bluuebunny/crossref_metadata_2025_split huggingface dataset:
NK Cell Natural Cytotoxicity and IFN-γ Production Are Not Always Coordinately Regulated: Engagement of DX9 KIR+ NK Cells by HLA-B7 Variants and Target Cells
Authors: Kurago Zoya B. , Lutz Charles T. , Smith Kelly D. , Colonna Marco 
Published: December 2022

AbstractDX9 mAb-binding killer cell-inhibitory receptors (KIR) recognize HLA-B molecules that express the Bw4 public serologic epitope. We assessed DX9+ NK cell fine specificity recognition of HLA-B7 variants and HLA-B27 alleles by 51Cr release natural cytotoxicity assays and by flow cytometry and enzyme-linked immunospot (ELISPOT) IFN-γ synthesis and release assays. 721.221 target cell expression of Bw4+ HLA-B27 alleles specifically inhibited DX9+ NK cell natural cytotoxicity and IFN-γ synthesis and release. A triple substitution of HLA-B7 at residues 80, 82, and 83 known to induce expression of the Bw4 serologic epitope also specifically inhibited DX9+ NK cell natural cytotoxicity and IFN-γ responses. Single HLA-B7 amino acid substitution variants were recognized in the same decreasing rank order by DX9+ NK cells and Bw4-reactive mAbs: G83R &gt; R82L &gt; N80T = HLA-B7. Natural cytotoxicity inhibition was reversed by the presence of blocking DX9 mAb. Natural cytotoxicity and IFN-γ production were coordinately regulated by a panel of HLA-B7 variants expressed on 721.221 cells, suggesting that these two effector functions are inhibited by the same KIR-mediated signaling mechanisms. In contrast, some NK cell clones killed 721.221 and K562 target cells equally well but released much more IFN-γ in response to K562 target cells. Differential regulation of natural cytotoxicity and IFN-γ release shows that NK cell effector functions respond to distinct signals.
TGF-β Promotes Immune Deviation by Altering Accessory Signals of Antigen-Presenting Cells
Authors: Takeuchi Masaru , Alard Pascale , Streilein J. Wayne 
Published: December 2022

AbstractMacrophages incubated with OVA in the presence of TGF-β2 induce immune deviation in vivo (impaired delayed hypersensitivity and IgG2a Ab production) when injected into naive, syngeneic mice. OVA-specific TCR transgenic naive T cells (DO11.10 T cells) produce Th1-type cytokines when stimulated in vitro with OVA-pulsed peritoneal exudate cells (PEC), but if PEC are first treated with TGF-β2 and then pulsed with OVA, the T cells secrete Th2-type cytokines instead. In this study, we investigated the mechanisms that are involved in the modified Ag-presenting functions of macrophages by TGF-β2 pretreatment. We have found that: 1) TGF-β2 impaired the capacity of PEC to produce IL-12 and to express CD40; 2) reduced CD40 expression on TGF-β2-treated PEC impaired IL-12 production when the cells were cocultured with DO11.10 T cells; 3) the failure of TGF-β2-treated PEC to stimulate DO11.10 T cells to secrete IFN-γ was due to their impaired IL-12 production. From these results, we conclude that TGF-β2 treatment impairs the ability of macrophages to produce IL-12 and to express CD40. As a consequence, TGF-β2-treated PEC fail to promote development of pT cells toward the Th1 phenotype.
Non-MHC-Restricted Cell-Mediated Lysis of Human Oligodendrocytes In Vitro: Relation with CD56 Expression
Authors: Antel Jack P. , McCrea Ellie , Ladiwala Uma , Qin Yu-fen , Becher Burkhard 
Published: December 2022

