bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bcl-2 prevents apoptosis induced by perforin and granzyme B, but not that mediated by whole cytotoxic lymphocytes.
Authors: Sutton V R , Vaux D L , Trapani J A 
Published: December 2022

Abstract
Two pathways have been implicated in the induction of apoptosis by cytotoxic T cells: the granule exocytosis pathway and a pathway using CD95 (Fas/APO-1). To test whether apoptosis induced by either of these pathways could be blocked by Bcl-2, we exposed bcl-2-transfected cells to CTL derived from normal, perforin-deficient, or CD95 ligand mutant (gld) mice. Although the levels of Bcl-2 expression achieved were able to protect FDC-P1 and Yac-1 transfectants from a variety of apoptotic stimuli, the cells were not protected from cytolysis mediated by CTL from any of these sources, by NK cells, or granules isolated from CTL. However, Bcl-2 expression significantly inhibited apoptosis induced by purified granzyme B and perforin. These results suggest that while Bcl-2 is capable of inhibiting the apoptotic pathway utilized by perforin and granzyme B, other granule components can bypass this block. We conclude that CTL harbor potent killing mechanism(s) in addition to those provided by CD95 ligand or perforin and granzyme B that cannot be overcome by Bcl-2.
The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression.
Authors: Reichel M , Nelson B H , Greenberg P D , Rothman P B 
Published: December 2022

Abstract
The common gamma-chain (gamma(c)) is a functional component of the IL-4R, yet cells lacking gamma(c) are able to respond to IL-4. This has led to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cells lacking gamma(c). An alternative possibility is that in the absence of gamma(c), the IL-4R alpha chain is able to transduce signals by homodimerization. To test this latter possibility, a chimeric receptor containing the extracellular domain of c-kit (the stem cell factor (SCF) receptor) and the cytoplasmic and transmembrane domains of the IL-4R alpha chain was generated. Treatment of cells expressing the chimeric receptor kit/IL-4R alpha with SCF induces activation of the IL-4R alpha-associated kinase JAK-1 and the transcription factor STAT6. However, tyrosine phosphorylation of JAK-3, which associates with gamma(c), is not induced by SCF in these cells. SCF-mediated ligation of kit/IL-4R alpha is sufficient to elicit IL-4-specific gene expression, including up-regulation of CD23 and synthesis of germ-line epsilon transcripts. In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation. Finally, in JAK-1-deficient HeLa cells, STAT6 activation by IL-4 is completely abolished. Together, these data demonstrate that the IL-4R alpha cytoplasmic domain is sufficient to activate JAK-1 and STAT6 and to induce expression of IL-4 target genes, thus identifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).
B7-2 requirement for helminth-induced granuloma formation and CD4 type 2 T helper cell cytokine expression.
Authors: Subramanian G , Kazura J W , Pearlman E , Jia X , Malhotra I , King C L 
Published: December 2022

Abstract
B7 ligands on APCs engage CD28/CTLA4 counter-receptors on T cells critical for T lymphocyte activation and functional differentiation of T helper subsets. To examine whether the ligands B7-1 (CD80) and B7-2 (CD86) affect gene expression of Th2 cytokines and development of Th2-mediated pathologic tissue reactions, mice were treated with anti-B7-1 or anti-B7-2 at the time of sensitization to footpad inoculation of Schistosoma mansoni eggs or induction of pulmonary granuloma by i.v. injected eggs. Anti-B7-2 treatment inhibited pulmonary granuloma formation by 74% and decreased levels of lung IL-5 and IL-13 transcripts compared with those in animals given control Ig by 20- and 5-fold, respectively, while anti-B7-1 administration has no effect. Anti-B7-2 treatment blocked CD4 cell gene expression of IL-4, IL-5, and IL-13, but had no effect on IFN-gamma or IL-10 in animals inoculated with S. mansoni ova, larvae from the filarial helminth Brugia malayi, or CFA. Anti-B7-1 administration had no effect on CD4 cell transcript levels of IL-4 and IL-5, but inhibited IFN-gamma in mice inoculated with ova. Similar effects of anti-B7-2 on CD4 cell cytokine expression were observed in IL-4 knockout mice, indicating the existence of an alternative pathway for induction and/or expression of these cytokine genes. These findings suggest a possible role for anti-B7-2 in the therapy of infectious and atopic diseases in which immunopathologic reactions are mediated by selected Th2 cytokines.
Functions and specificity of T cells following nucleic acid vaccination of mice against Mycobacterium tuberculosis infection.
Authors: Zhu X , Venkataprasad N , Thangaraj H S , Hill M , Singh M , Ivanyi J , Vordermeier H M 
Published: December 2022

