bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct In Vivo and In Vitro Cytokine Profiles of Draining Lymph Node Cells in Acute and Chronic Phases of Contact Hypersensitivity: Importance of a Type 2 Cytokine-Rich Cutaneous Milieu for the Development of an Early-Type Response in the Chronic Phase
Authors: Kitagaki Hideki , Kimishima Momoko , Teraki Yuichi , Hayakawa Jun , Hayakawa Kazuhito , Fujisawa Shigeki , Shiohara Tetsuo 
Published: December 2022

AbstractAlthough regional lymph nodes (LN) have been extensively studied as rich sources of effector T cells in contact hypersensitivity (CH), it remains unknown whether T cell responses in the LN reflect those in effector skin sites. We previously showed that repeated elicitation of CH results in a shift in the time course of Ag-specific CH from a delayed-type hypersensitivity response to an early-type response, a reflection of a shift in cutaneous cytokine expression from a type 1 to a type 2 profile. To investigate whether repeated elicitation of CH could also drive T cell development to the type 2 phenotype in the regional draining LN, sequential cytokine gene expression after hapten application was assessed during both the acute and the chronic phase of CH. In the draining LN the shift to type 2 cytokine production was also observed, but more mixed patterns of responses were induced than in the corresponding skin sites. The chronic LN cells (LNC), when stimulated in vitro, produced markedly lower levels of type 1 cytokines and higher levels of type 2 cytokines than the acute LNC. A successful passive transfer of an early-type response by the LNC was only induced in the recipient mice when the skin sites chronically treated with hapten were elicited. These results indicate that an early-type response by regional LNC would take place only in a milieu with sufficient levels of type 2 cytokines.
B Cell Responses to a Peptide Epitope. VIII. Immune Complex-Mediated Regulation of Memory B Cell Generation Within Germinal Centers
Authors: Nayak Bishnu P. , Agarwal Anshu , Nakra Pooja , Rao Kanury V. S. 
Published: December 2022

AbstractUsing an in vivo reconstitution assay, we examine here the role of immune complexes in both formation of germinal centers (GC) and processes that occur subsequently within. The presence of Ag, as immune complexes, was found not to constitute a limiting requirement for the initiation of GC formation. No detrimental effect either on numbers or sizes of the resulting GC was observed when Ag-containing immune complexes were omitted during reconstitution. Thus, both recruitment and proliferation of Ag-activated B cells within GC appear not to be limited by Ag concentrations. In contrast, the presence of immune complexes was observed to be obligatory for the generation of Ag-specific memory B cells. This optimally required immune complexes to be constituted by IgG-class Abs with epitope specificities that were homologous to those of the GC B cells. The GC reaction was also found to be characterized by an enhancement of Ab specificity for the homologous epitope. Although some improvement in specificity was noted in recall responses from immune complex-deficient GC, the presence of appropriate immune complexes served to further optimize the outcome. Here again, isotype and epitope-specificity of the Ab constituent in immune complexes proved to be important.
TNF-α Suppresses IFN-γ-Induced MHC Class II Expression in HT1080 Cells by Destabilizing Class IItrans-Activator mRNA
Authors: Han Yulong , Zhou Z-H. Lucy , Ransohoff Richard M. 
Published: December 2022

AbstractPrecise regulation of MHC class II gene expression is crucial for development and function of the immune system. Class II trans-activator (CIITA) has been shown to be required for constitutive and IFN-γ-induced MHC class II transcription. TNF-α is commonly coexpressed with IFN-γ during immune-mediated inflammatory responses and modulates IFN-γ-stimulated MHC class II expression. The effect of TNF-α on MHC class II expression depends on cell type and cellular differentiation state. We show here that TNF-α suppresses IFN-γ-induced CIITA mRNA accumulation, resulting in decreased MHC class II expression in human fibrosarcoma HT1080 cells. TNF-α also inhibits CIITA mRNA accumulation and protein expression in a tetracycline-regulated system without affecting promoter activity. CIITA mRNA, regulated by either IFN-γ or tetracycline, was destabilized in the presence of TNF-α, suggesting that TNF-α utilizes a distinct mechanism to suppress MHC class II expression in HT1080 cells. Consistent with this interpretation, TNF-α blocked IFN-γ-induced CIITA and MHC class II expression in mutant cells that are unresponsive to TGF-β or IFN-β. This is the first instance in which MHC class II expression is inhibited by destabilizing CIITA mRNA.
Apparent MHC-Independent Stimulation of CD8+ T Cells In Vivo During Latent Murine Gammaherpesvirus Infection
Authors: Coppola Michael A. , Flaño Emilio , Nguyen Phuong , Hardy Charles L. , Cardin Rhonda D. , Shastri Nilabh , Woodland David L. , Blackman Marcia A. 
Published: December 2022

