bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNF Receptor 2-Deficient CD8 T Cells Are Resistant to Fas/Fas Ligand-Induced Cell Death
Authors: Teh Hung-Sia , Seebaran Andrew , Teh Soo-Jeet 
Published: April 2014

AbstractApoptotic cell death plays a fundamental role in the maintenance of tissue homeostasis in complex biological systems. It is also a major mechanism for keeping immune reactions in check. Members of the TNF family of receptors and cytokines are implicated in the regulation of apoptotic signals that shape the immune system. In this study, we have examined the role of three members of the TNFR family, Fas (CD95), TNFR1 (p55), and TNFR2 (p75), in inducing cell death in Con A-activated CD4 and CD8 T cells. It was found that Con A-activated p55−/− CD4 or CD8 T cells were highly resistant to TNF-induced cell death. By contrast, although activated p75−/− CD4 or CD8 T cells were killed by TNF, they were more resistant to TNF-induced killing when compared with p75+/+ cells, particularly at higher concentrations of TNF. We also determined whether activated p55−/− and p75−/− T cells differ in their sensitivity to cell death induced by TCR cross-linking. We found that activated p55−/− CD4 or CD8 T cells were equally susceptible to TCR-induced cell death. More interestingly, the loss of the p75 receptor conferred resistance to TCR-induced death in activated CD8, but not CD4 T cells. This resistance to TCR-induced death in activated p75−/− CD8 T cells correlated with the resistance of these cells to Fas/Fas ligand-induced cell death.
An Early Oxygen-Dependent Step Is Required for Dexamethasone-Induced Apoptosis of Immature Mouse Thymocytes
Authors: Torres-Roca Javier F. , Tung James W. , Greenwald Daniel R. , Brown J. Martin , Herzenberg Leonore A. , Herzenberg Leonard A. , Katsikis Peter D. 
Published: April 2014

Abstract
The roles of oxygen and reactive oxygen intermediates in apoptosis are unclear at present. Although oxygen and reactive oxygen intermediates are not required for the execution of apoptosis, oxygen may be involved in at least some forms of apoptosis. In this study we show that dexamethasone (Dex)-induced apoptosis of immature mouse thymocytes is completely inhibited by hypoxic culture. In contrast, anti-CD95 thymocyte apoptosis is unaffected by hypoxia, indicating the existence of two forms of thymocyte apoptosis: an oxygen-dependent pathway (Dex induced) and an oxygen-independent pathway (anti-CD95 induced). Furthermore, hypoxia inhibited mitochondrial permeability transition (PT) in Dex-treated, but not in anti-CD95-treated, thymocytes, suggesting that the oxygen-sensitive step is upstream of mitochondria. Both Dex- and anti-CD95-induced PT and apoptosis were dependent on activation of IL-converting enzyme-like protease, as PT and apoptosis were inhibited by preincubation with Cbz-Val-Ala-Asp-fluoromethyl ketone, an irreversible inhibitor of IL-converting enzyme-like proteases. In addition, hypoxia inhibited the activation by Dex of caspase-3 (CPP32)-like proteases. Our data show that the private signaling pathways of Dex (oxygen dependent) and anti-CD95 (oxygen independent) both converge upstream of mitochondrial changes. The oxygen-dependent step in Dex-induced apoptosis lies upstream of caspase-3-like protease activation. Our observations support a model of apoptosis signaling in which independent pathways (oxygen dependent and oxygen independent) particular to each stimuli converge at a central point in the apoptotic cascade.
Functional Differences Between Monocyte Chemotactic Protein-1 Receptor A and Monocyte Chemotactic Protein-1 Receptor B Expressed in a Jurkat T Cell
Authors: Sanders Sheila K. , Crean Sheila M. , Boxer Peter A. , Kellner Debra , LaRosa Gregory J. , Hunt Stephen W. 
Published: April 2014