Abstract
The 38-kDa glycolipoprotein of Mycobacterium tuberculosis has been known to evoke prominent T cell and Ab responses in patients with active tuberculosis. In this study, we investigated its protective capacity using plasmid DNA immunization in a mouse experimental model. Prior knowledge of several antigenic determinants has been beneficial for analyzing the phenotype and specificity of T cells, which determine the efficacy of this vaccination procedure. C57BL/6 mice responded to the 38-kDa gene-pcDNA3 plasmid with strong CD4+ Th1 and CD8+ cytotoxic T cell responses of the IFN-gamma-producing Tc1 phenotype. After challenge with virulent tubercle bacilli, the bacterial load in the spleens and lungs of vaccinated mice was reduced to a level similar to that imparted by Mycobacterium bovis Bacille Calmette-Guérin vaccination. Notably, the specificity of CD4+ and CD8+ T cells from DNA-vaccinated and tubercle-infected mice was found to be strikingly different in respect of several peptide epitopes. The identified peptides recognized by T cells from protected mice are of further interest for the development of subunit-based vaccines against tuberculosis.
Impaired activation of nuclear factor-kappaB in endotoxin-tolerant rats is associated with down-regulation of chemokine gene expression and inhibition of neutrophilic lung inflammation.
Authors: Blackwell T S , Blackwell T R , Christman J W 
Published: December 2022

Abstract
We postulated that repeated injections of endotoxin could induce a state of endotoxin tolerance in rats that is mediated at least partially through a nuclear factor (NF)-kappaB-dependent mechanism. We treated rats with four doses of endotoxin (0.06 or 0.6 mg/kg/day) and evaluated the ability of these treatments to modulate activation of the transcription factor NF-kappaB induced by treatment with high dose endotoxin (6 mg/kg). In lung tissue, NF-kappaB activation in response to i.p. injection of high dose endotoxin was blocked by treatment with four daily doses of endotoxin at 0.6 mg/kg/day. Endotoxin tolerance in rats was associated with diminished endotoxin-induced mRNA expression of the NF-kappaB-dependent rat chemokine, cytokine-induced neutrophil chemoattractant. Treatment of rats with four daily doses of 0.6 mg/kg/day of endotoxin almost completely abolished the neutrophilic alveolitis that occurs in rats following i.p. injection of high dose endotoxin. These data indicate that in vivo tolerance to endotoxin challenge is associated with and possibly mediated by inhibition of NF-kappaB activation. Potentially, endotoxin tolerance could be exploited to limit inflammation in disease states whose pathobiology is related to excessive or unregulated inflammation.
Extracellular release of the type I intracellular IL-1 receptor antagonist from human airway epithelial cells: differential effects of IL-4, IL-13, IFN-gamma, and corticosteroids.
Authors: Levine S J , Wu T , Shelhamer J H 
Published: December 2022

Abstract
Three IL-1R antagonists (IL-1Ra) exist: secreted IL-1Ra and intracellular IL-1Ra (icIL-1Ra) types I and II. We have previously reported that human airway epithelial cells (HAEC) express icIL-1Ra type I, which can be up-regulated by corticosteroids. This study assessed whether cytokines and corticosteroids differentially effect icIL-1Ra type I protein release from HAEC to the extracellular compartment. We report that icIL-1Ra type I mRNA and intracellular protein are up-regulated in NCI-H292 cells, a human pulmonary mucoepidermoid carcinoma cell line, in response to IL-4, IL-13, IFN-gamma, and dexamethasone. The icIL-1Ra type I protein was detected in concentrated cell culture supernatants from NCI-H292 cells and normal human bronchial epithelial cells. The release of biologically relevant concentrations of active IL-1Ra from normal human bronchial epithelial cells was demonstrated by the ability of a neutralizing anti-IL-1Ra Ab to augment IL-1beta-mediated IL-8 secretion. IL-4, IL-13, and IFN-gamma induced immunoreactive IL-1Ra release into supernatants from NCI-H292 cells. Dexamethasone inhibited constitutive and cytokine-induced release of immunoreactive IL-1Ra. The release of icIL-1Ra type I protein was not related to cytotoxicity, as measured by lactate dehydrogenase. We propose that icIL-1Ra type I release from HAEC represents a novel mechanism by which IL-1 bioactivity in the airway microenvironment may be modulated. Cytokine-mediated icIL-1Ra type I synthesis may increase both intracellular protein and release to the extracellular space, where cell surface IL-1R can be antagonized. In contrast, corticosteroid-induced increases in icIL-1Ra type I synthesis and inhibition of extracellular protein release promote accumulation of icIL-1Ra type I protein within the intracellular compartment.
Negative signaling in B cells causes reduced Ras activity by reducing Shc-Grb2 interactions.
Authors: Tridandapani S , Chacko G W , Van Brocklyn J R , Coggeshall K M 
Published: December 2022

