bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glycosylphosphatidylinositol toxin of Plasmodium induces nitric oxide synthase expression in macrophages and vascular endothelial cells by a protein tyrosine kinase-dependent and protein kinase C-dependent signaling pathway.
Authors: Tachado S D , Gerold P , McConville M J , Baldwin T , Quilici D , Schwarz R T , Schofield L 
Published: December 2022

Abstract
In this study, we demonstrate that glycosylphosphatidylinositol (GPI) is a major toxin of Plasmodium falciparum origin responsible for nitric oxide (NO) production in host cells. Purified malarial GPI is sufficient to induce NO release in a time- and dose-dependent manner in macrophages and vascular endothelial cells, and regulates inducible NO synthase expression in macrophages. GPI-induced NO production was blocked by the NO synthase-specific inhibitor L-N-monomethylarginine. GPI also synergizes with IFN-gamma in regulating NO production. The structurally related molecules dipalmitoylphosphatidylinositol and iM4 glycoinositolphospholipid from Leishmania mexicana had no such activity, and the latter antagonized IFN-gamma-induced NO output. GPI activates macrophages by initiating an early onset tyrosine kinase-mediated signaling process, similar to that induced by total parasite extracts. The tyrosine kinase antagonists tyrphostin and genistein inhibited the release of NO by parasite extracts and by GPI, alone or in combination with IFN-gamma, demonstrating the involvement of one or more tyrosine kinases in the signaling cascade. GPI-induced NO release was also blocked by the protein kinase C inhibitor calphostin C, demonstrating a role for protein kinase C in GPI-mediated cell signaling, and by pyrrolidine dithiocarbamate, indicating the involvement of the NF-kappa B/c-rel family of transcription factors in cell activation. A neutralizing mAb to malarial GPI inhibited NO production induced by GPI and total malarial parasite extracts in human vascular endothelial cells and murine macrophages, indicating that GPI is a necessary agent of parasite origin in parasite-induced NO output. Thus, in contrast to dipalmitoylphosphatidylinositol and glycoinositolphospholipids of Leishmania, malarial GPI initiates a protein tyrosine kinase- and protein kinase C-mediated signal transduction pathway, regulating inducible NO synthase expression with the participation of NF-kappa B/c-rel, which leads to macrophage and vascular endothelial cell activation and downstream production of NO. These events may play a role in the etiology of severe malaria.
Role of IL-7 in the shaping of the pulmonary gamma delta T cell repertoire.
Authors: Hayes S M , Sirr A , Jacob S , Sim G K , Augustin A 
Published: December 2022

Abstract
Gamma delta T cells bearing the canonical fetal-type V gamma 6/V delta 1 rearrangements are the predominant gamma delta T cells in the lungs of adult mice. In contrast, these V gamma 6/V delta 1 T cells are virtually absent in the pulmonary epithelia of nude mice. The intraepithelial dominance of gamma delta T cells that express this particular TCR is thought to result from a preferred thymic pathway of gene rearrangement and not from TCR-mediated positive selection. We now show that gamma delta T cell precursors in the lung epithelium of both euthymic and athymic neonatal mice generate this rearrangement in situ. In athymic mice, these clonotypes do not survive, but can be rescued in vitro and in vivo by the lymphokine IL-7.
Differential dysregulation of nitric oxide production in macrophages with targeted disruptions in IFN regulatory factor-1 and -2 genes.
Authors: Salkowski C A , Barber S A , Detore G R , Vogel S N 
Published: December 2022

