bluuebunny/crossref_metadata_2025_split huggingface dataset:
Can the Low-Avidity Self-Specific T Cell Repertoire Be Exploited for Tumor Rejection?
Authors: Cordaro Tanina A. , de Visser Karin E. , Tirion Felicia H. , Schumacher Ton N. M. , Kruisbeek Ada M. 
Published: April 2014

AbstractCan self-specific T cells that have escaped intrathymic deletion be exploited to generate antitumor immunity? To determine whether antitumor immunity to a self-Ag for which central tolerance exists can be generated, a mouse model is used in which a fragment of the influenza nucleoprotein (NP) is expressed as a transgene under the control of the H-2K promoter in C57BL/10 mice (B10NP mice). In these mice an oligoclonal population of NP-specific T cells escapes thymic and peripheral deletion and can be activated upon immunization. The main hallmark of these self-specific CD8+ T cells is diminished avidity for the pertinent MHC/peptide complex. We show in this study that intranasal infection with influenza virus can stimulate low-avidity NP-specific T cells to recognize and destroy NP-expressing microtumors in the lung, but not NP-expressing tumors growing s.c. Only a memory NP-specific CD8+ T cell response can suppress the growth of an s.c. growing NP-expressing tumor. This delay in tumor growth is associated with a dramatic increase in the number of circulating NP-specific CD8+ T cells. In addition, cultured memory NP-specific T cells require ∼100-fold less Ag to induce NP-specific lysis than primary T cells, consistent with the observation that memory T cells have an increased avidity due to affinity maturation. Finally, during an NP-specific memory response, substantial numbers of low-avidity NP-specific T cells can be recovered from s.c. growing tumors. Together, these findings indicate that, when only a low-avidity repertoire is available to generate antitumor immunity, the best strategy may be to enhance memory responses.
Ox40 Costimulation Enhances the Development of T Cell Responses Induced by Dendritic Cells In Vivo
Authors: De Smedt Thibaut , Smith Jeffrey , Baum Peter , Fanslow William , Butz Eric , Maliszewski Charles 
Published: April 2014

AbstractDendritic cells (DCs) are bone marrow-derived APCs that display unique properties aimed at stimulating naive T cells. Several members of the TNF/TNFR families have been implicated in T cell functions. In this study, we examined the role that Ox40 costimulation might play on the ability of DCs to regulate CD4+ and CD8+ T cell responses in vivo. Administration of anti-mouse Ox40 mAb enhanced the Th response induced by immunization with Ag-pulsed DCs, and introduced a bias toward a Th1 immune response. However, anti-Ox40 treatment enhanced the production of Th2 cytokines in IFN-γ−/− mice after immunization with Ag-pulsed DCs, suggesting that the production of IFN-γ during the immune response could interfere with the development of Th2 lymphocytes induced by DCs. Coadministration of anti-Ox40 with DCs during Ag rechallenge enhanced both Th1 and Th2 responses induced during a primary immunization with DCs, and did not reverse an existing Th2 response. This suggests that Ox40 costimulation amplifies an ongoing immune response, regardless of Th differentiation potential. In an OVA-TCR class II-restricted adoptive transfer system, anti-Ox40 treatment greatly enhanced the level of cytokine secretion per Ag-specific CD4+ T cell induced by immunization with DCs. In an OVA-TCR class I-restricted adoptive transfer system, administration of anti-Ox40 strongly enhanced expansion, IFN-γ secretion, and cytotoxic activity of Ag-specific CD8+ T cells induced by immunization with DCs. Thus, by enhancing immune responses induced by DCs in vivo, the Ox40 pathway might be a target for immune intervention in therapeutic settings that use DCs as Ag-delivery vehicles.
UL16-Binding Proteins, Novel MHC Class I-Related Proteins, Bind to NKG2D and Activate Multiple Signaling Pathways in Primary NK Cells
Authors: Sutherland Claire L. , Chalupny N. Jan , Schooley Kenneth , VandenBos Tim , Kubin Marek , Cosman David 
Published: April 2014

Abstract
The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-γ production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors.
Sustained Expression of the Novel EBV-Induced Zinc Finger Gene, ZNF
EB, Is Critical for the Transition of B Lymphocyte Activation to Oncogenic Growth Transformation
Authors: Tune Cathryn E. , Pilon Marc , Saiki Yuriko , Dosch H.-Michael 
Published: April 2014