AbstractOligodendrocytes and their myelin membranes are the apparent target of the autoimmune response that characterizes the human adult central nervous system-demyelinating disease multiple sclerosis. Human oligodendrocytes do not express MHC class II molecules, a requirement for MHC-restricted injury mediated by myelin-reactive CD4+ T cells, the cell type implicated in initiating the disease process. In this study we observed that human adult central nervous system-derived oligodendrocytes can be susceptible to non-MHC-restricted lysis mediated by myelin basic protein-reactive CD4+ T cell lines. Cytotoxicity was significantly greater (37 ± 4 vs 7 ± 3%) with cell lines in which a high proportion of cells (mean, 28 ± 6%) expressed CD56 compared with cytotoxicity mediated by low CD56 cell lines (8 ± 2%). High CD56 cell lines, when rested in IL-2, lost cytotoxic activity and had reduced expression of CD56 (mean, 5 ± 2%). CD4+ T cells isolated from short term (3-day) anti-CD3/IL-2-activated mononuclear cell cultures did not express CD56 and were not cytotoxic to oligodendrocytes unless lectin was added. In contrast, an enriched population of non-T cells extracted from the same activated MNC cultures expressed CD56 as well as other NK cell-associated surface molecules and was cytotoxic. These results indicate the potential susceptibility of human oligodendrocytes to non-MHC-restricted injury mediated by both Ag-reactive and nonspecific cellular immune effector cells, with CD56 expression being a common feature of the effector cells.
IL-12 Receptor (IL-12R) Expression and Accumulation of IL-12Rβ1 and IL-12Rβ2 mRNAs in CD4+ T Cells by Costimulation with B7-2 Molecules
Authors: Igarashi Osamu , Yamane Hidehiro , Imajoh-Ohmi Shinobu , Nariuchi Hideo 
Published: December 2022

AbstractIL-12 is a crucial cytokine for the determination of a Th1/Th2 balance. It is important, therefore, to elucidate the mechanisms of IL-12R expression on Th cells. In this report, we present evidence to show that B7-2 costimulation plays a pivotal role in the expression of IL-12R on Th cells. A Th1 clone expressed a low density of IL-12R in a resting condition, the expression was enhanced by stimulation with specific Ag on splenic adherent cells and the enhancement was inhibited by anti-B7-2 or CTLA-4-Ig. When stimulated with anti-CD3 plus B7-2-transfected Chinese hamster ovary (CHO) cells, the clone strongly expressed IL-12R, although anti-CD3 by itself only weakly enhanced the expression. We obtained results that were similar to those in the Th1 clone in CD4+CD45RBlow memory T cells. In CD4+CD44low naive T cells, costimulation with B7-2-CHO was found to play a more important role in IL-12R expression. The accumulation of both IL-12Rβ1 and -β2 chain mRNAs was detected in naive T cells only when they were costimulated with anti-CD3 and B7-2-CHO, but β2 mRNA was not expressed upon anti-CD3 stimulation alone. On the other hand, both Th1 clones and memory T cells expressed low amounts of these mRNA without any stimulation, and the expression was weakly enhanced by anti-CD3 stimulation alone. For the maximum expression of these mRNAs, however, these cells also required costimulation with anti-CD3 and B7-2-CHO.
IL-1α and TNF-α Are Required for IL-12-Induced Development of Th1 Cells Producing High Levels of IFN-γ in BALB/c But Not C57BL/6 Mice
Authors: Shibuya Kazuko , Robinson Douglas , Zonin Francesca , Hartley Suzanne B. , Macatonia Steven E. , Somoza Chamorro , Hunter Christopher A. , Murphy Kenneth M. , O’Garra Anne 
Published: December 2022