Abstract
To elucidate the molecular basis for inhibition of B cell proliferation and differentiation by the Fc receptor for IgG (Fc(gamma)RII), we compared the signaling events in B cells stimulated by cross-linking surface Ig alone (positive signaling), or by co-cross-linking surface Ig and Fc(gamma)RII (negative signaling). Both modes of stimulation induced tyrosine kinase activation. Positive signaling induced activation of Ras, Raf-1 kinase, and mitogen-activated protein kinase; these events were significantly attenuated during negative signaling. Since Ras is activated by SOS and Vav, two known guanine nucleotide exchange factors, activation events associated with these molecules using the two different stimuli were examined. Results of these experiments indicated that tyrosine phosphorylation of Vav did not change upon co-cross-linking. In contrast, the association of Shc and Grb2 was abrogated under negative and induced under positive signaling conditions. Concomitantly, Shc was observed to associate with a tyrosine-phosphorylated 145-kDa protein, previously identified as Src homology 2-containing inositol phosphatase, only under conditions of negative signaling. Based on these results, we hypothesize that negative signaling via the Fc(gamma)RII in B cells is at least partly the result of a block in Ras activation, and that SOS, but not Vav, is the major guanine nucleotide exchange factor in B cells for Ras activation.
Down-regulation of terminal deoxynucleotidyl transferase by Ig heavy chain in B lineage cells.
Authors: Wasserman R , Li Y S , Hardy R R 
Published: December 2022

Abstract
The enzyme terminal deoxynucleotidyl transferase (TdT) adds nontemplate-derived nucleotides (N regions) to the junctions between recombining variable, diversity, and joining segments of Ig genes. The relative paucity of N regions in Ig light chains, together with the down-regulation of TdT transcription in pre-B cells (prior to light chain production), suggested that production of IgM heavy chain (mu) protein might negatively regulate TdT expression. In this study, we examined the effect of mu production on TdT gene expression in B lineage subsets from normal mice, from recombination-deficient mice (SCID and Rag-1-) carrying mu transgenes, and in transformed pro-B cell lines transfected with mu constructs. In normal mice, TdT is sharply down-regulated at the early pre-B stage in which cells have just completed productive mu rearrangement. Furthermore, the expression of mu transgenes in pro-B stage cells from recombination-deficient mice results in a similar decrease. Finally, transfection of genomic constructs encoding mu into pro-B cell lines results in a marked reduction of TdT expression. Taken together, these findings indicate that mu protein production results in the down-regulation of TdT. The ability of mu transgenes to alter TdT expression in cell lines also suggests that signaling through the pre-B receptor does not necessarily require interaction with an external stromal cell-derived ligand.
The Bop gene adjacent to the mouse CD8b gene encodes distinct zinc-finger proteins expressed in CTLs and in muscle.
Authors: Hwang I , Gottlieb P D 
Published: December 2022

Abstract
The Bop gene (for CD8b opposite) is located immediately upstream of the mouse CD8b gene. Expression of Bop gene transcripts was previously observed in several long term CTL lines and in thymus. The present studies demonstrate that expression of the Bop gene in lymphocytes appears to be confined to CD8-positive cells, and that Bop gene expression is inducible by Con A. They further show that a single Bop gene encodes protein products with distinct amino-terminal sequences that are expressed in CTLs (t-BOP) and in cardiac and skeletal muscle (skm-BOP), as well as what appears to be a noncoding cDNA (t-ncb) expressed only in CTLs. The t-BOP and t-ncb cDNAs in CTLs result from alternative splicing of a single primary transcript, whereas the Bop transcripts expressed in CTLs and in muscle appear to be transcribed from different promoters. The BOP proteins expressed in CTLs and muscle contain zinc finger-like motifs with homology to those of the ETO/MTG8 proto-oncogene and several other proteins of interest. Western blot analysis with a hamster anti-BOP mAb have detected the BOP protein in muscle cells and in COS 7 cells transfected with Bop cDNA constructs.
Characterization of the TCRB chain repertoire in the New World monkey Callithrix jacchus.
Authors: Uccelli A , Oksenberg J R , Jeong M C , Genain C P , Rombos T , Jaeger E E , Giunti D , Lanchbury J S , Hauser S L 
Published: December 2022