Abstract
EBV is a human tumor virus that infects and establishes latency in the majority of humans worldwide. In vitro, EBV growth transforms primary B lymphocytes into lymphoblastoid cell lines with high efficiency. We have used cDNA subtraction cloning to identify cellular target genes required for growth transformation and identified a new C2H2 (Krüppel-type) zinc finger gene, ZNFEB, that is trans-activated early following EBV infection. In this study, we characterize ZNFEB, including its intronless locus, and human and mouse protein variants. The gene is transiently expressed during normal lymphocyte activation, and its expression is sustained in EBV-positive but not EBV-negative B cell lines. There is limited expression in nonhemopoietic tissues. Its critical role in the growth transformation of B lineage cells is indicated by the abrogation of transformation with antisense strategies. ZNFEB maps to chromosome 18q12, a region with mutations in numerous, predominantly hemopoietic malignancies.
Myeloid Suppressor Lines Inhibit T Cell Responses by an NO-Dependent Mechanism
Authors: Mazzoni Alessandra , Bronte Vincenzo , Visintin Alberto , Spitzer Jessica H. , Apolloni Elisa , Serafini Paolo , Zanovello Paola , Segal David M. 
Published: April 2014

AbstractCD11b+Gr-1+ myeloid suppressor cells (MSC) accumulate in lymphoid organs under conditions of intense immune stress where they inhibit T and B cell function. We recently described the generation of immortalized MSC lines that provide a homogeneous source of suppressor cells for dissecting the mechanism of suppression. In this study we show that the MSC lines potently block in vitro proliferation of T cells stimulated with either mitogen or antigenic peptide, with as few as 3% of MSC cells causing complete suppression. Inhibition of mitogenic and peptide-specific responses is not associated with a loss in IL-2 production or inability to up-modulate the early activation markers, CD69 and CD25, but results in direct impairment of the three IL-2R signaling pathways, as demonstrated by the lack of Janus kinase 3, STAT5, extracellular signal-regulated kinase, and Akt phosphorylation in response to IL-2. Suppression is mediated by and requires NO, which is secreted by MSC in response to signals from activated T cells, including IFN-γ and a contact-dependent stimulus. Experiments with inducible NO synthase knockout mice demonstrated that the inhibition of T cell proliferation by CD11b+Gr-1+ cells in the spleens of immunosuppressed mice is also dependent upon NO, indicating that the MSC lines accurately represent their normal counterparts. The distinctive capacity of MSC to generate suppressive signals when encountering activated T cells defines a specialized subset of myeloid cells that most likely serve a regulatory function during times of heightened immune activity.
α4 Integrin Signaling Activates Phosphatidylinositol 3-Kinase and Stimulates T Cell Adhesion to Intercellular Adhesion Molecule-1 to a Similar Extent As CD3, but Induces a Distinct Rearrangement of the Actin Cytoskeleton
Authors: Hyduk Sharon J. , Cybulsky Myron I. 
Published: April 2014

AbstractDynamic regulation of β2 integrin-dependent adhesion is critical for a wide array of T cell functions. We previously showed that binding of high-affinity α4β1 integrins to VCAM-1 strengthens αLβ2 integrin-mediated adhesion to ICAM-1. In this study, we compared β2 integrin-mediated adhesion of T cells to ICAM-1 under two different functional contexts: α4 integrin signaling during emigration from blood into tissues and CD3 signaling during adhesion to APCs and target cells. Cross-linking either α4 integrin or CD3 on Jurkat T cells induced adhesion to ICAM-1 of comparable strength. Adhesion was dependent on phosphatidylinositol (PI) 3-kinase but not p44/42 mitogen-activated protein kinase (extracellular regulated kinase 1/2), because it was inhibited by wortmannin and LY294002 but not U0126. These data suggest that PI 3-kinase is a ubiquitous regulator of β2 integrin-mediated adhesion. A distinct morphological change consisting of Jurkat cell spreading and extension of filopodia was induced by α4 integrin signaling. In contrast, CD3 induced radial rings of cortical actin polymerization. Inhibitors of PI 3-kinase and extracellular regulated kinase 1/2 did not affect α4 integrin-induced rearrangement of the actin cytoskeleton, but treatment with ionomycin, a Ca2+ ionophore, modulated cell morphology by reducing filopodia and promoting lamellipodia formation. Qualitatively similar morphological and adhesive changes to those observed with Jurkat cells were observed following α4 integrin or CD3 stimulation of human peripheral blood T cells.
Reduced Expression of Bcl-2 in CD8+ T Cells Deficient in the IL-15 Receptor α-Chain
Authors: Wu Tzong-Shoon , Lee Jan-Mou , Lai Yein-Gei , Hsu Jen-Chi , Tsai Ching-Yen , Lee Ying-Hue , Liao Nan-Shih 
Published: April 2014