AbstractLike EBV-infected humans with infectious mononucleosis, mice infected with the rodent gammaherpesvirus MHV-68 develop a profound increase in the number of CD8+ T cells in the circulation. In the mouse model, this lymphocytosis consists of highly activated CD8+ T cells strikingly biased toward Vβ4 TCR expression. Moreover, this expansion of Vβ4+CD8+ T cells does not depend on the MHC haplotype of the infected animal. Using a panel of lacZ-inducible T cell hybridomas, we have detected Vβ4-specific T cell stimulatory activity in the spleens of MHV-68-infected mice. We show that the appearance and quantity of this activity correlate with the establishment and magnitude of latent viral infection. Furthermore, on the basis of Ab blocking studies as well as experiments with MHC class II, β2-microglobulin (β2m) and TAP1 knockout mice, the Vβ4-specific T cell stimulatory activity does not appear to depend on conventional presentation by classical MHC class I or class II molecules. Taken together, the data indicate that during latent infection, MHV-68 may express a T cell ligand that differs fundamentally from both conventional peptide Ags and classical viral superantigens.
Increased Susceptibility of TNF-α Lymphotoxin-α Double Knockout Mice to Systemic Candidiasis Through Impaired Recruitment of Neutrophils and Phagocytosis ofCandida albicans
Authors: Netea Mihai G. , van Tits Lambertus J. H. , Curfs Jo H. A. J. , Amiot Franck , Meis Jacques F. G. M. , van der Meer Jos W. M. , Kullberg Bart Jan 
Published: December 2022

AbstractTNF-α and lymphotoxin-α (LT) are members of the TNF family, and these cytokines play crucial roles in the defense against infection with Candida albicans. The aim of the present study was to investigate the role of endogenous TNF and LT during disseminated candidiasis in TNF−/−LT−/− knockout mice. The TNF- and LT-deficient animals had a significantly increased mortality following C. albicans infection compared with control mice, and this was due to a 10- to 1000-fold increased outgrowth of the yeast in their organs. No differences between TNF−/−LT−/− mice and TNF+/+LT+/+ were observed when mice were rendered neutropenic, suggesting that activation of neutrophils mediates the beneficial effects of endogenous TNF and LT. Histopathology of the organs, combined with neutrophil recruitment experiments, showed a dramatic delay in the neutrophil recruitment at the sites of Candida infection in the TNF−/−LT−/− mice. Moreover, the neutrophils of deficient animals were less potent to phagocytize Candida blastospores than control neutrophils. In contrast, the killing of Candida and the oxygen radical production did not differ between neutrophils of TNF−/−LT−/− and TNF+/+LT+/+ mice. Peak circulating IL-6 was significantly higher in TNF−/−LT−/− mice during infection. Peritoneal macrophages of TNF−/−LT−/− mice did not produce TNF, and synthesized significantly lower amounts of IL-1α, IL-1β, IL-6, and macrophage-inflammatory protein-1α than macrophages of TNF+/+LT+/+ animals did. In conclusion, endogenous TNF and/or LT contribute to host resistance to disseminated candidiasis, and their absence in TNF−/−LT−/− mice renders the animals susceptible through impaired recruitment of neutrophils and impaired phagocytosis of C. albicans.
IL-12 Is Dysregulated in Macrophages from IRF-1 and IRF-2 Knockout Mice
Authors: Salkowski Cindy A. , Kopydlowski Karen , Blanco Jorge , Cody M. Joshua , McNally Ranney , Vogel Stefanie N. 
Published: December 2022