Abstract
The monocyte chemotactic protein-1 (MCP-1) receptor (MCP-1R) is expressed on monocytes, a subpopulation of memory T lymphocytes, and basophils. Two alternatively spliced forms of MCP-1R, CCR2A and CCR2B, exist and differ only in their carboxyl-terminal tails. To determine whether CCR2A and CCR2B receptors function similarly, Jurkat T cells were stably transfected with plasmids encoding the human CCR2A or CCR2B gene. Nanomolar concentrations of MCP-1 induced chemotaxis in the CCR2B transfectants that express high, intermediate, and low levels of MCP-1R. Peak chemotactic activity was shifted to the right as receptor number decreased. Five-fold more MCP-1 was required to initiate chemotaxis of the CCR2A low transfectant, but the peak of chemotaxis was similar for the CCR2A and CCR2B transfectants expressing similar numbers of receptors. MCP-1-induced chemotaxis was sensitive to pertussis toxin, implying that both CCR2A and CCR2B are Giα protein coupled. MCP-1 induced a transient Ca2+ flux in the CCR2B transfectant that was partially sensitive to pertussis toxin. In contrast, MCP-1 did not induce Ca2+ flux in the CCR2A transfectant. Since MCP-1 can stimulate chemotaxis of the CCR2A transfectant without inducing Ca2+ mobilization, Ca2+ flux may not be required for MCP-1-induced chemotaxis in the Jurkat transfectants. These results indicate that functional differences exist between the CCR2A and CCR2B transfectants that can be attributed solely to differences in the carboxyl-terminal tail.
Two Distinct Stages in the Transition from Naive CD4 T Cells to Effectors, Early Antigen-Dependent and Late Cytokine-Driven Expansion and Differentiation
Authors: Jelley-Gibbs Dawn M. , Lepak Nancy M. , Yen Michael , Swain Susan L. 
Published: April 2014

AbstractEfficient peptide presentation by professional APC to naive and effector CD4 T cells in vitro is limited to the first 1–2 days of culture, but is nonetheless optimum for effector expansion and cytokine production. In fact, prolonging Ag presentation leads to high levels of T cell death, decreased effector expansion, and decreased cytokine production by recovered effectors. Despite the absence of Ag presentation beyond day 2, T cell division continues at a constant rate throughout the 4-day culture. The Ag-independent later stage depends on the presence of IL-2, and we conclude optimum effector generation depends on an initial 2 days of TCR stimulation followed by an additional 2 days of Ag-independent, cytokine driven T cell expansion and differentiation.
Functional Defects of NK Cells Treated with Chloroquine Mimic the Lytic Defects Observed in Perforin-Deficient Mice
Authors: Austin Taylor Mesha , Bennett Michael , Kumar Vinay , Schatzle John D. 
Published: April 2014

Abstract
NK cells are the primary effectors mediating acute rejection of incompatible bone marrow cell grafts. To reduce rejection, we evaluated the ability of chloroquine (CHQ) to prevent perforin-dependent NK cell activity. Perforin is a key cytotoxic component released from the lytic granules of activated NK cells. Generation of functional perforin requires an acidic protease activity that occurs in the secretory, lytic lysosomes. Our hypothesis was that CHQ, a lysosomotropic reagent, would raise the pH of the acidic compartment in which perforin is processed and thereby block perforin maturation and cytotoxicity. We have measured NK cytotoxicity in vivo by clearance of YAC-1 tumor cells from the lungs and by rejection of incompatible bone marrow transplants and in vitro by cytolysis of YAC-1 and Jurkat cells. The engraftment of bone marrow cells was monitored by recolonization of the spleen with hemopoietic cells from transplants of MHC class I-deficient bone marrow cells into lethally irradiated recipient mice. Transplant rejection was compared in two inbred strains of mice: 129, which apparently use perforin-dependent cytotoxicity, and C57BL/6, in which rejection can be perforin-independent. CHQ treatment reduced NK cell activity in 129 mice in which perforin is important for mediating rejection. CHQ affected the fraction of NK cell cytolysis that was Fas independent. In addition, we found that CHQ prevents perforin processing by LAK cells in vitro. These data indicate that CHQ may impair rejection of incompatible bone marrow transplants and other functions mediated by NK and cytotoxic T cells.
CD30 Signals Integrate Expression of Cytotoxic Effector Molecules, Lymphocyte Trafficking Signals, and Signals for Proliferation and Apoptosis
Authors: Muta Hiromi , Boise Lawrence H. , Fang Lei , Podack Eckhard R. 
Published: April 2014

