bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity
Authors: Shimizu Jun , Yamazaki Sayuri , Sakaguchi Shimon 
Published: December 2022

AbstractThis study shows that removal of a T cell subpopulation can evoke effective tumor immunity in otherwise nonresponding animals. Elimination of CD25-expressing T cells, which constitute 5–10% of peripheral CD4+ T cells in normal naive mice, elicited potent immune responses to syngeneic tumors in vivo and eradicated them. The responses were mediated by tumor-specific CD8+ CTLs and tumor-nonspecific CD4−8− cytotoxic cells akin to NK cells. Furthermore, in vitro culture of CD25+4+ T cell-depleted splenic cell suspensions prepared from tumor-unsensitized normal mice led to spontaneous generation of similar CD4−8− cytotoxic cells capable of killing a broad spectrum of tumors; reconstitution of CD25+4+ T cells inhibited the generation. In this culture, self-reactive CD25−4+ T cells responding to self peptides/class II MHC complexes on APCs spontaneously proliferated upon removal of CD25+4+ T cells, secreting large amounts of IL-2. The IL-2 thus produced appeared to be responsible for the generation of CD4−8− NK cells as lymphokine-activated killer cells, because direct addition of an equivalent amount of IL-2 to the culture of CD4−8− cells generated similar lymphokine-activated killer/NK cells, whereas coculture of normal CD4−8− cells with CD25−4+ T cells from IL-2-deficient mice did not. Thus, removal of immunoregulatory CD25+4+ T cells can abrogate immunological unresponsiveness to syngeneic tumors in vivo and in vitro, leading to spontaneous development of tumor-specific effector cells as well as tumor-nonspecific ones. This novel way of evoking tumor immunity would help to devise effective immunotherapy for cancer in humans.
Generation of Mature Dendritic Cells from a CD14+ Cell Line (XS52) by IL-4, TNF-α, IL-1β, and Agonistic Anti-CD40 Monoclonal Antibody
Authors: Yamada Nobuo , Katz Stephen I. 
Published: December 2022

AbstractWe established a model system to generate mature dendritic cells (DC) from a GM-CSF-dependent cell line, XS52, which had been isolated from the epidermis of newborn BALB/c mice. Screening of various soluble factors revealed that IL-4 induces phenotypic maturation of XS52 (as evaluated by enhanced expression of class II, CD40, CD80, CD86, CD11c, and loss of expression of CD14) in a time-dependent manner. The addition of TNF-α, IL-1β, and agonistic anti-CD40 mAb further enhanced expression of these maturation markers. Consistent with their phenotypic maturation, these cells (termed XS-DC) exhibited potent Ag-presenting capacity to both naive and primed T cells. In addition, injection of hapten-conjugated XS-DC induced contact hypersensitivity in vivo, suggesting their potential as tools for vaccination. Expression of CD14 by the starting cell population, the requirement for GM-CSF and IL-4, and the relatively long culture period are the common characteristics shared between our cells and human monocyte-derived DC, whose analogues in mice have not been identified. Because large numbers of skin-associated mature DC devoid of other cell lineages are easily obtained, this model system may facilitate the study of molecular events associated with maturation of DC and the use of DC for immunization.
Primary Human CD4+ T Cells Contain Heterogeneous IκB Kinase Complexes: Role in Activation of the IL-2 Promoter
Authors: Khoshnan Ali , Kempiak Stephan J. , Bennett Brydon L. , Bae David , Xu Weiming , Manning Anthony M. , June Carl H. , Nel Andre E. 
Published: December 2022

