bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased proliferation, cytotoxicity, and gene expression after stimulation of human peripheral blood T lymphocytes through a surface ganglioside (GD3)
Authors: Norihisa Y , McVicar D W , Ghosh P , Houghton A N , Longo D L , Creekmore S P , Blake T , Ortaldo J R , Young H A 
Published: December 2022

Abstract
Previous studies have suggested that gangliosides have an important role in cell signaling and recognition. However, their specific function in these processes has not been clearly defined. A mAb, R24, that reacts specifically with a cell surface ganglioside (GD3) has been demonstrated to stimulate proliferation of T cells derived from human peripheral blood. In this study, we have investigated the mechanisms by which the R24 mAb affects T cell functions. We have observed that the R24 mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface marker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a, and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL-4 activity was present in culture supernatants 72 h after R24 stimulation. In some donors, increased IL-6 and TNF-alpha activity also was detected after R24 treatment. Furthermore, R24 treatment resulted in translocation of c-rel, but little or no NF kappa B p50 or p65, from the cytoplasm to the nucleus and an increase of NF kappa B binding complexes containing c-rel and p50. This treatment also caused increased tyrosine phosphorylation of specific protein substrates. R24-stimulated increases in proliferation, cytotoxicity, and cell surface protein expression could be blocked by cyclosporin and staurosporin, indicating that cyclophilin/calcineurin and protein kinase C may be involved in the R24 signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhibitor, blocked the R24-stimulated increase in proliferation but not cytotoxicity at concentrations consistent with specificity for tyrosine kinases. These results suggest that multiple biochemical pathways are involved in the activation of human T cells by R24.
Environmental signals influencing expression of the IFN-gamma receptor on human T cells control whether IFN-gamma promotes proliferation or apoptosis.
Authors: Novelli F , Di Pierro F , Francia di Celle P , Bertini S , Affaticati P , Garotta G , Forni G 
Published: December 2022

Abstract
IFN-gamma R expression is subject to contrasting modulation on human T cells. IFN-gamma R constitutive expression is low on three human malignant T cells (ST4, PF382, and Jurkat) growing in medium supplemented with serum. The addition of IFN-gamma down-modulates IFN-gamma R expression and increases both proliferation and MHC class I Ag expression. By contrast, when malignant T cells are cultured in medium without serum, IFN-gamma R expression dramatically increases and the cells undergo a slow apoptotic death. The addition of IFN-gamma enhances apoptosis and inhibits cell rescue in serum-supplemented medium. This opposite ability of IFN-gamma to stimulate malignant T cell proliferation or death correlates with the intensity of IFN-gamma R cell expression, high expression being a marker for cell apoptosis. IFN-gamma R up-modulation also occurs on malignant T cells undergoing apoptosis after treatment with dexamethasone, on irradiated normal CD3+ PBL, and on cultured normal CD3+ thymocytes. Moreover, the ability of IFN-gamma to augment apoptosis of highly IFN-gamma R-positive thymocytes suggests that its role in promoting T cell apoptosis is also important in physiologic conditions.
Conditional ablation of dendritic cells in transgenic mice.
Authors: Salomon B , Lorès P , Pioche C , Racz P , Jami J , Klatzmann D 
Published: December 2022

Abstract
Dendritic cells (DC) are professional Ag-presenting cells that play a major role in T cell-mediated immune responses and in thymocyte differentiation. To better analyze their physiological importance, we sought to generate transgenic mice presenting a conditional DC deficiency. We used a strategy based on the cell-specific expression of a suicide gene. The DC-targeted expression is obtained using HIV regulatory sequences; indirect evidence has suggested that these sequences control a preferential expression in DC. The suicide gene is the herpes simplex virus type 1 thymidine kinase (HSV1-TK) which allows conditional ablation of dividing HSV1-TK-expressing cells by converting nucleoside analogs such as ganciclovir (GCV) into toxic molecules. We generated transgenic mice expressing an HSV1-TK gene transcribed from HIV regulatory sequences. A low but significant HSV1-TK expression was observed in mature DC and DC precursors grown from granulocyte-macrophage colony-stimulating factor-supplemented bone marrow cultures. These HSV1-TK-expressing DC precursors are specifically killed by GCV. We next treated transgenic mice with GCV, and obtained a specific ablation of DC in spleen and thymus. Ninety percent of spleen DC could be depleted within a week, indicating a turnover rate of approximately 15% per day. Interestingly, this DC depletion always correlated with a major thymic atrophy and disappearance of CD4+CD8+ thymocytes. This animal model should help to assess the physiological role of DC in the immune response and in thymocyte differentiation. It should also help to appreciate the consequences of DC dysfunction in pathological situations, such as HIV-infection or allograft rejection.
Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells.
Authors: Smith C I , Baskin B , Humire-Greiff P , Zhou J N , Olsson P G , Maniar H S , Kjellén P , Lambris J D , Christensson B , Hammarström L 
Published: December 2022