AbstractAlthough CD30 has long been recognized as an important marker on many lymphomas of diverse origin and as activation molecule on B cells and T cells, its primary function has remained obscure. We now report that CD30 signals may serve to inhibit effector cell activity by integrating gene expression changes of several pathways important for cytotoxic NK and T cell effector function. In the large granular lymphoma line YT, CD30 signals down-regulate the expression of cytotoxic effector molecules, Fas ligand, perforin, granzyme B, and abrogate cytotoxicity. c-myc, a regulator of proliferation and an upstream regulator of Fas ligand expression, is completely suppressed by CD30. Furthermore, CD30 signals strongly induce CCR7, suggesting a role for CD30 signals in the homing of lymphocytes to lymph nodes. The up-regulation of Fas, death receptor 3, and TNF-related apoptosis-inducing ligand by CD30 indicates an increase in susceptibility to apoptotic signals whereas up-regulation of TNFR-associated factor 1 and cellular inhibitor of apoptosis 2 protect cells from certain types of apoptosis. Using gene microarrays, 750 gene products were induced and 90 gene products were suppressed &gt;2-fold by CD30 signals. Signals emanating from CD30 use both TNFR-associated factor 2-dependent and -independent pathways. The integration of CD30 signals in a lymphoma line suggests that CD30 can down-modulate lymphocyte effector function and proliferation while directing the cells to lymph nodes and increasing their susceptibility to certain apoptotic signals. These studies may provide a molecular mechanism for the recently observed CD30-mediated suppression of CTL activity in vivo in a diabetes model.
Functional Modulation of Human Macrophages Through CD46 (Measles Virus Receptor): Production of IL-12 p40 and Nitric Oxide in Association with Recruitment of Protein-Tyrosine Phosphatase SHP-1 to CD46
Authors: Kurita-Taniguchi Mitsue , Fukui Aya , Hazeki Kaoru , Hirano Akiko , Tsuji Shoutaro , Matsumoto Misako , Watanabe Michiko , Ueda Shigeharu , Seya Tsukasa 
Published: April 2014

Abstract
Human CD46, formerly membrane cofactor protein, binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity, including down-regulation of IL-12 production, has been reported on macrophages (Mφ) by cross-linking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. In this study, we found that 6- to 8-day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit protein-tyrosine phosphatase SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and NO. These responses were induced by stimulation with mAbs F(ab′)2 against CD46 that block MV binding or by a wild-type MV strain Kohno MV strain (KO; UV treated or untreated) that was reported to induce early phase CD46 down-regulation. Direct ligation of CD46 by these reagents, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6- to 8-day GM-CSF-cultured Mφ, while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. These and previous results provide strong evidence that CD46 serves as a signal modulatory molecule and that the properties of ligands determine suppression or activation of an innate immune system at a specific maturation stage of human Mφ.
Mucosal and Plasma IgA from HIV-1-Exposed Uninfected Individuals Inhibit HIV-1 Transcytosis Across Human Epithelial Cells
Authors: Devito Claudia , Broliden Kristina , Kaul Rupert , Svensson Lennart , Johansen Kari , Kiama Peter , Kimani Joshua , Lopalco Lucia , Piconi Stefania , Bwayo Job J. , Plummer Francis , Clerici Mario , Hinkula Jorma 
Published: April 2014