AbstractNF-κB transcription factors play an important role in the activation of the IL-2 gene in response to TCR ligation. The release of NF-κB factors to the nucleus requires phosphorylation and degradation of the inhibitory κ-B proteins (IκBs). IκBα and IκBβ phosphorylation is dependent on dual signaling by the TCR and the CD28 accessory receptor. This pathway involves a multisubunit IκB kinase (IKK) complex, which includes the IKKα (IKK-1) and IKKβ (IKK-2) kinases. We demonstrate that stimulation of primary human CD4+ T cells by CD3/CD28 activates two distinct endogenous IKK complexes, a heterodimeric IKKα/β and a homodimeric IKKβ complex. IKKβ overexpression in a Jurkat cell line resulted in the formation of a constitutively active IKK complex, which was CD3/CD28 inducible. In contrast, ectopic expression of IKKα assembled into a complex with negligible IκB kinase activity. Moreover, IKKβ, but not IKKα, overexpression enhanced transcriptional activation of the CD28 response element in the IL-2 promoter. Conversely, only kinase-inactive IKKβ interfered in the activation of the IL-2 promoter. Sodium salicylate, an inhibitor of IKKβ, but not IKKα, activity, inhibited IL-2 promoter activation as well as IL-2 secretion and interfered in activation of both the heterodimeric as well as the homodimeric IKK complexes in primary CD4+ T cells. Taken together, these data demonstrate the presence of an IKKβ-mediated signaling pathway that is activated by TCR and CD28 coligation and regulates IL-2 promoter activity.
Inducible Nitric Oxide Synthase Protection Against Coxsackievirus Pancreatitis
Authors: Zaragoza Carlos , Ocampo Christopher J. , Saura Marta , Bao Clare , Leppo Michelle , Lafond-Walker Anne , Thiemann David R. , Hruban Ralph , Lowenstein Charles J. 
Published: December 2022

Abstract
Coxsackievirus infection causes myocarditis and pancreatitis in humans. In certain strains of mice, Coxsackievirus causes a severe pancreatitis. We explored the role of NO in the host immune response to viral pancreatitis. Coxsackievirus replicates to higher titers in mice lacking NO synthase 2 (NOS2) than in wild-type mice, with particularly high viral titers and viral RNA levels in the pancreas. Mice lacking NOS have a severe, necrotizing pancreatitis, with elevated pancreatic enzymes in the blood and necrotic acinar cells. Lack of NOS2 leads to a rapid increase in the mortality of infected mice. Thus, NOS2 is a critical component in the immune response to Coxsackievirus infection.
CD8+ T Cells Modulate Late Allergic Airway Responses in Brown Norway Rats
Authors: Suzuki Masaru , Taha Rame , Ihaku Daizo , Hamid Qutayba , Martin James G. 
Published: December 2022

AbstractTo test the hypothesis that CD8+ T cells may suppress the allergen-induced late airway response (LAR) and airway eosinophilia, we examined the effect of administration of Ag-primed CD8+ T cells on allergic airway responses, bronchoalveolar lavage (BAL) leukocytes, and mRNA expression for cytokines (IL-4, IL-5, and IFN-γ) in OVA-sensitized Brown Norway rats. On day 12 postsensitization to OVA, test rats were administered 2 million CD8+ T cells i.p. isolated from either the cervical lymph nodes (LN group; n = 8) or the spleen (Spl group; n = 6) of sensitized donors. On day 14, test rats were challenged with aerosolized OVA. Control rats were administered PBS i.p. on day 12, and challenged with OVA (n = 10) or BSA (n = 6) on day 14. The lung resistance was measured for 8 h after challenge. BAL was performed at 8 h. Cytospin slides of BAL were analyzed for major basic protein by immunostaining and for cytokine mRNA by in situ hybridization. The LAR was significantly less in the LN group (1.8 ± 0.5 U; p &lt; 0.01) and BSA controls (1.4 ± 0.7; p &lt; 0.01), but not in the Spl group (6.7 ± 2.2), compared with that in OVA controls (8.1 ± 1.8). In BAL, the number of major basic protein-positive cells was lower in the LN and Spl groups compared with OVA controls (p &lt; 0.05 and p &lt; 0.01). IL-4- and IL-5-positive cells were decreased in the LN group compared with the OVA controls (p &lt; 0.01). INF-γ-positive cells were increased in the LN and Spl groups compared with the OVA controls (p &lt; 0.01). Serum OVA-specific IgE levels were unaffected by CD8+ T cell transfers. These results indicate that Ag-primed CD8+ T cells have a potent suppressive effect on LAR.
Alloantibody-Mediated Class I Signal Transduction in Endothelial Cells and Smooth Muscle Cells: Enhancement by IFN-γ and TNF-α
Authors: Bian Hong , Reed Elaine F. 
Published: December 2022