Abstract
The gene mutated in the human disease, X-linked agammaglobulinemia (XLA), is related to the Src gene family of cytoplasmic protein-tyrosine kinases and is designated Btk (Bruton's agammaglobulinemia tyrosine kinase; formerly Atk/Bpk; the human gene is denoted BTK, using capital letters according to the kinase nomenclature). We have recently reported that this gene is expressed in B lymphocytes and that the specific mRNA was undetectable in T cells using Northern blotting. Further analyses of different sources of B and T lymphocytes confirmed this pattern. However, BTK transcripts were undetectable in four plasmacytoma lines. Moreover, as virtually normal amounts of BTK transcripts were found in PBMC from two patients carrying a point mutation in BTK, despite low B cell numbers, we anticipated that the gene would also be expressed in cells of other lineages. The erythroleukemia cell line K-562, the promyelocytic line HL-60 and the histiocytic lymphoma line U-937 were found to have BTK mRNA levels comparable to B cells. BTK mRNA was also detected in monocytes from healthy donors as well as in the human immature basophilic cell line KU812, in the human mast cell leukemia cell line HMC-1 and in the CD34 expressing myeloblast KG-1. A similar expression pattern was obtained when BTK protein was analyzed by immunoprecipitation and Western blotting. Using a polymerase chain reaction-based analysis, a small amount (less than 1% of the level in B cells) of BTK mRNA was identified in T lymphocytes. Our findings are compatible with a general expression of the BTK gene in hematopoietic cells, except in T lymphocytes and plasma cells, in which the transcript level is selectively down-regulated.
Characterization of DAF-2, a high molecular weight form of decay-accelerating factor (DAF; CD55), as a covalently cross-linked dimer of DAF-1.
Authors: Nickells M W , Alvarez J I , Lublin D M , Atkinson J P 
Published: December 2022

Abstract
Human E express two surface forms of decay-accelerating factor (DAF; CD55). On SDS-PAGE under reducing conditions the major form, DAF-1, migrates as a 70-kDa protein and the minor form, DAF-2, present at &lt; 10% the amount of DAF-1, migrates as a 140-kDa protein (Kinoshita, T., S. I. Rosenfeld, and V. Nussenzweig. 1987. J. Immunol. 138:2994). Both forms possess decay-accelerating activity and, after purification from solubilized E, reinsert into sheep E, indicating a glycosylphosphatidylinositol anchor. In contrast to human cells, these two forms of DAF from orangutan E are expressed in approximately equal amounts (Nickells, M. W., and J. P. Atkinson. 1990. J. Immunol. 144:4262). An orangutan B lymphocyte cell line, CP81, also expresses similar quantities of both forms. These sources of orangutan DAF were utilized for further characterization of DAF-2. Orangutan and human DAF-1 were 98% and 95% homologous at the nucleotide and amino acid levels, respectively. Northern and Southern analyses of orangutan DAF were also similar to those for human DAF. Tryptic peptide maps of DAF-1 and DAF-2 were identical. After treatment with phosphatidylinositol-specific phospholipase C and glycosidases, the change in M(r) of DAF-2 was consistent with it possessing two glycosylphosphatidylinositol anchors and twice as much oligosaccharide as DAF-1. Biosynthetic analysis demonstrated a single 46-kDa precursor for both forms. Taken together, these data indicate that DAF-2 is a covalently cross-linked dimer of DAF-1. Analysis of a series of human DAF deletion mutants localized the cross-link(s) within the short consensus repeat domains.
Protective immunity linked with a distinct developmental stage of a filarial parasite.
Authors: Eisenbeiss W F , Apfel H , Meyer T F 
Published: December 2022

