFP Knockout Mice Reveal FADD Is Dispensable in Thymic Development but Essential in Peripheral T Cell Homeostasis
Authors: Zhang Yuhang , Rosenberg Stephen , Wang Hanming , Imtiyaz Hongxia Z. , Hou Ying-Ju , Zhang Jianke 
Published: April 2014

Abstract
Fas-associated death domain protein (FADD)/mediator of receptor-induced toxicity-1 is required for signaling induced by death receptors such as Fas. In earlier studies, FADD-deficient mice died in utero, and a FADD deficiency in embryonic stem cells inhibited T cell production in viable FADD−/−→RAG-1−/− chimeras. To analyze the temporal requirement of FADD in the development and function in the T lineage, it is necessary to establish viable mutant mice producing detectable FADD-deficient T cells. We generated mice that express a functional FADD:GFP fusion gene reconstituting normal embryogenesis and lymphopoiesis in the absence of the endogenous FADD. Efficient T cell-specific deletion of FADD:GFP was achieved, as indicated by the presence of a high percentage of GFP-negative thymocytes and peripheral T cells in mice expressing Lck-Cre or CD4-Cre. Sorted GFP-negative thymocytes and peripheral T cells contained undetectable levels of FADD and were resistant to apoptosis induced by Fas, TNF, and TCR restimulation. These T cell-specific FADD-deficient mice contain normal thymocyte numbers, but fewer peripheral T cells. Purified peripheral FADD-deficient T cells failed to undergo extensive homeostatic expansion after adoptive transfer into lymphocyte-deficient hosts, and responded poorly to proliferation induced by ex vivo TCR stimulation. Furthermore, deletion of FADD in preactivated mature T cells using retrovirus-Cre resulted in no proliferation. These results demonstrate that FADD plays a dispensable role during thymocyte development, but is essential in maintaining peripheral T cell homeostasis and regulating both apoptotic and proliferation signals.
Restoration by IL-15 of MHC Class I Antigen-Processing Machinery in Human Dendritic Cells Inhibited by Tumor-Derived Gangliosides
Authors: Tourkova Irina L. , Shurin Galina V. , Chatta Gurkamal S. , Perez Lori , Finke James , Whiteside Theresa L. , Ferrone Soldano , Shurin Michael R. 
Published: April 2014

AbstractWe have recently reported that MHC class I Ag-processing machinery (APM) component expression in dendritic cells (DC) might be down-regulated by tumor cells. However, the tumor-derived factors responsible for inhibition of the APM component expression in DC generated in the tumor microenvironment as well as potential protective mechanism have not yet been investigated. In this article, we demonstrate that expression of several MHC class I APM components, including MB1 (β5), LMP2, LMP7, LMP10, and ERp57, is significantly down-regulated in human DC generated in the presence of primary oral squamous cell carcinoma cell lines or coincubated with purified gangliosides. Suppression of MHC class I APM component expression in DC generated in the presence of tumor cells was significantly attenuated by the inhibition of glucosyl transferase in tumor cells, suggesting that tumor-induced MHC class I APM component down-regulation in DC was mediated in part by oral squamous cell carcinoma-derived gangliosides. Furthermore, rIL-15 restored both tumor cell-induced and ganglioside-induced MHC class I APM component expression in DC, as well as their ability to present Ags to autologous Ag-specific T cells. These results demonstrate that IL-15 restores MHC class I APM component expression in DC down-regulated by tumor-derived gangliosides.
Krüppel-Like Factor 2, a Novel Immediate-Early Transcriptional Factor, Regulates IL-2 Expression in T Lymphocyte Activation
Authors: Wu Jinghai , Lingrel Jerry B. 
Published: April 2014