Abstract
Recent studies have reported that IFN regulatory factor-1 (IRF-1) regulates nitric oxide (NO.) production in murine macrophages (M phi). Since IRF-2 recognizes the same consensus sequence as IRF-1, we postulated that IRF-2 may also regulate NO.. Therefore, the ability of M phi from INF-2 homozygous (IRF-2-/-) and heterozygous (IRF-2+/-) knockout mice to produce NO. following LPS and/or IFN-gamma stimulation was compared with the responses of IRF-1-/-, IRF-1+/-, and C57BL/6+/+ M phi. IRF-2-/- M phi produced less LPS-induced NO2- than IRF-2+/- or C57BL/6 M phi. LPS and IFN-gamma synergized to increase NO2- production from IRF-2-/- M phi to approximately 50% of IRF-2+/- and C57BL/6 levels. Unexpectedly, IRF-2-/-, IRF-2+/- and C57BL/6 M phi produced comparable levels of inducible NO synthase mRNA in response to treatment with LPS and IFN-gamma. IRF-1-/- M phi produced barely detectable NO2- and low, but detectable, inducible NO. synthase mRNA in response to IFN-gamma and LPS. These results indicate that IRF-1 and IRF-2 differ in their mechanism of NO. regulation and that IRF-2 regulates inducible NO. synthase post-transcriptionally.
Differential expression of homing molecules on recirculating lymphocytes from sheep gut, peripheral, and lung lymph.
Authors: Abitorabi M A , Mackay C R , Jerome E H , Osorio O , Butcher E C , Erle D J 
Published: December 2022

Abstract
The adhesion molecules integrin alpha 4 beta 7 and L-selectin have been hypothesized to help direct selective migration (homing) of lymphocytes to the gut and peripheral lymph nodes, respectively. An important prediction of current models is that lymphocytes selectively recirculating through an organ will preferentially express adhesion receptors for organ-specific endothelial ligands. To test this prediction, we directly examined the expression of cell adhesion molecules on lymphocytes recirculating through the gut, the periphery, and the lung. Integrin beta 7 was highly expressed on CD4+CD45R- "memory/effector" T cells recirculating through the gut (mesenteric efferent and lower thoracic duct lymph). In contrast, cells recirculating through the periphery (prescapular efferent lymph) and the lung (caudal mediastinal efferent lymph) had much less beta 7 expression. A similar pattern of organ-specific beta 7 expression was seen on B cells. Beta 7 expression corresponded with adhesion to the gut mucosal addressin, MAdCAM-1, in vitro. The peripheral lymph node homing receptor, L-selectin, was expressed at higher levels on CD4+CD45R- T cells from peripheral lymph than on cells from gut or lung lymph. These results provide additional strong support for alpha 4 beta 7 and L-selectin involvement in lymphocyte homing to the gut and to peripheral lymph nodes, respectively. Lymphocytes emigrating from the lung expressed low levels of both homing receptors and likely utilize molecules other than alpha 4 beta 7 and L-selectin for migration to the lung and associated lymphoid tissue.
Herpesvirus saimiri open reading frame 14, a protein encoded by T lymphotropic herpesvirus, binds to MHC class II molecules and stimulates T cell proliferation.
Authors: Yao Z , Maraskovsky E , Spriggs M K , Cohen J I , Armitage R J , Alderson M R 
Published: December 2022

Abstract
Herpesvirus saimiri (HVS) is an oncogenic, lymphotropic, gamma-herpesvirus that transforms human and simian T cells in vitro and causes lymphomas and leukemias in various species of New World primates. Nucleotide sequence analysis of the HVS genome revealed an open reading frame with 22% amino acid identity to the mouse mammary tumor virus 7 superantigen. In this study, we demonstrate that this open reading frame, HVS14, encodes a heavily glycosylated protein that is secreted. Both the HVS14 present in the supernatant of transfected cells and a chimeric HVS14.Fc fusion protein were found to bind to heterodimeric MHC class II HLA-DR molecules. The supernatant from HVS14-transfected cells induced the proliferation of human PBMC, which could be specifically inhibited by HVS14-specific mAbs. Purified peripheral blood T cells were induced to proliferate in the presence of accessory cells and HVS14-containing supernatant. Whereas the HVS14 protein stimulated T cell proliferation, the HVS14.Fc fusion protein blocked proliferative responses to soluble Ags in vitro. Collectively, these data indicate that HVS14 can function as an immunomodulator that may contribute to the immunopathology of HVS infection.
Autoimmune lpr/lpr mice deficient in CD40 ligand: spontaneous Ig class switching with dichotomy of autoantibody responses.
Authors: Ma J , Xu J , Madaio M P , Peng Q , Zhang J , Grewal I S , Flavell R A , Craft J 
Published: December 2022