AbstractMice that lack IL-15 or the IL-15R α-chain (IL-15Rα) are deficient in peripheral CD8+, but not in CD4+, T cells. This CD8+ T cell-specific deficiency has now been investigated further by characterization of a new strain of IL-15Rα−/− mice. The adult mutant mice exhibited a specific reduction in the percentage of CD8-single positive TCRhigh thymocytes. The expression of Bcl-2 was reduced in both CD8+ thymocytes and naive T cells of the mutant animals, and the susceptibility of these cells to death was increased. Memory CD8+ cells were profoundly deficient in IL-15Rα−/−mice, and the residual memory-like CD8+ cells contained a high percentage of dead cells and failed to up-regulate Bcl-2 expression compared with naive CD8+ cells. Moreover, exogenous IL-15 both up-regulated the level of Bcl-2 in and reduced the death rate of wild-type and mutant CD8+ T cells activated in vitro. These results indicate that IL-15 and IL-15Rα regulate the expression of Bcl-2 in CD8+ T cells at all developmental stages. The reduced Bcl-2 content in CD8+ cells might result in survival defect and contribute to the reduction of CD8+ cells in IL-15Rα−/−mice.
IL-1β Enhances CD40 Ligand-Mediated Cytokine Secretion by Human Dendritic Cells (DC): A Mechanism for T Cell-Independent DC Activation
Authors: Luft Thomas , Jefford Michael , Luetjens Petra , Hochrein Hubertus , Masterman Kelly-Anne , Maliszewski Charlie , Shortman Ken , Cebon Jonathan , Maraskovsky Eugene 
Published: April 2014

AbstractCD40 ligand (CD40L) is a membrane-bound molecule expressed by activated T cells. CD40L potently induces dendritic cell (DC) maturation and IL-12p70 secretion and plays a critical role during T cell priming in the lymph nodes. IFN-γ and IL-4 are required for CD40L-mediated cytokine secretion, suggesting that T cells are required for optimal CD40L activity. Because CD40L is rapidly up-regulated by non-T cells during inflammation, CD40 stimulation may also be important at the primary infection site. However, a role for T cells at the earliest stages of infection is unclear. The present study demonstrates that the innate immune cell-derived cytokine, IL-1β, can increase CD40L-induced cytokine secretion by monocyte-derived DC, CD34+-derived DC, and peripheral blood DC independently of T cell-derived cytokines. Furthermore, IL-1β is constitutively produced by monocyte-derived DC and monocytes, and is increased in response to intact Escherichia coli or CD40L, whereas neither CD34+-derived DC nor peripheral blood DC produce IL-1β. Finally, DC activated with CD40L and IL-1β induce higher levels of IFN-γ secretion by T cells compared with DC activated with CD40L alone. Therefore, IL-1β is the first non-T cell-derived cytokine identified that enhances CD40L-mediated activation of DC. The synergy between CD40L and IL-1β highlights a potent, T cell-independent mechanism for DC activation during the earliest stages of inflammatory responses.
Lipid Protein Interactions: The Assembly of CD1d1 with Cellular Phospholipids Occurs in the Endoplasmic Reticulum
Authors: De Silva A. Dharshan , Park J.-June , Matsuki Naoto , Stanic Aleksandar K. , Brutkiewicz Randy R. , Medof M. Edward , Joyce Sebastian 
Published: April 2014