AbstractThe development of Th1- or Th2-type responses determines the type of immune response that is elicited in response to Ag. Responsiveness to IL-12 is critical for the development of Th1-type CD4+ T cells required for cell-mediated immune responses. Addition of IL-12 to primary cultures of CD4+ T cells stimulated with OVA and splenocytes or dendritic cells resulted in the development of a Th1 phenotype with the capacity to secrete high levels of IFN-γ upon restimulation with splenic APC. The present study shows that using dendritic cells to present Ag upon restimulation reveals a requirement for additional cofactors, including IL-1α and TNF-α, which were provided by spleen cells but not dendritic cells. Furthermore, these cofactors are required for optimal IL-12-induced Th1 development in BALB/c but not C57BL/6 mice. This differential requirement for such cofactors in IL-12-driven Th1 development may play a role in genetic predisposition to Th1 or Th2 responses to infectious agents.
A Tyrosine-Based Signal Present in Ig α Mediates B Cell Receptor Constitutive Internalization
Authors: Cassard Sylvanie , Salamero Jean , Hanau Daniel , Spehner Daniele , Davoust Jean , Fridman Wolf Herman , Bonnerot Christian 
Published: December 2022

AbstractB lymphocytes express Ag receptors (BCR) that are composed of ligand binding subunits, the membrane Igs, associated with Ig α/Ig β heterodimers. One main BCR function is to bind and to internalize Ags. Peptides generated from these internalized Ags may be presented to T lymphocytes. Here, we have analyzed the involvement of BCR Ig α/Ig β components in BCR constitutive endocytosis. The role of Ig α subunit in BCR constitutive endocytosis was first determined in the context of an IgM-based BCR. In contrast with BCR that contain wild-type Ig α, surface BCR lacking Ig α cytoplasmic domain were not constitutively internalized. The respective roles of Ig α and Ig β subunits were then analyzed by expressing chimeric molecules containing the cytoplasmic domains of either subunits in a B cell line. Only the Ig α cytoplasmic domain contained an internalization signal that allowed constitutive endocytosis of Ig α chimeras via coated pits and accumulation in sorting-recycling endosomes. This internalization signal is contained in its immunoreceptor tyrosine-based activation motif. These results indicate that Ig α, through its immunoreceptor tyrosine-based activation motif, may account for the ability of IgM/IgD BCR to constitutively internalize monovalent Ags.
Pentoxifylline Inhibits Ig κ Gene Transcription and Rearrangements in Pre-B Cells
Authors: Wang Weihong , Rath Satyajit , Durdik Jeannine M. , Sen Ranjan 
Published: December 2022

Abstract
Pentoxifylline (PF) has been used in a wide variety of clinical situations; however, the molecular consequences of this drug are not well characterized. In this paper we assayed the effects of PF in two models of pre-B differentiation. In 70Z pre-B cells, transcriptional induction of rearranged Ig κ-chain gene in response to LPS was suppressed by PF, without affecting the induction of Rel family proteins. In contrast, κ induction by IFN-γ was not suppressed by PF, indicating that the drug inhibited certain activation pathways. We also found that LPS-induced activation of germline κ transcription and Vκ to Jκ recombination were inhibited by PF in the pre-B cell line 38B9. These observations suggest that PF may adversely affect B lymphopoiesis during chronic administration.
Effects of Aminoguanidine on Latent Murine Tuberculosis
Authors: Flynn JoAnne L. , Scanga Charles A. , Tanaka Kathryn E. , Chan2 John 
Published: December 2022

AbstractA unique feature of Mycobacterium tuberculosis is its ability to establish latent infection in the human host, which can reactivate to cause disease years later. In the present study, the mechanisms involved in the control of latent tuberculous infection were examined using two murine experimental tuberculosis models. Analysis of the model involving infection of mice with a relatively low inoculum of the virulent Erdman strain of M. tuberculosis indicated that in vivo inhibition of reactive nitrogen intermediate (RNI) production by the nitric oxide synthase inhibitor aminoguanidine resulted in reactivation. This reactivation was evidenced by hepatosplenomegaly, a robust tissue granulomatous reaction, and increased bacillary load. IFN-γ, TNF-α, and inducible nitric oxide synthase were all expressed throughout the latent phase of infection. Reactivation of latent tuberculous infection by aminoguanidine treatment was confirmed using a second murine tuberculosis model based on treatment with antimycobacterial drugs. Results obtained using this drug-based model also suggested the existence of an RNI-independent antimycobacterial mechanism(s) operative in the latent phase of infection. Together, these data suggest that both RNI-dependent and -independent mechanisms contribute to the prevention of tuberculous reactivation.
Identification of a T Cell Subset Capable of both IFN-γ and IL-10 Secretion in Patients with ChronicBorrelia burgdorferiInfection
Authors: Pohl-Koppe Annette , Balashov Konstantin E. , Steere Allen C. , Logigian Eric L. , Hafler David A. 
Published: December 2022