AbstractChronic rejection is the major limiting factor to long term survival of solid organ allografts. The hallmark of chronic rejection is transplant atherosclerosis, which is characterized by the intimal proliferation of smooth muscle cells, endothelial cells, and fibroblasts, leading to vessel obstruction, fibrosis, and eventual graft loss. The mechanism of chronic rejection is poorly understood, but it is suspected that the associated vascular changes are a result of anti-HLA Ab-mediated injury to the endothelium and smooth muscle of the graft. In this study we have investigated whether anti-HLA Abs, developed by transplant recipients following transplantation, are capable of transducing signals via HLA class I molecules, which stimulate cell proliferation. In this report we show that ligation of class I molecules with Abs to distinct HLA-A locus and HLA-B locus molecules results in increased tyrosine phosphorylation of intracellular proteins and induction of fibroblast growth factor receptor expression on endothelial and smooth muscle cells. Treatment of cells with IFN-γ and TNF-α up-regulated MHC class I expression and potentiated anti-HLA Ab-induced fibroblast growth factor receptor expression. Engagement of class I molecules also stimulated enhanced proliferative responses to basic fibroblast growth factor, which augmented endothelial cell proliferation. These findings support a role for anti-HLA Abs and cytokines in the transduction of proliferative signals, which stimulate the development of myointimal hyperplasia associated with chronic rejection of human allografts.
Highly Th2-Skewed Cytokine Profile of β-Lactam-Specific T Cells from Nonatopic Subjects with Adverse Drug Reactions
Authors: Brugnolo Francesca , Annunziato Francesco , Sampognaro Salvatore , Campi Paolo , Manfredi Mariangela , Matucci Andrea , Blanca Miguel , Romagnani Sergio , Maggi Enrico , Parronchi Paola 
Published: December 2022

Abstract
A positive lymphocyte transformation test to β-lactams (β-L) was found in 12 of 29 subjects with adverse drug reaction (ADR) to β-L, irrespective of either the type of clinical manifestation or the presence of specific serum IgE. Short-term T cell lines specific for penicillin G, amoxicillin, and ampicillin could be generated only from subjects with ADR (eight with positive and one with negative lymphocyte transformation test), while streptokinase and Dermatophagoides pteronyssinus group 1 (Der p 1)-specific T cells were obtained from all these subjects, from 7 atopic Der p-sensitive donors without history of ADR and 17 healthy nonatopic donors. Streptokinase-specific T cells from all subjects showed intracellular expression of IFN-γ with poor or no IL-4, whereas Der p 1-specific T cells exhibited IFN-γ but low or no IL-4 expression in nonatopics, and remarkable IL-4 expression in atopic donors. By contrast, all penicillin G-, ampicillin-, and amoxicillin-specific short-term T cell lines showed high intracellular expression of IL-4, IL-5, and IL-13, but poor or no expression of IFN-γ, thus exhibiting a clear-cut Th2 profile. Accordingly, most penicillin G-specific T cell clones derived from two subjects with ADR released high concentrations of IL-4 alone or IL-4 and IFN-γ. These data suggest that cytokines produced by Th2 cells play an important role in all β-L-induced ADR, even when late clinical manifestations occur and an IgE-mediated mechanism is apparently indemonstrable.
Cutting Edge: Combined Treatment of TNF-α and IFN-γ Causes Redistribution of Junctional Adhesion Molecule in Human Endothelial Cells
Authors: Ozaki Harunobu , Ishii Kenji , Horiuchi Hisanori , Arai Hidenori , Kawamoto Takahiro , Okawa Katsuya , Iwamatsu Akihiro , Kita Toru 
Published: December 2022