AbstractCD1d1 is a member of a family of lipid Ag-presenting molecules. The cellular ligands associated with CD1d1 were isolated and characterized by biochemical means as an approach to elucidate the mechanism by which CD1 molecules assemble in vivo. Natural ligands of mouse CD1d1 included cellular phosphatidylinositol and phosphatidylinositol-glycans that are synthesized in the endoplasmic reticulum. Further biochemical data revealed that the two CD1d1 mutants, one defective in recycling from-and-to the plasma membrane and the other in efficiently negotiating the secretory pathway, associated with phosphatidylinositol. Thus phosphatidylinositol associated with CD1d1 in the early secretory pathway. Phosphatidylinositol also associated with CD1d1 in Pig-A-deficient cells that are defective in the first glycosylation step of glycosylphosphatidylinositol biosynthesis. Moreover, cellular phosphatidylinositol-glycans are not Vα14Jα15 natural T cell Ags. Therefore, we predict that cellular lipids occlude the hydrophobic Ag-binding groove of CD1 during assembly until they are exchanged for a glycolipid Ag(s) within the recycling compartment for display on the plasma membrane. In this manner, cellular lipids might play a chaperone-like role in the assembly of CD1d1 in vivo, akin to the function of invariant chain in MHC class II assembly.
Multiple Pathways of TWEAK-Induced Cell Death
Authors: Nakayama Masafumi , Ishidoh Kazumi , Kayagaki Nobuhiko , Kojima Yuko , Yamaguchi Noriko , Nakano Hiroyasu , Kominami Eiki , Okumura Ko , Yagita Hideo 
Published: April 2014

AbstractTWEAK, a recently identified member of the TNF family, is expressed on IFN-γ-stimulated monocytes and induces cell death in certain tumor cell lines. In this study, we characterized the TWEAK-induced cell death in several tumor cell lines that exhibited distinct features. Although the TWEAK-induced cell death in Kym-1 cells was indirectly mediated by TNF-α and was inhibited by cycloheximide, the TWEAK-induced cell death in HSC3 cells or IFN-γ-treated HT-29 cells was not inhibited by anti-TNF-α mAb or cycloheximide, suggesting a direct triggering of cell death via TWEAK receptor in the latter cell lines. The TWEAK-induced apoptosis in HSC3 cells and IFN-γ-treated HT-29 cells was associated with caspase-8 and caspase-3 activation. Although a pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone, inhibited the TWEAK-induced cell death in HSC3 cells, it rather sensitized HT-29 cells to TWEAK-induced cell death by necrosis. This necrosis was abrogated by lysosomal proteinase inhibitors, particularly a cathepsin B inhibitor, [l-3-trans-(propylcarbamoyl)oxirane-2-carbonyl]-l-isoleucyl-l-proline methyl ester. During the process of TWEAK-induced necrosis, cathepsin B was released from lysosome to cytosol. Although DR3 has been reported to be a receptor for TWEAK, all TWEAK-sensitive tumor cell lines used in this study did not express DR3 at either protein or mRNA level, but did bind CD8-TWEAK specifically. These results indicated that TWEAK could induce multiple pathways of cell death, including both caspase-dependent apoptosis and cathepsin B-dependent necrosis, in a cell type-specific manner via TWEAK receptor(s) distinct from DR3.
CD40 Signaling in B Cells Regulates the Expression of the Pim-1 Kinase Via the NF-κB Pathway
Authors: Zhu Nongliao , Ramirez Luis M. , Lee Rosaline L. , Magnuson Nancy S. , Bishop Gail A. , Gold Michael R. 
Published: April 2014