Abstract
Callithrix jacchus is an outbred New World primate characterized by a naturally occurring bone marrow chimerism, restricted polymorphism at many MHC loci, and unusual susceptibility to viral pathogens, adenocarcinoma, colitis, and, following immunization with myelin antigens, a demyelinating disease of the central nervous system closely resembling human multiple sclerosis. Here we characterize the TCRB repertoire in this species, representing the first such analysis in a New World monkey. Two TCRBC, 13 BJ, 2 BD, and 15 BV genes were identified. Overall, a high degree of similarity with human TCRBV-D-J-C gene sequences was observed, indicating a close phylogenetic relationship. Biased usage in favor of genes from the TCRBC1-BJ1 cluster was present in 77% of sequences, in contrast to preferential usage of BC2-BJ2 genes known to occur in humans and mice. Complementarity-determining region 3 averaged 10 amino acids in length and were diverse. Framework regions of TCRBV genes were extensively conserved. Phylogenetic analysis of TCRBV sequences from different species indicated that TCR genes are highly stable across primates. Thus, a diverse TCRB repertoire is generated in C. jacchus despite the limited polymorphism of class I MHC loci. Extensive homology to human TCR genes, natural chimerism, and susceptibility to inflammatory disorders are characteristics of C. jacchus that create a useful model system for the study of human autoimmunity.
On the essential involvement of neutrophils in the immunopathologic disease: herpetic stromal keratitis.
Authors: Thomas J , Gangappa S , Kanangat S , Rouse B T 
Published: December 2022

Abstract
Corneal infection with herpes simplex virus-1 in immunocompetent mice induces an immunopathologic response termed herpetic stromal keratitis (HSK). The earliest sign of disease is neutrophil infiltration, which lasts for 48 to 72 h and then disappears. However, a secondary neutrophil infiltration, this time more massive, occurs, beginning 8 to 9 days postinfection, a time in which HSK becomes clinically evident. The role of neutrophils in HSK expression was investigated by eliminating such cells using a specific mAb (RB6-8C5). In neutrophil-depleted immunocompetent mice, virus replicated more abundantly, but no effects on HSK expression were observed, possibly because sustained neutropenia could not be maintained. However, using a severe combined immunodeficient mouse model, in which HSK does not occur unless given adoptive transfer of CD4+ T cells, the effects of neutrophil depletion were more pronounced. There were significantly less incidence and severity of HSK in CD4+ T cell-reconstituted severe combined immunodeficient mice that were depleted of neutrophils as compared with controls. Neutrophil-depleted mice displayed moderate to severe periocular skin lesions, progressively became cachetic, and developed signs of encephalitis. Virus was recovered at higher titers and for longer periods from eyes of neutrophil-depleted animals. Brain virus titers were also significantly higher on day 12 postinfection as compared with control animals. These results suggest that herpes simplex virus infection of the cornea rapidly invokes recruitment of neutrophils that may aid in viral clearance, and that neutrophils directly or indirectly serve as agonists in perpetuating a CD4+ T cell-mediated inflammatory reaction.
Down-regulation of Fc(epsilon)RI expression on human basophils during in vivo treatment of atopic patients with anti-IgE antibody.
Authors: MacGlashan D W , Bochner B S , Adelman D C , Jardieu P M , Togias A , McKenzie-White J , Sterbinsky S A , Hamilton R G , Lichtenstein L M 
Published: December 2022

Abstract
Treatment of allergic disease by decreasing circulating IgE with anti-IgE Abs is currently under clinical study. Based on previous unrelated studies, it appeared likely that Fc(epsilon)RI expression on basophils and mast cells might also be regulated by levels of circulating IgE Ab. Therefore, the expression of IgE and Fc(epsilon)RI on human basophils was examined in 15 subjects receiving humanized anti-IgE mAb intravenously. Treatment with the anti-IgE mAb decreased free IgE levels to 1% of pretreatment levels and also resulted in a marked down-regulation of Fc(epsilon)RI on basophils. Median pretreatment densities of Fc(epsilon)RI were approximately 220,000 receptors per basophil and after 3 mo of treatment, the densities had decreased to a median of 8,300 receptors per basophil. Flow cytometric studies, conducted in parallel, showed similar results and also showed in a subset of 3 donors that receptors decreased with a t1/2 of approximately 3 days. The responsiveness of the cells to IgE-mediated stimulation using anti-IgE Ab was marginally decreased (approximately 40%) while the response of the same cells to stimulation with dust mite Ag, Dermatophagoides farinae, was reduced by approximately 90%. One possible explanation for these results is that Fc(epsilon)RI density is directly or indirectly regulated by plasma-free IgE levels.
IL-2 signaling controls actin organization through Rho-like protein family, phosphatidylinositol 3-kinase, and protein kinase C-zeta.
Authors: Gómez J , García A , R-Borlado L , Bonay P , Martínez-A C , Silva A , Fresno M , Carrera A C , Eicher-Streiber C , Rebollo A 
Published: December 2022