AbstractA novel population of both IFN-γ- and IL-10-secreting human T cells that differentiate in the presence of exogenous IL-12 in vitro has recently been described. Whether this T cell population exists in vivo is unknown. Borrelia burgdorferi, the etiologic agent of Lyme disease, can induce a chronic infection in the presence of a vigorous humoral immune response. We established T cell lines specific for B. burgdorferi and tetanus toxoid from subjects with chronic B. burgdorferi infection and healthy controls in limiting dilution experiments and assessed proliferation and cytokine secretion. As expected, higher frequencies of B. burgdorferi-specific precursor T cells were observed in Lyme patients compared with controls. In both groups of subjects, T cell lines specific for B. burgdorferi secreted high amounts of IFN-γ. However, in patients with Lyme disease, 27% of T cell lines secreted not only IFN-γ but also IL-10, which was only observed in 0.6% of B. burgdorferi-reactive T cell lines generated from controls and in none of the tetanus toxoid-reactive T cell lines generated from either Lyme patients and controls. Single cell PHA cloning confirmed that both cytokines were secreted from one clonally expanded precursor cell. Whole mononuclear cells from B. burgdorferi-infected individuals, but not from controls, secreted IL-12. Moreover, neutralizing anti-IL-12 mAbs inhibited the generation of the IFN-γ/IL-10 population. These data demonstrate that this novel population of IL-12-induced IFN-γ/IL-10-secreting T cells is generated in response to chronic B. burgdorferi infection.
Th2 Cells Are Required for theSchistosoma mansoniEgg-Induced Granulomatous Response
Authors: Kaplan Mark H. , Whitfield Joel R. , Boros Dov L. , Grusby Michael J. 
Published: December 2022

AbstractThe development of Schistosoma mansoni ova-induced granulomas is regulated by cytokines secreted by distinct Th cell subsets. To determine the importance of Th1 and Th2 cells in granuloma formation, we have studied the immune response to S. mansoni ova in Stat4- and Stat6-deficient mice, which lack Th1 and Th2 cells, respectively. Lymphocytes from both naive and infected Stat6-deficient mice produced minimal levels of Th2 cell cytokines and Ag-specific IgG1 and IgE, but showed enhanced production of IFN-γ and Ag-specific IgG2a and IgG2b following schistosome egg injection. This shift away from a Th2 cell-mediated immune response was coupled with the development of pulmonary and hepatic granulomas that were greatly decreased in size compared with those in control littermates. Hepatic granulomas in Stat6-deficient mice were composed of predominantly mononuclear cells with very sparse appearance of eosinophils, and their diminished size was accompanied by decreased amounts of liver hydroxyproline content as a measure of collagen deposition. In contrast, lymphocytes from infected Stat4-deficient mice produced Th2 cell cytokines in amounts comparable to those produced by control littermates, but low levels of IFN-γ. While infected Stat4-deficient mice developed pulmonary granulomas following schistosome egg injection that were modestly impaired in size, the granuloma size and amount of collagen deposition in the liver were equivalent to those seen in control littermates. These studies demonstrate that Th2 cells are required for the full development of the granulomas and tissue-destructive fibrotic pathology associated with the immune response to S. mansoni ova.
LeishmaniaLipophosphoglycan Reduces Monocyte Transendothelial Migration: Modulation of Cell Adhesion Molecules, Intercellular Junctional Proteins, and Chemoattractants
Authors: Lo Siu K. , Bovis Lisa , Matura Rosemarie , Zhu Baixin , He Suhui , Lum Hazel , Turco Salvatore J. , Ho John L. 
Published: December 2022