AbstractThe ability of CD40 signaling to regulate B cell growth, survival, differentiation, and Ig class switching involves many changes in gene expression. Using cDNA expression arrays and Northern blotting, we found that CD40 signaling increased the mRNA levels for pim-1, a protooncogene that encodes a serine/threonine protein kinase. Subsequent experiments showed that CD40 engagement also increased both Pim-1 protein levels and Pim-1 kinase activity in B cells. We then investigated the signaling pathways by which CD40 regulates Pim-1 expression and found that CD40 up-regulates Pim-1 primarily via the activation of NF-κB. Inhibiting the activation of NF-κB, either by treating cells with a chemical inhibitor, BAY11-7082, or by inducibly expressing a superrepressor form of IκBα, significantly impaired the ability of CD40 to increase Pim-1 protein levels. Because Pim-1 expression is associated with cell proliferation and survival, we asked whether this correlated with the ability of CD40 signaling to prevent anti-IgM-induced growth arrest in the WEHI-231 murine B cell line, a model for Ag-induced clonal deletion. We found that the anti-IgM-induced growth arrest in WEHI-231 cells correlated with a substantial decrease in Pim-1 levels. In contrast, culturing WEHI-231 cells with either anti-CD40 Abs or with the B cell mitogen LPS, both of which prevent the anti-IgM-induced growth arrest, also prevented the rapid decline in Pim-1 levels. This suggests that Pim-1 could regulate the survival and proliferation of B cells.
Transient Disruption of Autocrine TGF-β Signaling Leads to Enhanced Survival and Proliferation Potential in Single Primitive Human Hemopoietic Progenitor Cells
Authors: Fan Xiaolong , Valdimarsdottir Gudrun , Larsson Jonas , Brun Ann , Magnusson Mattias , Jacobsen Sten Eirik , ten Dijke Peter , Karlsson Stefan 
Published: April 2014

Abstract
Hemopoietic stem cells (HSCs) are maintained at relative quiescence by the balance between the positive and negative regulatory factors that stimulate or inhibit their proliferation. Blocking the action of negative regulatory factors may provide a new approach for inducing HSCs into proliferation. A variety of studies have suggested that TGF-β negatively regulates cell cycle progression of HSCs. In this study, a dominant negatively acting mutant of TGF-β type II receptor (TβRIIDN) was transiently expressed in HSCs by using adenoviral vector-mediated gene delivery, such that the effects of disrupting the autocrine TGF-β signaling in HSCs can be directly examined at a single cell level. Adenoviral vectors allowing the expression of TβRIIDN and green fluorescence protein in the same CD34+CD38−Lin− cells were constructed. Overexpression of TβRIIDN specifically disrupted TGF-β-mediated signaling. Autocrine TGF-β signaling in CD34+CD38−Lin− cells was studied in single cell assays under serum-free conditions. Transient blockage of autocrine TGF-β signaling in CD34+CD38−Lin− cells enhanced their survival. Furthermore, the overall proliferation potential and proliferation kinetics in these cells were significantly enhanced compared with the CD34+CD38−Lin− cells expressing green fluorescence protein alone. Therefore, we have successfully blocked the autocrine TGF-β-negative regulatory loop of primitive hemopoietic progenitor cells.
Activated Human T Cells Accomplish MHC Class II Expression Through T Cell-Specific Occupation of Class II Transactivator Promoter III
Authors: Holling Tjadine M. , van der Stoep Nienke , Quinten Edwin , van den Elsen Peter J. 
Published: April 2014

AbstractActivated human T cells express HLA-DR, HLA-DQ, and HLA-DP on their surface, but the regulation and functioning of MHC class II molecules in T lymphocytes are poorly understood. Because the MHC class II transactivator (CIITA) is essential for MHC class II expression, we have investigated transcriptional activation of CIITA in activated T cells. In this study, we show that in human activated CD4+ T cells, CIITA promoter III (CIITA-PIII) drives the expression of CIITA. The in vivo genomic footprint analysis revealed activated T cell-specific occupation of CIITA-PIII. Subsequent EMSA analysis of several promoter regions showed differences in banding pattern among activated T cells, naive T cells, primary B cells, and Raji B cells. Activating response element (ARE)-1 is shown to interact with the acute myeloid leukemia 2 transcription factor in nuclear extracts derived from both T and B cells. Interestingly, the acute myeloid leukemia 3 transcription factor was bound in nuclear extracts of T cells only. The ARE-2 sequence is able to bind CREB/activating transcription factor family members in both T and B cells. In addition, a yet unidentified Ets family member was found to interact with site C in activated T cells, whereas in B cells site C was bound by PU.1 and Pip/IFN regulatory factor 4/IFN consensus sequence binding protein for activated T cells. In Jurkat T cells, both ARE-1 and ARE-2 are crucial for CIITA-PIII activity, similar to Raji B cells. The differential banding pattern in in vivo genomic footprinting and transcription factor binding at the ARE-1 and site C between T cells and B cells probably reflects differences in CIITA-PIII activation pathways employed by these cell types.