AbstractAg presentation to T lymphocytes and subsequent activation are characterized by a cascade of signaling events, some of which result in the transcriptional activation of a diverse set of genes. An important example is the induction of the IL-2 gene, which is a critical event in the escalation of T cell activation. Previous studies have found that expression of Krüppel-like factor 2 (KLF2), a zinc finger transcription factor, is extinguished after T cell activation. However, the biological role of KLF2 during T cell activation is still unknown. In this study we found that KLF2 protein degradation is delayed, and KLF2 expression is up-regulated during the early stage of T cell activation in primary T cells. Within a few hours, this process is reversed, and KLF2 expression is turned off. Next, we found that the expression of KLF2 significantly increases IL-2 production 4-fold in activated T cells, resulting from activation of the IL-2 promoter. By narrowing down the 2.0-kb IL-2 promoter region, we found that the KLF2 responsive element in the IL-2 promoter is a CACCC element, the KLF consensus binding motif. Moreover, KLF2 binds to this promoter in vivo under different conditions. Our studies show that KLF2 regulates IL-2 promoter activity in the earliest stages of T cell activation, indicating that KLF2 may act as a novel immediate-early transcriptional factor to maximally prime T cell activation.
High Sensitivity of CD4+CD25+ Regulatory T Cells to Extracellular Metabolites Nicotinamide Adenine Dinucleotide and ATP: A Role for P2X7 Receptors
Authors: Aswad Fred , Kawamura Hiroki , Dennert Gunther 
Published: April 2014

AbstractAlthough regulatory lymphocytes play an important role in the immune system, the regulation of their functions is poorly understood and remains to be elucidated. In this study we demonstrate that micromolar concentrations of the common cell metabolite NAD induce death in murine forkhead/winged helix transcription factor gene-expressing CD4+CD25+ regulatory T cells with high efficiency and within minutes. Similar, but less dramatic, effects are demonstrable with ATP and its nonhydrolysable derivative, benzoylbenzoyl-ATP. Other T cell subsets are more resistant, with CD8 cells being the least sensitive and CD4 cells expressing intermediate sensitivity. The higher sensitivity of CD4+CD25+ cells is demonstrable in vivo. Injection of NAD or benzoylbenzoyl-ATP causes preferential induction of a cell death signal in CD4+CD25+ cells. Transmission of the death signal requires functional P2X7 receptors, pointing to a role for these receptors in regulation and homeostasis of CD4+CD25+ regulatory T cells. Consistent with this, P2X7R gene-deleted mice possess increased levels of forkhead/winged helix transcription factor gene-expressing CD4+CD25+ cells.
CD1d-Restricted NKT Cells Contribute to the Age-Associated Decline of T Cell Immunity
Authors: Faunce Douglas E. , Palmer Jessica L. , Paskowicz Kelly K. , Witte Pamela L. , Kovacs Elizabeth J. 
Published: April 2014

Abstract
NKT cells are known to regulate effector T cell immunity during tolerance, autoimmunity, and antitumor immunity. Whether age-related changes in NKT cell number or function occur remains unclear. Here, we investigated whether young vs aged (3 vs 22 mo old) mice had different numbers of CD1d-restricted NKT cells and whether activation of NKT cells by CD1d in vivo contributed to age-related suppression of T cell immunity. Flow cytometric analyses of spleen and LN cells revealed a 2- to 3-fold increase in the number of CD1d tetramer-positive NKT cells in aged mice. To determine whether NKT cells from aged mice differentially regulated T cell immunity, we first examined whether depletion of NK/NKT cells affected the proliferative capacity of splenic T cells. Compared with those from young mice, intact T cell preparations from aged mice had impaired proliferative responses whereas NK/NKT-depleted preparations did not. To examine the specific contribution of NKT cells to age-related T cell dysfunction, Ag-specific delayed-type hypersensitivity and T cell proliferation were examined in young vs aged mice given anti-CD1d mAb systemically. Compared with young mice, aged mice given control IgG exhibited impaired Ag-specific delayed-type hypersensitivity and T cell proliferation, which could be significantly prevented by systemic anti-CD1d mAb treatment. The age-related impairments in T cell immunity correlated with an increase in the production of the immunosuppressive cytokine IL-10 by splenocytes that was likewise prevented by anti-CD1d mAb treatment. Together, our results suggest that CD1d activation of NKT cells contributes to suppression of effector T cell immunity in aged mice.
Turning On/Off Tumor-Specific CTL Response during Progressive Tumor Growth
Authors: Huang Yujun , Obholzer Nikolaus , Fayad Raja , Qiao Liang 
Published: April 2014