Abstract
Repeated low dose infections of the jird Meriones unguiculatus, with the filarial parasite Acanthocheilonema viteae cause a substantial reduction of the total worm burden, suggesting a parasite-driven immune mechanism that controls super-infections. Quantitative recovery of parasites from tissues of triple infected jirds reveals that the larvae derived from a subsequent challenge infection are inactivated or severely impaired several days after transmission, precisely during their molt from the L3 to the L4 stage. Moreover, only larvae undergoing the molt from L3 to L4 stages are capable of stimulating an immune response directed against the challenge infection, indicating that protective Ag are produced during the molting period. Consistent with this, inactivated L3 or live L4 do not produce the same effect. In contrast to susceptible animals, immune jirds elicit high serum antibody titers against molting Ag. Indirect fluorescence antibody-binding tests with sera from protected jirds reveal specific labeling of the surface of molting L3 and not other larval stages, implying a stage-specific elimination process. The identification of molting L3 as a natural target for host immune mechanisms, emphasizes the central importance of this larval stage for future efforts aimed toward the development of a filarial vaccine.
Signal transduction pathways mediating astrocyte IL-6 induction by IL-1 beta and tumor necrosis factor-alpha.
Authors: Norris J G , Tang L P , Sparacio S M , Benveniste E N 
Published: December 2022

Abstract
One immune function of astrocytes is IL-6 production. Synthesis of IL-6 within the central nervous system (CNS) can produce several different responses, acting on glia, neurons, and lymphocytes infiltrating brain tissue, and some of these effects are associated with CNS autoimmune disease. IL-6 gene expression in astrocytes is regulated by cytokines, infectious agents, neuropeptides, and neurotransmitters, and most of these stimuli interact synergistically. To examine the integration of these diverse factors in the control of IL-6 production, we have studied the involvement of underlying signal transduction processes using neonatal rat astrocytes. We have focused on signal transduction related to the stimulation of IL-6 gene expression by IL-1 beta and TNF-alpha. Our results indicate that stimuli related to protein kinase C (PKC), such as PMA and calcium ionophore A23187, increase IL-6 expression, whereas pharmacologic inhibitors of PKC inhibit IL-6 induction by IL-1 beta and TNF-alpha. Furthermore, both IL-1 beta and TNF-alpha stimulate PKC activity in astrocytes. Stimulators of the cAMP pathway, such as cholera toxin, forskolin, and dibutyryl cAMP, also induced astrocyte IL-6 gene expression. However, inhibition of the cAMP pathway effector, protein kinase A, did not reduce the induction of astrocyte IL-6 gene expression in response to IL-1 beta or TNF-alpha, and an ELISA for cAMP detected only very small increases in cAMP synthesis in response to these cytokines. These data suggest that although cAMP does activate astrocyte IL-6 gene expression, it is the PKC pathway that plays a primary role in the stimulation of astrocyte IL-6 gene expression by IL-1 beta and TNF-alpha.
Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. VI. Potentiation of demyelination with and characterization of an immunopathologic CD4+ T cell line specific for an immunodominant VP2 epitope.
Authors: Gerety S J , Rundell M K , Dal Canto M C , Miller S D 
Published: December 2022

Abstract
Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a relevant mouse model of multiple sclerosis. Demyelination is linked to persistent TMEV infection of the central nervous system and characterized by perivascular inflammatory mononuclear infiltrates and primary demyelination. Our previous results have shown that susceptibility correlates with the temporal development of chronic virus-specific delayed-type hypersensitivity (DTH) responses and suggest that inflammatory processes mediated by T cells specific for an immunodominant determinant on virus capsid protein 2 (VP2(74-86)) play a major immunopathologic role in SJL/J mice. In this study we have further defined the T cell-dependent nature and specificity of the demyelinating process in susceptible SJL/J mice by showing that thymectomized irradiated bone marrow-restored mice fail to develop chronic demyelination and that i.v. adoptive transfer of polyclonal TMEV-specific T cells before intracerebral infection with a suboptimal dose of the BeAn strain of TMEV led to increased incidence and accelerated onset of clinical disease. The data also show that demyelination is dependent on the activity of virus-specific CD4+ T cells because in vivo depletion with anti-CD4, but not anti-CD8, mAb led to significantly diminished incidence and severity of demyelination concomitant with a decrease in TMEV-specific DTH reactivity. In addition, the adoptive transfer of a TMEV-specific, DTH-mediating CD4+ I-A(s)-restricted Th1 line (sTV1) specific for the immunodominant VP2(74-86) epitope also led to increased incidence and accelerated onset of clinical disease only in TMEV-infected recipients. Collectively, the results of this and the companion paper demonstrate the highly significant immunopathologic contribution of CD4+ T cell responses specific for an immunodominant viral epitope to the chronic central nervous system demyelination observed in TMEV-infected SJL/J mice.
IL-6-anti-IL-6 autoantibody complexes with IL-6 activity in sera from some patients with systemic sclerosis.
Authors: Suzuki H , Takemura H , Yoshizaki K , Koishihara Y , Ohsugi Y , Okano A , Akiyama Y , Tojo T , Kishimoto T , Kashiwagi H 
Published: December 2022