AbstractWe previously identified the structural requirement for the inhibitory activity of Leishmania lipophosphoglycan (LPG) to block endothelial adhesion to monocytes. Here we showed that LPG reduces transendothelial migration of monocytes. LPG pretreatment of endothelial cells (2 μM, 1 h) reduced monocyte migration across endothelial cells activated by bacterial endotoxin (LPS) or IL-1β (60 and 46%, respectively). A fragment of LPG (i.e., repeating phosphodisaccharide (consisting of galactosyl-mannose)) and LPG coincubated with LPG-neutralizing mAb lacks inhibitory activity on monocyte migration. Pretreatment of monocytes with LPG (2 μM, 1 h) also did not affect monocyte migration through control or LPS-activated endothelial cells. FACS analysis reveals that LPG treatment blocked the LPS-mediated expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 on endothelial cells and monocyte adhesion without altering the integrity of the endothelial monolayer. LPG (2 μM, 1 h) alone was capable of altering the expression and distribution of two junctional adhesion molecules, CD31 and vascular endothelium cadherin, as well as reversing the effects of LPS on these proteins. The induction of endothelial cells by LPS to transcribe and release monocyte chemoattractant protein-1 (MCP-1) was significantly reduced by LPG (40–65%). LPG treatment of nonactivated endothelial cells also suppressed by 55 to 75% the monocyte migration triggered by a MCP-1 chemoattractant gradient, and coincubation of LPG with neutralizing mAb abrogated the inhibitory activity. Together, these data point to a novel anti-inflammatory function of LPG in reducing monocyte migration across endothelial cells via a mechanism of inhibition of endothelial expression of cell adhesion molecules, modulation of intercellular junctional proteins, and synthesis of MCP-1.
Importance of the B7-2 Molecule for Low Dose Melphalan-Induced Acquisition of Tumor-Eradicating Immunity by Mice Bearing a Large MOPC-315 Tumor
Authors: Mokyr Margalit B. , Kalinichenko Tatiana V. , Gorelik Leonid , Bluestone Jeffrey A. 
Published: December 2022

AbstractWe have previously shown that low dose melphalan (l-phenylalanine mustard; l-PAM) therapy of hitherto immunosuppressed mice bearing a large (20-mm) s.c. MOPC-315 tumor leads to the acquisition of potent CD8+ T cell-mediated antitumor immunity which in turn eradicates the large tumor burden not eradicated by the direct antitumor effects of the drug. Here we show the preferential importance of the B7-2 costimulatory molecule for the curative effectiveness of low dose l-PAM for mice bearing a large MOPC-315 tumor by demonstrating that treatment with anti-B7-2 mAb, but not anti-B7-1 mAb, reduced the percentage of mice cured by the low dose l-PAM. In addition, we show the preferential importance of the B7-2 molecule for the low dose l-PAM-induced acquisition of the ability of tumor-infiltrating lymphocytes from MOPC-315 tumor bearers to secrete IL-2 and IFN-γ as well as to exert an anti-MOPC-315 CTL effect. The preferential importance of the B7-2 molecule may be due to the higher level of B7-2 than of B7-1 expression on B220+ cells and on tumor cells from the s.c. tumor nodule of low dose l-PAM-treated MOPC-315 tumor bearers and the selective up-regulation of the B7-2 molecule in the draining of these mice. Thus, the B7-2 molecule plays a dominant role in the acquisition of T cell-dependent tumor-eradicating immunity in low dose l-PAM-treated mice bearing a large MOPC-315 tumor, suggesting that one of the mechanisms by which chemotherapy may enhance antitumor immunity is through up-regulation of critical costimulatory molecules that enhance antitumor responses.
Cytokine Regulation of Human Microglial Cell IL-8 Production
Authors: Ehrlich Laura C. , Hu Shuxian , Sheng Wen S. , Sutton Richard L. , Rockswold Gaylan L. , Peterson Phillip K. , Chao Chun C. 
Published: December 2022