AbstractProinflammatory cytokines such as TNF-α and IFN-γ induce cell adhesion molecules in endothelial cells and promote transmigration of leukocytes across endothelial cells. However, when those two were administered together, leukocyte transmigration paradoxically decreased. We cloned a human and bovine homologue of the junctional adhesion molecule (JAM), a novel molecule at the tight junction, and examined the effects of proinflammatory cytokines on JAM in HUVECs. The combined treatment of TNF-α plus IFN-γ caused a disappearance of JAM from intercellular junctions. However, flow cytometry, cell ELISA, and subcellular fractionation analysis demonstrated that the amount of JAM was not reduced. This suggested that JAM changed its distribution in response to proinflammatory cytokines. This redistribution of JAM might be involved in a decrease in transendothelial migration of leukocytes at inflammatory sites.
Cutting Edge: Purinergic Signaling Regulates Radical-Mediated Bacterial Killing Mechanisms in Macrophages Through a P2X7-Independent Mechanism
Authors: Sikora Andrew , Liu Judy , Brosnan Celia , Buell Gary , Chessel Iain , Bloom Barry R. 
Published: December 2022

Abstract
Signaling by extracellular nucleotides through P2 purinergic receptors affects diverse macrophage functions; however, its role in regulating antimicrobial radicals during bacterial infection has not been investigated. Mycobacterium tuberculosis-infected macrophages released ATP in a dose-dependent manner, which correlated with nitrite accumulation. P2 receptor inhibitors, including oxidized ATP, blocked NO synthase (NOSII) up-regulation and NO production induced by infection with M. tuberculosis or bacille Calmette-Guérin, or treatment with LPS or TNF-α. Oxidized ATP also inhibited oxygen radical production and activation of NF-κB and AP-1 in response to infection and inhibited NO-dependent killing of bacille Calmette-Guérin by macrophages. Experiments using macrophages derived from P2X7 gene-disrupted mice ruled out an essential role for P2X7 in NOSII regulation. These data demonstrate that P2 receptors regulate macrophage activation in response to bacteria and proinflammatory stimuli, and suggest that extracellular nucleotides released from infected macrophages may enhance production of oxygen radicals and NO at sites of infection.
Cas-L Is Required for β1 Integrin-Mediated Costimulation in Human T Cells
Authors: Kamiguchi Kenjiro , Tachibana Kouichi , Iwata Satoshi , Ohashi Yoshiyuki , Morimoto Chikao 
Published: December 2022

Abstractβ1 integrins provide a costimulus for TCR/CD3-driven T cell activation and IL-2 production in human peripheral T cells. However, this β1 integrin-mediated costimulation is impaired in a human T lymphoblastic line, Jurkat. We studied the molecular basis of this impaired costimulation and found that Cas-L, a 105-kDa docking protein, is marginally expressed in Jurkat T cells, whereas Cas-L is well expressed in peripheral T cells. Cas-L is a binding protein and a substrate for focal adhesion kinase and is tyrosine phosphorylated by β1 integrin stimulation. We here show that the transfection of wild-type Cas-L in Jurkat T cells restores β1 integrin-mediated costimulation. However, Cas-L transfection had no effect on CD28-mediated costimulation, indicating that Cas-L is specifically involved in the β1 integrin-mediated signaling pathway. Furthermore, transfection of the Cas-LΔSH3 mutant failed to restore β1 integrin-mediated costimulation in Jurkat cells. Cas-LΔSH3 mutant lacks the binding site for focal adhesion kinase and is not tyrosine phosphorylated after β1 integrin stimulation. These findings strongly suggest that the tyrosine phosphorylation of Cas-L plays a key role in the signal transduction in the β1 integrin-mediated T cell costimulation.
How Specific Should Immunological Memory Be?
Authors: Borghans José A. M. , Noest André J. , De Boer Rob J. 
Published: December 2022