Abstract
Anti-IL-6 IgG autoantibodies, often found in sera from patients with systemic sclerosis, may increase to the level sufficient to bind significant amounts of IL-6 in serum. In our study of the role of anti-IL-6 autoantibodies in serum, we found that some sera with the autoantibodies possessed considerably higher IL-6 levels (more than 100 pg/ml) compared with most of sera without the autoantibodies. Size-exclusion HPLC of the sera with these autoantibodies demonstrated that a significant part of the serum IL-6 activity was attributable to circulating IL-6-anti-IL-6 autoantibody complexes. Gel filtration of IL-6-anti-IL-6 IgG complexes made in vitro by incubation of rIL-6 and IgG purified from the autoantibody-positive sera demonstrated that the complexes at 200 to 250 kDa were dominant ones and that IL-6 bound to the autoantibodies retained more than 60% of the original IL-6 activity. Moreover, IL-6-anti-IL-6 autoantibody complexes were shown to bind to recombinant soluble IL-6 receptors. Estimated affinity of anti-IL-6 IgG autoantibodies from two patients was fairly high (4.2 x 10(9) to 3.3 x 10(10) L/M). Therefore, the retention of IL-6 activity by IL-6-anti-IL-6 autoantibody complexes may be explained by intact receptor-binding sites on the autoantibody-bound IL-6 molecules. Taken together, these results suggest that the properties of anti-IL-6 autoantibodies are consistent with a potential role as specific carriers for IL-6 in the circulation.
Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment.
Authors: Fowler D H , Kurasawa K , Husebekk A , Cohen P A , Gress R E 
Published: December 2022

Abstract
A murine parent-into-F1 graft-vs-host reaction (GVHR) model that utilizes LPS to induce lethality was used to evaluate the in vivo regulatory role of donor cells of Th2 cytokine phenotype. Transfer of B6 spleen cells into B6C3F1 hosts was lethal when LPS endotoxin (15 micrograms) was administered on day 7 after cell transfer. Parental cells of Th2 cytokine phenotype were generated by treating B6 mice in vivo with a combination of IL-2 and IL-4 or with high dose IL-2. The CD4-enriched population from these cytokine-treated mice expressed and secreted increased levels of IL-4 and IL-10, with concomitantly decreased IL-2 and IFN-gamma. Cell mixing experiments (parental spleen cells+parental CD4-enriched. Th2-type cells) demonstrated that the Th2-type cells protected F1 hosts from LPS-induced lethality. These mice were analyzed to study possible mechanisms by which this protection was mediated. Compared with mice undergoing LPS-induced lethality during GVHR, Th2-protected mice had: 1) lower levels of donor CD8+ lymphoid engraftment, 2) in vivo suppression of IFN-gamma mRNA, 3) in vivo augmentation of IL-4 mRNA, and 4) a reduction in serum TNF-alpha. We thus conclude that donor cells of Th2 cytokine phenotype prevent LPS-induced, TNF-alpha-mediated lethality during GVHR, and that this protection is associated with regulation of both cellular- and cytokine-mediated events. As a result, we propose that cells of Th2 cytokine phenotype may represent a novel approach for establishing allogeneic lymphoid engraftment without lethal graft-vs-host disease.
Cytotoxic lymphocyte granzymes trigger a target cell internal disintegration pathway leading to cytolysis and DNA breakdown.
Authors: Nakajima H , Henkart P A 
Published: December 2022