Abstract
HIV-1-specific IgA has been described in the genital tract and plasma of HIV-1 highly exposed, persistently seronegative (HEPS) individuals, and IgA from these sites has been shown to neutralize HIV-1. This study examines the ability of IgA isolated from HEPS individuals to inhibit transcytosis across a tight epithelial cell layer. A Transwell system was established to model HIV-1 infection across the human mucosal epithelium. The apical-basolateral transcytosis of primary HIV-1 isolates across this mucosal model was examined in the presence and the absence of IgA isolated from the genital tract, saliva, and plasma of HEPS individuals enrolled in both a sex worker cohort in Nairobi, Kenya, and a discordant couple cohort in Italy. In the absence of IgA, HIV-1 primary isolates were actively transported across the epithelial membrane and were released on the opposite side of the barrier. These transcytosed HIV-1 particles retained their ability to infect human mononuclear cells. However, IgA purified from the mucosa and plasma of HEPS individuals was able to inhibit HIV-1 transcytosis. Inhibition was seen in three of six cervicovaginal fluid samples, five of 10 saliva samples, and three of six plasma samples against at least one of the two primary HIV-1 isolates tested. IgA from low risk, healthy control subjects had no inhibitory effect on HIV-1 transcytosis. The ability of mucosal and plasma IgA to inhibit HIV-1 transcytosis across the mucosal epithelium may represent an important mechanism for protection against the sexual acquisition of HIV-1 infection in HEPS individuals.
IL-1β Converting Enzyme Is a Target for Nitric Oxide-Releasing Aspirin: New Insights in the Antiinflammatory Mechanism of Nitric Oxide-Releasing Nonsteroidal Antiinflammatory Drugs
Authors: Fiorucci Stefano , Santucci Luca , Cirino Giuseppe , Mencarelli Andrea , Familiari Luigi , Soldato Piero Del , Morelli Antonio 
Published: April 2014

AbstractCaspase-1, the IL-1β converting enzyme (ICE), is required for intracellular processing/maturation of IL-1β and IL-18. NO releasing nonsteroidal antiinflammatory drugs (NSAIDs) are a new class of NSAID derivatives that spare the gastric mucosa. Here, we tested the hypothesis that NCX-4016, a NO-aspirin derivative, inhibits proinflammatory cytokine release from endotoxin (LPS)-challenged monocytes. Our results demonstrated that exposing LPS-stimulated human monocytes to NCX-4016 resulted in a 40–80% inhibition of IL-1β, IL-8, IL-12, IL-18, IFN-γ, and TNF-α release with an EC50 of 10–20 μM for IL-1β and IL-18. Incubating LPS-primed monocytes with NCX-4016 resulted in intracellular NO formation as assessed by measuring nitrite/nitrate, intracellular cGMP concentration, and intracellular NO formation. Exposing LPS-stimulated monocytes to aspirin or celecoxib caused a 90% inhibition of prostaglandin E2 generation but had no effect on cytokine release. NCX-4016, similar to the NO donor S-nitroso-N-acetyl-d-l-penicillamine, inhibited caspase-1 activity with an EC50 of ≈20 μM. The inhibition of caspase-1 by NCX-4016 was reversible by the addition of DTT, which is consistent with S-nitrosylation as the mechanism of caspase-1 inhibition. NCX-4016, but not aspirin, prevented ICE activation as measured by assessing the release of ICE p20 subunit. IL-18 immunoneutralization resulted in a 60–80% reduction of IL-1β, IL-8, IFN-γ, and TNF-α release from LPS-stimulated monocytes. Taken together, these data indicate that incubating human monocytes with NCX-4016 causes intracellular NO formation and suppresses IL-1β and IL-18 processing by inhibiting caspase-1 activity. Caspase-1 inhibition is a new, cycloxygenase-independent antiinflammatory mechanism of NO-aspirin.
Temporal Development of Autoreactive Th1 Responses and Endogenous Presentation of Self Myelin Epitopes by Central Nervous System-Resident APCs in Theiler’s Virus-Infected Mice
Authors: Katz-Levy Yael , Neville Katherine L. , Padilla Josette , Rahbe Sandra , Begolka Wendy S. , Girvin Ann M. , Olson Julie K. , Vanderlugt Carol L. , Miller Stephen D. 
Published: April 2014

AbstractTheiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a chronic-progressive, immune-mediated CNS demyelinating disease and a relevant model of multiple sclerosis. Myelin destruction is initiated by TMEV-specific CD4+ T cells targeting persistently infected CNS-resident APCs leading to activation of myelin epitope-specific CD4+ T cells via epitope spreading. We examined the temporal development of virus- and myelin-specific T cell responses and acquisition of virus and myelin epitopes by CNS-resident APCs during the chronic disease course. CD4+ T cell responses to virus epitopes arise within 1 wk after infection and persist over a &gt;300-day period. In contrast, myelin-specific T cell responses are first apparent ∼50–60 days postinfection, appear in an ordered progression associated with their relative encephalitogenic dominance, and also persist. Consistent with disease initiation by virus-specific CD4+ T cells, CNS mononuclear cells from TMEV-infected SJL mice endogenously process and present virus epitopes throughout the disease course, while myelin epitopes are presented only after initiation of myelin damage (&gt;50–60 days postinfection). Activated F4/80+ APCs expressing high levels of MHC class II and B7 costimulatory molecules and ingested myelin debris chronically accumulate in the CNS. These results suggest a process of autoimmune induction in which virus-specific T cell-mediated bystander myelin destruction leads to the recruitment and activation of infiltrating and CNS-resident APCs that process and present endogenous myelin epitopes to autoreactive T cells in a hierarchical order.
Targeting Signal 1 Through CD45RB Synergizes with CD40 Ligand Blockade and Promotes Long Term Engraftment and Tolerance in Stringent Transplant Models
Authors: Rothstein David M. , Livak Mauren F. A. , Kishimoto Koji , Ariyan Charlotte , Qian He-Ying , Fecteau Scott , Sho Masayuki , Deng Songyan , Zheng Xin Xiao , Sayegh Mohamed H. , Basadonna Giacomo P. 
Published: April 2014

AbstractThe induction and maintenance of allograft tolerance is a daunting challenge. Although combined blockade of CD28 and CD40 ligand (CD40L)-costimulatory pathways prevents allograft rejection in some murine models, this strategy is unable to sustain engraftment in the most immunogenic allograft and strain combinations. By targeting T cell activation signals 1 and 2 with the novel combination of anti-CD45RB and anti-CD40L, we now demonstrate potent enhancement of engraftment in C57BL/6 recipients that are relatively resistant to costimulatory blockade. This combination significantly augments the induction of tolerance to islet allografts and dramatically prolongs primary skin allograft survival. Compared with either agent alone, anti-CD45RB plus anti-CD40L inhibits periislet infiltration by CD8 cells, B cells, and monocytes; inhibits Th1 cytokines; and increases Th2 cytokine expression within the graft. These data indicate that interference with activation signals one and two may provide synergy essential for prolonged engraftment in situations where costimulatory blockade is only partially effective.
Increased T Cell Autoreactivity in the Absence of CD40-CD40 Ligand Interactions: A Role of CD40 in Regulatory T Cell Development
Authors: Kumanogoh Atsushi , Wang Xiaosong , Lee Ihnsook , Watanabe Chie , Kamanaka Masahito , Shi Wei , Yoshida Kanji , Sato Takehito , Habu Sonoko , Itoh Misako , Sakaguchi Noriko , Sakaguchi Shimon , Kikutani Hitoshi 
Published: April 2014