Abstract
Fas-deficient MRL/Mp-lpr/lpr mice develop a syndrome that resembles human systemic lupus erythematosus, including production of IgG autoantibodies against small nuclear ribonucleoproteins (snRNPs), dsDNA, and self IgG (rheumatoid factor). To investigate the necessity for T-B cell contact in MRL autoimmunity, mice deficient in CD40 ligand (CD40L) were backcrossed onto this background, and Ab synthesis was assessed. In comparison to their CD40L-intact lpr/lpr counterparts, CD40L-deficient lpr/lpr mice had elevated levels of serum IgM and lower levels of IgG; however, a subset of animals had IgG2a, and to a lesser extent, IgG2b levels similar to those found in wild-type lpr/lpr mice. Levels of both isotypes in CD40L-deficient lpr/lpr mice were significantly greater than those found in nonautoimmune CD40L-deficient animals. IgG autoantibodies, including those directed against small nuclear ribonucleoproteins, also arose in CD40L-deficient lpr/lpr mice; however, they did not develop IgG rheumatoid factors or anti-dsDNA, and lacked histologic evidence of overt glomerulonephritis at age 3 mo, in contrast to CD40L-intact lpr/lpr animals. These results indicate that isotype switching occurs in lpr/lpr mice deficient in CD40L, and that production of IgG autoantibodies to ribonucleoproteins is at least partially preserved. They also suggest that different mechanisms may be responsible for eliciting autoantibody responses in lpr/lpr mice.
Peripheral V gamma 9/V delta 2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons.
Authors: Poccia F , Boullier S , Lecoeur H , Cochet M , Poquet Y , Colizzi V , Fournie J J , Gougeon M L 
Published: December 2022

Abstract
Gamma delta T cells represent a minor population of human peripheral lymphocytes, the majority of them expressing the V delta 2/V gamma 9 TCR. Their accumulation in infectious disease lesions and their reactivity toward mycobacterial Ags suggest that V gamma 9/V delta 2 T cells play a role during infectious diseases. We have shown previously a significant expansion of the V delta 1 subset parallel to a dramatic decrease of the V delta 2 subset in PBMC from HIV-infected persons. To understand the mechanisms involved in the deletion of V delta 2 T cells, we analyzed their ability to respond in vitro to several V gamma 9/V delta 2 t cell-specific ligands. We observed that in 60% of asymptomatic HIV-infected persons, V delta 2 T cells exhibited a functional anergy to Daudi and to Mycobacterium tuberculosis stimulations. These observations were supported by the defective expansion of this subset to the recently described nonpeptidic phosphorylated Ag, TUBAg-1. Since V delta 2 responsiveness to mycobacterial Ags was shown to be normally dependent on IL-2 secretion by Th1-type CD4 T cells, the ability of IL-2 to restore V delta 2 T cells' responsiveness to TUBAg-1 was tested. V delta 2 T cell anergy persisted in spite of the presence of IL-2, and was frequently correlated with a defect in CD25 expression on stimulated V delta 2 T cells. Since V delta 2 anergy was associated with an in vivo depletion of this subset, we studied whether programmed cell death could be involved in this process, particularly because of their activated phenotype. Although peripheral V delta 2 T cells from some HIV-infected persons showed an increased susceptibility to spontaneous and activation-induced apoptosis, statistical comparison between HIV+ and HIV- donors indicated that there was no difference between both groups in the rate of V delta 2 apoptosis. Finally, V delta 2 complementarity-determining region 3 TCR analysis indicated that, in vivo, the remaining V delta 2 T cells were still polyclonal. All together these results suggest that the qualitative and quantitative alterations of the V delta 2 subset in the course of HIV infection are the consequence of a chronic antigenic stimulation, and raise the question of the contribution of a cellular ligand induced or modified by chronic HIV infection.
Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains.
Authors: Verdaguer J , Yoon J W , Anderson B , Averill N , Utsugi T , Park B J , Santamaria P 
Published: December 2022