Abstract
Two approaches have been used to assess the hypothesis that granzymes secreted by cytotoxic lymphocytes act within the target cells to trigger an internal disintegration pathway leading to target cell lysis. The lytic properties of several clones of rat basophilic leukemia cells transfected with either cytolysin (perforin) alone (RBL-cy) or a combination of cytolysin and granzyme A (RBL-cy-gza) were compared with cloned CTL. Analysis of the kinetics of target cell 125I-DNA vs 51Cr release with three tumor targets showed negligible DNA release with RBL-cy, less extensive 125I-DNA release relative to 51Cr release with RBL-cy-gza effector cells, whereas CTL caused greater or equal DNA release than 51Cr release at all time points. Using three different tumor target cells, comparison of RBL-cy-gza and RBL-cy clones in multiple experiments shows that RBL-cy-gza are on average more than threefold more lytic than RBL-cy. This distinction was not seen with red cell targets, in which an internal disintegration pathway does not operate. A second approach to this issue consisted of cytoplasmic loading of tumor target cells with aprotinin, a macromolecular protease inhibitor known to inhibit granzyme A and probably other granzymes. Although the control BSA-loaded target cells were essentially identical to nonloaded targets in all cases, aprotinin-loaded targets showed substantially lower release of both 51Cr and 125I-DNA with both CTL and RBL-cy-gza effector cells. In contrast, aprotinin-loaded targets were lysed with the same efficiency as control targets by RBL-cy effector cells. We conclude that secreted granzymes contribute to target lysis by triggering a target cell internal disintegration pathway that leads to both lysis and DNA breakdown.
Cloning, genomic organization, and chromosomal localization of the Scya5 gene encoding the murine chemokine RANTES.
Authors: Danoff T M , Lalley P A , Chang Y S , Heeger P S , Neilson E G 
Published: December 2022

Abstract
RANTES is a member of the C-C subfamily of chemokines that functions as a proinflammatory chemoattractant for CD4+ T cells, monocytes, and eosinophils, and as an activator of basophils to release histamine. Like other members of the chemokine superfamily, RANTES has been implicated in a number of chronic inflammatory and autoimmune processes based on its function and its pattern of regulation. To begin study of the transcriptional regulation of RANTES, we have determined the genomic organization of the gene encoding the small inducible cytokine A5 (Scya5) and performed an initial analysis of its promoter elements. The Scya5 gene is located on chromosome 11. By Southern blot, it is a single-copy gene approximately 4.5 kb long composed of 3 exons. This chromosomal localization and pattern of genomic organization is conserved among the other C-C subfamily of chemokines. Primer extension analysis was used to identify the transcriptional initiation site that is located 27 bp downstream of a typical TATAA box. Sequence analysis of 1040 bp 5' to the start site of the Scya5 gene revealed a number of regulatory motifs that are also shared among the chemokine family including a PU.1 box, a NF-kappa B, and an IFN regulatory factor-1 response element. This region of genomic DNA was also cloned into a luciferase reporter vector. Transfection of this reporter construct into murine proximal tubular cells reveals that TNF-alpha can induce a transcriptional activation of the gene, as would be predicted from the rise in mRNA transcripts encoding RANTES in cells stimulated with TNF-alpha.
Testing the importance of each residue in a HLA-B27-binding peptide using monoclonal antibodies.
Authors: Fukazawa T , Wang J , Huang F , Wen J , Tyan D , Williams K M , Raybourne R B , Yu D T 
Published: December 2022

Abstract
When a peptide derived from histone 3.3 was incubated with mouse L cells transfected with HLA-B27, the cells became highly reactive with Ye-2, an anti-HLA-B27 mAb. The critical residues were analyzed by testing analogues in which each of the nine residues in the peptide was consecutively substituted by 19 other amino acids. The conclusions were separately verified using a different HLA-B27-positive cell line. The ability of some of these peptides to bind to HLA-B27 was also assayed by their ability to stabilize HLA-B27 in a mutant cell line which required HLA-B27-binding peptides to express HLA-B27 at 37 degrees C. These experiments showed that in P4, P5, P6, P7, P8, and P9, all 20 different amino acids could be substituted without eliminating the ability of the analogues to bind to HLA-B27. The residues which were responsible for the HLA-B27-peptide complex reacting with the Ye-2 antibody were P8 and P9. The latter might mediate its effect by altering either the surface conformation of the closely associated HLA-B27 heavy chain or the conformation of the peptide itself.