AbstractMacrophages derived from IFN-regulatory factor-1 (IRF-1) and IRF-2 knockout (−/−) and wild-type (+/+) mice were utilized to examine the role of these transcription factors in the regulation of IL-12 mRNA and protein expression. Induction of IL-12 p40 mRNA by LPS was markedly diminished in both IRF-1−/− and IRF-2−/− macrophages. In contrast, IRF-1−/−, but not IRF-2−/−, macrophages exhibited impaired LPS-induced IL-12 p35 mRNA expression. The ability of IFN-γ to augment LPS-induced IL-12 p40 mRNA further when both stimuli were present simultaneously was significantly diminished in both IRF-1−/− and IRF-2−/− macrophages, with the most profound impairment observed for IRF-1−/− macrophages. Reductions in IL-12 mRNA expression after stimulation with LPS or LPS plus IFN-γ were accompanied by substantial reductions in IL-12 p40 and IL-12 p70 protein in both IRF-1−/− and IRF-2−/− macrophages. Priming IRF-1−/− and IRF-2−/− macrophages with IFN-γ for 24 h before LPS treatment partially restored impaired IL-12 mRNA and protein production in both IRF-1−/− and IRF-2−/− macrophages. Depressed IL-12 levels were paralleled by significant reductions in IFN-γ mRNA expression in IRF-1−/− and IRF-2−/− macrophages. These results indicate that both IRF-1 and IRF-2 are critical transcription factors in the regulation of macrophage IL-12 and consequently IFN-γ production.
Activation of Mitogen-Activated Protein Kinase Regulates Eotaxin-Induced Eosinophil Migration
Authors: Boehme Stefen A. , Sullivan Sue K. , Crowe Paul D. , Santos Mark , Conlon Paul J. , Sriramarao P. , Bacon Kevin B. 
Published: December 2022

AbstractEotaxin is a potent eosinophil chemoattractant that plays an important role in regulating eosinophil tissue levels both in healthy individuals and in diseases associated with significant eosinophil infiltrates, such as the allergic inflammation observed in asthma. Here, we demonstrate that treatment of eosinophils with eotaxin induces the phosphorylation of the mitogen-activated protein kinases (MAPKs) p42 and p44, leading to kinase activation. Blockade of MAPK activation by the MAPK kinase inhibitor PD98059 leads to a dramatic decrease in eotaxin-induced eosinophil rolling in vivo and chemotaxis in vitro. This blockade in the leukocyte migration process is consistent with the observed inhibition of actin polymerization and rearrangement within the eosinophil following treatment with MAPK inhibitor. It is suggested, therefore, that the intrinsic mechanism of eotaxin-induced eosinophil rolling and migration involves activation of the p42/p44 MAPK, possibly through regulation of the cytoskeletal rearrangements necessary for chemotaxis.
Cutting Edge: Blockade of the CD28/B7 Costimulatory Pathway Inhibits Intestinal Allograft Rejection Mediated by CD4+ But Not CD8+ T Cells
Authors: Newell Kenneth A. , He Gang , Guo Zhong , Kim Oliver , Szot Gregory L. , Rulifson Ingrid , Zhou Ping , Hart John , Thistlethwaite J. Richard , Bluestone Jeffrey A. 
Published: December 2022

AbstractThe effect of blocking the CD28/B7 costimulatory pathway on intestinal allograft rejection was examined in mice. Murine CTLA4Ig failed to prevent the rejection of allografts transplanted into wild-type or CD4 knockout (KO) mice but did inhibit allograft rejection by CD8 KO recipients. This effect was associated with decreased intragraft mRNA for IFN-γ and TNF-α and increased mRNA for IL-4 and IL-5. This altered pattern of cytokine production was not observed in allografts from murine CTLA4Ig-treated CD4 KO mice. These data demonstrate that blockade of the CD28/B7 pathway has different effects on intestinal allograft rejection mediated by CD4+ and CD8+ T cells and suggest that these T cell subsets have different costimulatory requirements in vivo. The results also suggest that the inhibition of CD4+ T cell-mediated allograft rejection by CTLA4Ig may be related to down-regulation of Th1 cytokines and/or up-regulation of Th2 cytokines.
Cutting Edge: A Novel Mechanism for Rescue of B Cells from CD95/Fas-Mediated Apoptosis
Authors: Catlett Ian M. , Bishop Gail A. 
Published: December 2022

AbstractCD95-induced apoptosis contributes to the maintenance of homeostasis in both B and T lymphocyte-mediated immunity. B cells increase CD95 expression in response to activation signals and become susceptible to CD95-induced apoptosis. Protection from CD95-mediated death signals can be induced in mature B cells by signals delivered through the B cell Ag receptor. In this paper we demonstrate for the first time that rescue from apoptosis can occur independently of de novo protein synthesis. This rescue from apoptosis prevents activation of caspase 8, the apical caspase in the CD95 death pathway, and CD95-FADD (Fas-associated death domain containing protein) association does not occur normally. Thus B cell activation signals can biochemically modify proximal elements of the CD95 death pathway and regulate the sensitivity of cells to apoptosis induction at an early stage in programmed cell death.
Cutting Edge: Inhibition of Experimental Tumor Metastasis by Dendritic Cells Pulsed with α-Galactosylceramide
Authors: Toura Isao , Kawano Tetsu , Akutsu Yasunori , Nakayama Toshinori , Ochiai Takenori , Taniguchi Masaru 
Published: December 2022