AbstractProtection against infection hinges on a close interplay between the innate immune system and the adaptive immune system. Depending on the type and context of a pathogen, the innate system instructs the adaptive immune system to induce an appropriate immune response. Here, we hypothesize that the adaptive immune system stores these instructions by changing from a naive to an appropriate memory phenotype. In a secondary immune reaction, memory lymphocytes adhere to their instructed phenotype. Because cross-reactions with unrelated Ags can be detrimental, such a qualitative form of memory requires a sufficient degree of specificity of the adaptive immune system. For example, lymphocytes instructed to clear a particular pathogen may cause autoimmunity when cross-reacting with ignored self molecules. Alternatively, memory cells may induce an immune response of the wrong mode when cross-reacting with subsequent pathogens. To maximize the likelihood of responding to a wide variety of pathogens, it is also required that the immune system be sufficiently cross-reactive. By means of a probabilistic model, we show that these conflicting requirements are met optimally by a highly specific memory lymphocyte repertoire. This explains why the lymphocyte system that was built on a preserved functional innate immune system has such a high degree of specificity. Our analysis suggests that 1) memory lymphocytes should be more specific than naive lymphocytes and 2) species with small lymphocyte repertoires should be more vulnerable to both infection and autoimmune diseases.
Immune System Development and Function in Prolactin Receptor-Deficient Mice
Authors: Bouchard Brigitte , Ormandy Christopher J. , Di Santo James P. , Kelly Paul A. 
Published: December 2022

AbstractProlactin (PRL) is the primary lactogenic pituitary hormone that plays an essential role in many aspects of reproduction, from fertilization to mammary gland development and maternal behavior. PRL has also been reported to play a role in immunoregulation. Because initial observations indicated that hypophysectomized rats present abnormalities of the immune system, including increased thymic atrophy and lymphopenia, a number of studies have focused on the potential immunomodulatory roles of PRL. This hormone exerts its biological activities following binding to specific cell surface PRL receptors (PRLRs). In this report, we have characterized the development and function of the immune system in PRLR-deficient mice. Compared with wild-type control mice, PRLR−/− mice demonstrate no alterations in thymic or splenic cellularity or in the composition of the lymphocyte subsets present in primary (bone marrow and thymus) or secondary (spleen and lymph nodes) lymphoid organs. Lymphocytes from PRLR−/− mice are functional in vitro, as they can proliferate normally to mitogens, cytokines, and allogeneic cells. PRLR−/− splenocytes display normal NK-mediated cytotoxicity to YAC-1 target cells. In vivo studies have revealed that PRLR−/− mice are able to 1) generate normal steady-state Ig levels, 2) mount a normal specific Ig response following immunization with a T-dependent Ag, 3) eliminate injected allogeneic tumor cells, and 4) effectively control Listeria monocytogenes infection. Taken together, these results show that immune system development and function proceed normally in the absence of PRL-mediated signaling and suggest that PRLR pathways are not essential for immunomodulation in vivo.
The Transcription Factors Elf-1 and GATA-1 Bind to Cell-Specific Enhancer Elements of Human High-Affinity IgE Receptor α-Chain Gene
Authors: Nishiyama Chiharu , Yokota Toyokazu , Okumura Ko , Ra1 Chisei 
Published: December 2022