AbstractMutations in the CD40 ligand (CD40L) gene lead to X-linked immunodeficiency with hyper-IgM, which is often associated with autoimmune diseases. To determine the contribution of defective CD40-CD40L interactions to T cell autoreactivity, we reconstituted CD40-CD40L interactions by transferring T cells from CD40-deficient mice to syngenic athymic nude mice and assessed autoimmunity. T cells from CD40-deficient mice triggered autoimmune diseases accompanied with elevations of various autoantibodies, while those from wild-type mice did not. In CD40-deficient mice, the CD25+ CD45RBlow CD4+ subpopulation which regulates T cell autoreactivity was markedly reduced. CD40-deficient APCs failed to induce T regulatory cells 1 producing high levels of an inhibitory cytokine, IL-10 in vitro. Furthermore, autoimmune development was inhibited when T cells from CD40-deficient mice were cotransferred with CD45RBlow CD4+ T cells from wild-type mice or with T regulatory cells 1 induced on CD40-expressing APCs. Collectively, our results indicate that CD40-CD40L interactions contribute to negative regulation of T cell autoreactivity and that defective interactions can lead to autoimmunity.
Gene Duplications at the Chemokine Locus on Mouse Chromosome 4: Multiple Strain-Specific Haplotypes and the Deletion of Secondary Lymphoid-Organ Chemokine and EBI-1 Ligand Chemokine Genes in thepltMutation
Authors: Nakano Hideki , Gunn Michael D. 
Published: April 2014

AbstractThe murine paucity of lymph node T cell (plt) mutation leads to abnormalities in leukocyte migration and immune response. The causative defect is thought to be a loss of secondary lymphoid-organ chemokine (SLC) expression in lymphoid tissues. We now find that the plt defect is due to the loss of both SLC and EBI-1 ligand chemokine (ELC) expression in secondary lymphoid organs. In an examination of the plt locus, we find that commonly used inbred mouse strains demonstrate at least three different haplotypes. Polymorphism at this locus is due to duplications of at least four genes, three of them encoding chemokines. At least two cutaneous T cell-attracting chemokine (CTACK), three SLC, and four ELC genes or pseudogenes are present in some haplotypes. All haplotypes share a duplication that includes two SLC genes, which demonstrate different expression patterns, a single functional ELC gene, and an ELC pseudogene. The plt mutation represents a deletion that includes the SLC gene expressed in secondary lymphoid organs and the single functional ELC gene, leaving only an SLC gene that is expressed in lymphatic endothelium and an ELC pseudogene. This lack of CCR7 ligands in the secondary lymphoid organs of plt mice provides a basis for their severe abnormalities in leukocyte migration and immune response.
Tec Kinase Signaling in T Cells Is Regulated by Phosphatidylinositol 3-Kinase and the Tec Pleckstrin Homology Domain
Authors: Yang Wen-Chin , Ching Keith A. , Tsoukas Constantine D. , Berg Leslie J. 
Published: April 2014

AbstractTec, the prototypical member of the Tec family of tyrosine kinases, is abundantly expressed in T cells and other hemopoietic cell types. Although the functions of Itk and Txk have recently been investigated, little is known about the role of Tec in T cells. Using antisense oligonucleotide treatment to deplete Tec protein from primary T cells, we demonstrate that Tec plays a role in TCR signaling leading to IL-2 gene induction. Interestingly, Tec kinases are the only known family of tyrosine kinases containing a pleckstrin homology (PH) domain. Using several PH domain mutants overexpressed in Jurkat T cells, we show that the Tec PH domain is required for Tec-mediated IL-2 gene induction and TCR-mediated Tec tyrosine phosphorylation. Furthermore, we show that Tec colocalizes with the TCR after TCR cross-linking, and that both the Tec PH and Src homology (SH) 2 domains play a role in this association. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, abolishes Tec-mediated IL-2 gene induction and Tec tyrosine phosphorylation, and partially suppresses Tec colocalization with the activated TCR. Thus, our data implicate the Tec kinase PH domain and phosphatidylinositol 3-kinase in Tec signaling downstream of the TCR.