Abstract
A unique lymphoid lineage, Vα14 NKT cells, bearing an invariant Ag receptor encoded by Vα14 and Jα281 gene segments, play crucial roles in various immune responses, including protective immunity against malignant tumors. A specific ligand of Vα14 NKT cells is determined to be α-galactosylceramide (α-GalCer) which is presented by the CD1d molecule. Here, we report that dendritic cells (DCs) pulsed with α-GalCer effectively induce potent antitumor cytotoxic activity by specific activation of Vα14 NKT cells, resulting in the inhibition of tumor metastasis in vivo. Moreover, a complete inhibition of B16 melanoma metastasis in the liver was observed when α-GalCer-pulsed DCs were injected even 7 days after transfer of tumor cells to syngeneic mice where small but multiple metastatic nodules were already formed. The potential utility of DCs pulsed with α-GalCer for tumor immunotherapy is discussed.
Distribution Fate and Mechanism of Immune Modulation Following Mucosal Delivery of Plasmid DNA Encoding IL-10
Authors: Chun Sangjun , Daheshia Massoud , Lee Sujin , Eo Seong Kug , Rouse Barry T. 
Published: December 2022

AbstractDNA vaccination has been widely studied in several models of vaccination and in the treatment of inflammatory diseases, even though the mechanism involved is still unclear. This report demonstrates that mucosal administration of plasmid DNA leads to rapid and widespread distribution around the body. Dissemination likely occurred via the bloodstream because plasmid DNA was present in blood plasma. The plasmid DNA was also detectable in several tissues including draining lymph nodes, spleen, liver, bone marrow, and even the dermis of ear pinnae. Except for the site of administration, plasmid DNA was no longer detectable in tissues after 3 wk postadministration. RNA and protein expression was also found in the tissues and bloodstream. Animals previously primed by HSV infection and subsequently given IL-10 DNA via the nasal mucosa, showed diminished Ag-induced delayed type hypersensitivity reactions for up to 5 wk posttreatment. The mechanism of modulation involved diminished the Ag-specific proliferation and production of Th1 cytokines. The Ag-specific silencing effects persisted beyond the duration of detectable plasmid encoded protein and was maintained upon adoptive transfer of T cells into a plasmid-free environment. The silenced T cells were not a source of IL-10, and their anergic state was reversible by exposure to Ag in the presence of exogenous IL-2.
Caspase-1 Regulates the Inflammatory Process Leading to Autoimmune Demyelination
Authors: Furlan Roberto , Martino Gianvito , Galbiati Francesca , Poliani Pietro L. , Smiroldo Simona , Bergami Alessendra , Desina Gaetano , Comi Giancarlo , Flavell Richard , Su Michael S. , Adorini Luciano 
Published: December 2022

Abstract
T cell-mediated inflammation is considered to play a key role in the pathogenic mechanisms sustaining multiple sclerosis (MS). Caspase-1, formerly designated IL-1β-converting enzyme, is crucially involved in immune-mediated inflammation because of its pivotal role in regulating the cellular export of IL-1β and IL-18. We studied the role of caspase-1 in experimental autoimmune encephalomyelitis (EAE), the animal model for MS. Caspase-1 is transcriptionally induced during EAE, and its levels correlate with the clinical course and transcription rate of proinflammatory cytokines such as TNF-α, IL-1β, IFN-γ, and IL-6. A reduction of EAE incidence and severity is observed in caspase-1-deficient mice, depending on the immunogenicity and on the amount of the encephalitogenic myelin oligodendrocyte glycoprotein (MOG) peptide used. In caspase-1-deficient mice, reduced EAE incidence correlates with defective development of anti-MOG IFN-γ-producing Th1 cells. Finally, pharmacological blockade of caspase-1 in Biozzi AB/H mice, immunized with spinal cord homogenate or MOG35–55 peptide, by the caspase-1-inhibitor Z-Val-Ala-dl-Asp-fluoromethylketone, significantly reduces EAE incidence in a preventive but not in a therapeutic protocol. These results indicate that caspase-1 plays an important role in the early stage of the immune-mediated inflammatory process leading to EAE, thus representing a possible therapeutic target in the acute phase of relapsing remitting MS.
Direct Neurite-Mast Cell Communication In Vitro Occurs Via the Neuropeptide Substance P
Authors: Suzuki R. , Furuno T. , McKay D. M. , Wolvers D. , Teshima R. , Nakanishi M. , Bienenstock J. 
Published: December 2022