Abstract
IL-2 and IL-4 induce proliferation of TS1 alpha beta cells. Activation of the zeta isoform of protein kinase C is an important step in IL-2-, but not IL-4-mediated proliferation. In addition, protein kinase C-zeta is implicated in IL-2-mediated actin organization. Given the established involvement of the Rho family of small guanine nucleotide-binding proteins in organization of actin structures, we analyze the possible relationships between Rho and protein kinase C-zeta. Using the Rho-like protein family-specific toxin B from Clostridium difficile, we report in this work that IL-2, but not IL-4, induces a Rho-dependent activation of protein kinase C-zeta. This signaling event is mediated by the activation of phosphatidylinositol 3-kinase. In contrast, IL-4 induces a Rho-independent, phosphatidylinositol 3-kinase-mediated activation of protein kinase C-zeta, but this pathway has no implications in cytoskeleton organization.
Lymphotactin is produced by NK cells and attracts both NK cells and T cells in vivo.
Authors: Hedrick J A , Saylor V , Figueroa D , Mizoue L , Xu Y , Menon S , Abrams J , Handel T , Zlotnik A 
Published: December 2022

Abstract
Injection of lymphotactin (Lptn) into the peritoneum caused an influx of lymphocytes at 24 h. Phenotypic analysis of the cellular influx showed that a large proportion of these cells were T lymphocytes; however, a large number of NK cells was also present. This effect of murine Lptn (mLptn) was specific since the cellular influx was blocked with a mLptn-specific mAb. Similar results were observed when Lptn was injected s.c. and the tissue was analyzed by immunohistochemistry using an anti-CD3epsilon mAb. Microchemotaxis assays confirmed that murine NK cells respond to mLptn, and also showed human NK clones to be similarly responsive to recombinant human Lptn (rhLptn). Immunohistochemical analysis of IL-2-activated murine NK cells and Northern analysis of human NK clones revealed that these cells also produce Lptn, suggesting that a self-regulatory migration mechanism exists in NK cells. Together these data confirm, in vivo, the lymphocyte specificity of Lptn previously observed in vitro and extend its chemotactic effects to the NK cell lineage. We also investigated the functional consequences of truncating the carboxyl terminus of hLptn. This truncated molecule (which is missing the carboxyl-terminal 22 amino acids of hLptn) had no detectable activity on human PBLs. In addition, while hLptn was found to attract murine splenocytes in vitro, the carboxyl-terminal truncated hLptn was again inactive on murine splenocytes. This observation indicates the presence of structural features in the carboxyl terminus of Lptn that are necessary for its biologic activity.
Integrin-mediated intracellular Ca2+ signaling in Jurkat T lymphocytes.
Authors: Weismann M , Guse A H , Sorokin L , Bröker B , Frieser M , Hallmann R , Mayr G W 
Published: December 2022

Abstract
T lymphocytes interact with components of the extracellular matrix after transendothelial migration on their way to sites of inflammation. To characterize the molecular basis of the interaction between T lymphocytes with different extracellular matrix proteins, we investigated the role of intracellular Ca2+ as a signal mediating such interactions and identified the cell surface integrins involved in this process. When Jurkat T lymphocytes loaded with the calcium-sensitive fluorescent dye fura-2 were placed on coverslips coated with human fibronectin, human collagen types I, IV, and VI, human tenascin, human laminin I, or mouse laminin I, an elevation in intracellular Ca2+ concentration was observed. In contrast, contact of the Jurkat T lymphocytes with vitronectin and thrombospondin did not induce Ca2+ signals in more cells as compared with control measurements in which cells were in contact with only BSA or polylysine. Furthermore, the percentage of Jurkat T lymphocytes responding with Ca2+ signals to collagen types I and IV, fibronectin, and laminin I was completely reduced to levels observed on BSA or polylysine when the cells were pretreated with specific anti-integrin Abs, suggesting a role for cell surface integrins as mediators of cell matrix-induced intracellular Ca2+ signaling. Similar results were obtained with peripheral human T lymphocytes activated by phytohemagglutinin.