AbstractKey regulatory regions necessary for the expression of the gene encoding FcεRI α-chain, a component of the high-affinity IgE receptor primarily responsible for IgE-dependent allergic response, were investigated. Two regions, −74/−69 and −55/−47, which contained binding motifs for proteins belonging to the Ets family and the GATA family, respectively, were shown to be necessary for the activation of the α-chain promoter. Both the regulatory elements enhanced the promoter activity only in α-chain-producing cells PT18 and RBL-2H3 (mast cell lines), indicating that the elements required specific trans-acting proteins present in the α-chain-producing cells. EMSA using nuclear extracts and in vitro-translated proteins revealed that Elf-1 and GATA-1 bound to the enhancer elements. This is the first report describing the regulation in the expression of the FcεRI α-chain.
ICAM-1-Coupled Signaling Pathways in Astrocytes Converge to Cyclic AMP Response Element-Binding Protein Phosphorylation and TNF-α Secretion
Authors: Etienne-Manneville Sandrine , Chaverot Nathalie , Strosberg A. Donny , Couraud Pierre-Olivier 
Published: December 2022

Abstract
In the CNS, astrocytes play a key role in immunological and inflammatory responses through ICAM-1 expression, cytokine secretion (including TNF-α), and regulation of blood-brain barrier permeability. Because ICAM-1 transduces intracellular signals in lymphocytes and endothelial cells, we investigated in the present study ICAM-1-coupled signaling pathways in astrocytes. Using rat astrocytes in culture, we report that ICAM-1 binding by specific Abs induces TNF-α secretion together with phosphorylation of the transcription factor cAMP response element-binding protein. We show that ICAM-1 binding induces cAMP accumulation and activation of the mitogen-activated protein kinase extracellular signal-regulated kinase. Both pathways are responsible for cAMP response element-binding protein phosphorylation and TNF-α secretion. Moreover, these responses are partially dependent protein kinase C, which acts indirectly, as a common activator of cAMP/protein kinase A and extracellular signal-regulated kinase pathways. These results constitute the first evidence of ICAM-1 coupling to intracellular signaling pathways in glial cells and demonstrate the convergence of these pathways onto transcription factor regulation and TNF-α secretion. They strongly suggest that ICAM-1-dependent cellular adhesion to astrocytes could contribute to the inflammatory processes observed during leukocyte infiltration in the CNS.
Phenotypic Identification of Antigen-Dependent and Antigen-Independent CD8 CTL Precursors in the Draining Lymph Node During Acute Cutaneous Herpes Simplex Virus Type 1 Infection
Authors: McNally James M. , Dempsey Deborah , Wolcott R. Michael , Chervenak Robert , Jennings Stephen R. 
Published: December 2022

AbstractOptimal immunological control of cutaneous herpes simplex virus type 1 (HSV-1) infections initiated in the hind footpad of C57BL/6 (B6, H-2b) mice is dependent upon the presence of functional HSV-1-specific T lymphocytes. The class I MHC-restricted, CD8+ T cell subpopulation is involved in the clearance of infectious HSV-1 from the skin and limiting HSV-1 replication and spread within the peripheral nervous system. However, the frequency of HSV-1-specific CTL precursors (CTLp), as a measure of potential anti-viral CD8+ T cell function, is relatively low compared with other acute viral infections. To gain insight into the basis for this low functional frequency, changes in the CD8+ T cell subpopulation phenotype associated with activation and differentiation were investigated. Analysis of the phenotypic changes showed that HSV-1-specific CTLp were found predominantly within a subpopulation of CD8+ T cells expressing high levels of CD44 (CD44high) and high levels of the IL-2 receptor α-chain (CD25high). A second activated subpopulation of CD8+ T cells expressing the CD44high CD25low phenotype did not contain detectable HSV-1-specific CTLp, even after the addition of HSV-1-infected stimulator cells as a source of an exogenous Ag. These data suggested that HSV-1-specific CD8+ T cells must increase expression of CD25 before attaining the potential to become CTL effector cells. These findings also indicated that the up-regulation of CD44 alone is not sufficient to identify precisely HSV-1-specific CD8+ T cells.