AbstractCommunication between nerves and mast cells is a prototypic demonstration of neuroimmune interaction. However, whether mast cell activation occurs as a direct response to neuronal activation or requires an intermediary cell is unclear. Addressing this issue, we used an in vitro coculture approach comprising cultured murine superior cervical ganglia and rat leukemia basophilic cells (RBLs; possesses properties of mucosal-type mast cells). Following loading with the calcium fluorophore, Fluo-3, neurite-RBL units (separated by &lt;50 nm) were examined by confocal laser scanning microscopy. Addition of bradykinin, or scorpion venom, dose-dependently elicited neurite activation (i.e., Ca2+ mobilization) and, after a lag period, RBL Ca2+ mobilization. Neither bradykinin nor scorpion venom had any direct effect on the RBLs in the absence of neurites. Addition of a neutralizing substance P Ab or a neurokinin (NK)-1 receptor antagonist, but not an NK-2 receptor antagonist, dose-dependently prevented the RBL activation that resulted as a consequence of neural activation by either bradykinin or scorpion venom. These data illustrate that nerve-mast cell cross-talk can occur in the absence of an intermediary transducing cell and that the neuropeptide substance P, operating via NK-1 receptors, is an important mediator of this communication. Our findings have implications for the neuroimmune signaling cascades that are likely to occur during airways inflammation, intestinal hypersensitivity, and other conditions in which mast cells feature.
Inefficient Phospholipase C Activation and Reduced Lck Expression Characterize the Signaling Defect of Umbilical Cord T Lymphocytes
Authors: Miscia Sebastiano , Di Baldassarre Angela , Sabatino Giuseppe , Bonvini Ezio , Rana Rosa Alba , Vitale Marco , Di Valerio Valentina , Manzoli Francesco Antonio 
Published: December 2022

AbstractAdult and neonatal immunocompetent cells exhibit important functional distinctions, including differences in cytokine production and susceptibility to tolerance induction. We have investigated the molecular features that characterize the immune response of cord blood-derived T lymphocytes compared with that of adult T lymphocytes. Our findings demonstrate that phospholipase C (PLC) isozymes, which play a pivotal role in the control of protein kinase C activation and Ca2+ mobilization, are differently expressed in cord and adult T lymphocytes. PLCβ1 and δ1 are expressed at higher levels in cord T cells, while PLCβ2 and γ1 expression is higher in adult T lymphocytes. PLCδ2 and γ2 appear to be equally expressed in both cell types. In addition, a functional defect in PLC activation via CD3 ligation or pervanadate treatment, stimuli that activate tyrosine kinases, was observed in cord blood T cells, whereas treatment with aluminum tetrafluoride (AlF4−), a G protein activator, demonstrated a similar degree of PLC activation in cord and adult T cells. The impaired PLC activation of cord blood-derived T cells was associated with a a very low expression of the Src kinase, Lck, along with a reduced level of ZAP70. No mitogenic response to CD3 ligation was observed in cord T cells. However, no signaling defect was apparent downstream of PLC activation, as demonstrated by the mitogenic response of cord T cells to the pharmacologic activation of protein kinase C and Ca2+ by treatment with PMA and ionomycin. Thus, neonatal cord blood-derived T cells show a signaling immaturity associated with inadequate PLCγ activation and decreased Lck expression.
B Cell Apoptosis Triggered by Antigen Receptor Ligation Proceeds Via a Novel Caspase-Dependent Pathway
Authors: Chen Weiping , Wang Hong-Gang , Srinivasula Srinivasa M. , Alnemri Emad S. , Cooper Neil R. 
Published: December 2022

AbstractIn contrast to positive signaling leading to proliferation, the mechanisms involved in negative signaling culminating in apoptosis after B cell Ag receptor (BCR) ligation have received little study. We find that apoptosis induced by BCR cross-linking on EBV-negative mature and immature human B cell lines involves the following sequential, required events: a cyclosporin A-inhibitable, likely calcineurin-mediated step; and activation of caspase-2, -3, and -9. Caspase-2 is activated early and plays a major role in the apoptotic pathway, while caspase-9 is activated later in the apoptotic pathway and most likely functions to amplify the apoptotic signal. Caspase-8 and -1, which are activated by ligation of the CD95 and TNF-R1 death receptors, are not involved. Apoptosis induced by BCR ligation thus proceeds via a previously unreported intracellular signaling pathway.