AbstractIL-8 involvement in neutrophil activation and chemotaxis may be important in inflammatory responses within the central nervous system, secondary to meningitis, encephalitis, and traumatic injury. The source of IL-8 within the brain during these inflammatory processes, however, is unknown. To explore the role of microglia in the production of IL-8, human fetal microglia, which are the resident macrophages of the brain, were treated with LPS and pro- and anti-inflammatory cytokines to determine their effects on IL-8 production. We found that IL-8 protein levels increased in response to LPS or IL-1β, or to TNF-α, which also corresponded to elevated IL-8 mRNA levels by RT-PCR. Pretreatment with IL-4, IL-10, or TGF-β1 potently inhibited the stimulatory effects of these proinflammatory agents. These findings indicate that human microglia synthesize IL-8 in response to proinflammatory stimuli, and that anti-inflammatory cytokines down-regulate the production of this chemokine. These results may have important therapeutic implications for certain central nervous system insults involving inflammation.
Cutting Edge: Impaired Mast Cell Development and Innate Immunity in Mac-1 (CD11b/CD18, CR3)-Deficient Mice
Authors: Rosenkranz Alexander R. , Coxon Angela , Maurer Marcus , Gurish Michael F. , Austen K. Frank , Friend Daniel S. , Galli Stephen J. , Mayadas Tanya N. 
Published: December 2022

AbstractMac-1 (CD11b/CD18, CR3), a β2 integrin expressed on leukocytes, is important in leukocyte migration. We demonstrate that Mac-1 is also expressed on peritoneal mast cells and LPS stimulated bone marrow-derived cultured mast cells, and that Mac-1-deficient mice, which lack this receptor, have significant reductions in the numbers of mast cells resident in the peritoneal cavity, peritoneal wall, and dorsal skin. The reduced numbers of mast cells in Mac-1-deficient mice may have important functional consequences, in that Mac-1-deficient mice exhibit significantly increased mortality after cecal ligation and puncture, a model of acute septic peritonitis in which host resistance has been shown to be dependent on both mast cells and complement. These findings demonstrate that Mac-1 is required for the expression of normal levels of mast cells in the peritoneal cavity, peritoneal wall, and certain areas of the skin, as well as for maintaining adequate mast cell-dependent host defense against bacterial infection.
MHC Class I Mosaic Mice Reveal Insights into Control of Ly49C Inhibitory Receptor Expression in NK Cells
Authors: Andersson Malena , Freland Sofia , Johansson Maria H. , Wallin Robert , Sandberg Johan K. , Chambers Benedict J. , Christensson Birger , Lendahl Urban , Lemieux Suzanne , Salcedo Margarita , Ljunggren Hans-Gustaf 
Published: December 2022

AbstractWe have analyzed lymphocyte development in natural MHC class I chimeric mice, generated through a transgenic approach in β2-microglobulin (β2m)−/− mice. In these mice, MHC class I+ cells coexist with an equal proportion of MHC class I-deficient cells. These MHC class I mosaic mice had normal numbers of CD8+ T cells, which had a target cell specificity similar to that of wild-type mice. Consequently, the mice did not develop any signs of autoimmunity. They also had normal numbers of NK cells. This allowed an examination of the MHC class I influence on the expression of the Ly49C inhibitory receptor on NK cells. This receptor binds to H-2Kb. It is expressed at low levels on NK cells in wild-type mice of the H-2b haplotype, but at markedly higher levels on NK cells in β2m−/− mice and other strains of mice lacking expression of H-2Kb. Relatively little is known about how MHC class I molecules affect expression of the Ly49 receptors. Through the analysis of the present MHC class I mosaic mice, we demonstrate that the expression levels of Ly49C on NK cells is a consequence not only of MHC class I expression in the environment, but also of the expression of MHC class I molecules by the NK cells themselves. These findings are discussed in relation to the biological role of the calibration of the Ly49 inhibitory receptor expression in relation to self-MHC class I.