Abstract
Therapeutic vaccinations used to induce CTLs and treat firmly established tumors are generally ineffective. To understand the mechanisms underlying the failure of therapeutic vaccinations, we investigated the fate of tumor-specific CD8+ T cells in tumor-bearing mice with or without vaccinations. Our data demonstrate that tumor-specific CD8+ T cells are activated at the early stage of tumor growth, tumor-specific CTL response reaches a maximal level during progressive tumor growth, and tumor-specific CD8+ T cells lose cytolytic function at the late stage of tumor growth. The early stage therapeutic vaccination induces efficient antitumor activity by amplifying the CTL response, whereas the late-stage therapeutic vaccination is invalid due to tumor-induced dysfunction of CD8+ T cells. However, at the late stage, tumor-specific CD8+ T cells are still present in the periphery. These tumor-specific CD8+ T cells lose cytolytic activity, but retain IFN-γ secretion function. In contrast to in vitro cultured tumor cells, in vivo growing tumor cells are more resistant to tumor-specific CTL killing, despite an increase of tumor Ag gene expression. Both tumor-induced CD8+ T cell dysfunction at the late stage and immune evasion developed by in vivo growing tumor cells contribute to an eventual inefficacy of therapeutic vaccinations. Our study suggests that it is important to design a vaccination regimen according to the stages of tumor growth and the functional states of tumor-specific CD8+ T cells.
Selective Defect in Antigen-Induced TCR Internalization at the Immune Synapse of CD8 T Cells Bearing the ZAP-70(Y292F) Mutation
Authors: Davanture Suzel , Leignadier Julie , Milani Pascale , Soubeyran Philippe , Malissen Bernard , Malissen Marie , Schmitt-Verhulst Anne-Marie , Boyer Claude 
Published: April 2014

Abstract
Cbl proteins have been implicated in ligand-induced TCR/CD3 down-modulation, but underlying mechanisms are unclear. We analyzed the effect of mutation of a cbl-binding site on ZAP-70 (ZAP-Y292F) on dynamics, internalization, and degradation of the TCR/CD3 complex in response to distinct stimuli. Naive CD8 T cells expressing the P14 transgenic TCR from ZAP-Y292F mice were selectively affected in TCR/CD3 down-modulation in response to antigenic stimulation, whereas neither anti-CD3 Ab-, and PMA-induced TCR down-modulation, nor constitutive receptor endocytosis/cycling were impaired. We further established that the defect in TCR/CD3 down-modulation in response to Ag was paralleled by an impaired TCR/CD3 internalization and CD3ζ degradation. Analysis of T/APC conjugates revealed that delayed redistribution of TCR at the T/APC contact zone was paralleled by a delay in TCR internalization in the synaptic zone in ZAP-Y292F compared with ZAP-wild-type T cells. Cbl recruitment to the synapse was also retarded in ZAP-Y292F T cells, although F-actin and LFA-1 redistribution was similar for both cell types. This study identifies a step involving ZAP-70/cbl interaction that is critical for rapid internalization of the TCR/CD3 complex at the CD8 T cell/APC synapse.
Human M-Ficolin Is a Secretory Protein That Activates the Lectin Complement Pathway
Authors: Liu Yu , Endo Yuichi , Iwaki Daisuke , Nakata Munehiro , Matsushita Misao , Wada Ikuo , Inoue Keiichi , Munakata Mitsuru , Fujita Teizo 
Published: April 2014

Abstract
Three types of ficolins have been identified in humans: L-ficolin, M-ficolin, and H-ficolin. Similar to mannose-binding lectin, L-ficolin and H-ficolin are the recognition molecules in the lectin complement pathway. Another human ficolin, M-ficolin, is a nonserum ficolin that is expressed in leukocytes and lung; however, little is known about its physiologic roles. In this study, we report the characterization of M-ficolin in terms of its protein localization and lectin activity. M-ficolin was localized in secretory granules in the cytoplasm of neutrophils, monocytes, and type II alveolar epithelial cells in lung. M-ficolin precipitated with mannose-binding lectin-associated serine proteases (MASP)-1 and MASP-2 in a coimmunoprecipitation assay, indicating that M-ficolin forms complexes with MASP-1 and MASP-2. M-ficolin-MASP complexes activated complement on N-acetylglucosamine (GlcNAc)-coated microplates in a C4 deposition assay. M-ficolin bound to several neoglycoproteins bearing GlcNAc, N-acetylgalactosamine, and sialyl-N-acetyllactosamine, suggesting that M-ficolin can recognize the common carbohydrate residues found in microbes. Indeed, M-ficolin bound to Staphylococcus aureus through GlcNAc. These results indicate that M-ficolin, like its family members, functions as a recognition molecule of the lectin complement pathway and plays an important role in innate immunity.