Abstract
The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activation and recruitment of effector T cells in most spontaneous models of autoimmune diseases remains elusive. Here we report on the use of single TCR-beta transgenic mice to study the mechanisms that drive the accumulation of pathogenic T cells in the pancreatic islets of nonobese diabetic (NOD) mice, a model for insulin-dependent diabetes mellitus. Expression of the V(beta)8.1+ TCR-beta rearrangement of a diabetogenic H-2Kd-restricted beta cell cytotoxic CD8+ T cell (beta-CTL) clone in NOD mice caused a 10-fold increase in the peripheral precursor frequency of beta-CTL and a selective acceleration of the recruitment of CD8+ T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell depletion, and led to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expressed an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequence homologous to those expressed by most islet-derived beta-CTL from nontransgenic NOD mice. TCR-beta transgene expression did not change the peripheral frequency of beta cell-specific CD4+ T cells, the rate at which these cells accumulated in the pancreatic islets, or the incidence of diabetes. Taken together, our data indicate that retention of CD8+ and CD4+ T cells in the pancreatic islets of NOD mice is driven by beta cell autoantigens, rather than by local superantigens or non-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus.
A dominant negative mutant of an IFN regulatory factor family protein inhibits both type I and type II IFN-stimulated gene expression and antiproliferative activity of IFNs.
Authors: Thornton A M , Ogryzko V V , Dent A , Sharf R , Levi B Z , Kanno Y , Staudt L M , Howard B H , Ozato K 
Published: December 2022

Abstract
Type I (alpha,beta) and type II (gamma) IFNs elicit antiproliferative and antiviral activities through two distinct transcription pathways involving 1) IRF family proteins and ISGF3, and 2) STAT1. We have employed a dominant negative strategy to study the role of IRF family proteins in eliciting the biologic activities of IFN. A truncated IRF protein retaining the DNA-binding domain (DBD) of ICSBP (a member of the IRF family) was stably transfected into U937 monocytic cells. Clones expressing DBD had markedly reduced ISRE-binding activity and were defective in expressing several type I IFN-inducible genes. STAT1 was one such type I IFN-inducible gene whose expression was also inhibited in DBD clones. As a result, the expression of several IFN-gamma-inducible genes was also inhibited in these clones, indicating functional coupling of the type I and type II IFN transcription pathways. Furthermore, DBD clones grew more slowly than control clones and were refractory to antiproliferative effects of both types of IFNs. We found that IFN treatment of U937 cells leads to a G1 arrest and an increase in underphosphorylated retinoblastoma gene product. However, IFN treatment did not change the cell cycle profile, nor retinoblastoma gene product phosphorylation state in DBD clones. These data indicate that expression of DBD disrupts cell cycle regulatory mechanisms. Combined with the previously noted failure of DBD clones to elicit antiviral activity, the present work shows that IRF family proteins play an integral part in growth control activities of IFNs.
The immune response to Trichophyton tonsurans: distinct T cell cytokine profiles to a single protein among subjects with immediate and delayed hypersensitivity.
Authors: Slunt J B , Taketomi E A , Woodfolk J A , Hayden M L , Platts-Mills T A 
Published: December 2022

Abstract
Skin testing with an extract from the dermatophyte fungus Trichophyton tonsurans can result in either immediate (IH) or delayed hypersensitivity (DH). These experiments were designed to examine in vitro T cell cytokine production in response to purified proteins from T. tonsurans in subjects with different skin test reactivities. Peripheral blood mononuclear cells were obtained from subjects with immediate, delayed, or negative skin tests, and cellular proliferation was studied. Subjects with either IH or DH had positive proliferative responses to crude extracts and two purified proteins, protein IV (83 kDa) and Tri t 1 (30 kDa). Nine cell lines were established from 5 IH subjects, which produced a cytokine profile characteristic of Th2/Th0 cells, i.e., ratio of IFN-gamma to IL-4 or IL-5 &lt;2:1. By contrast 8 of 10 cell lines from DH subjects had a Th1 profile, i.e., IFN-gamma to IL-4 or IL-5 &gt;20:1. Lymphocytes from subjects with negative skin tests show very poor proliferative responses; however, 6 cell lines derived from these individuals showed a cytokine profile characteristic of Th1 cells. Levels of IL-5 were significantly different when comparing the IH group with the DH group (p &lt; 0.001). The results demonstrate that a single defined protein from T. tonsurans can produce distinct T cell cytokine profiles that correspond to in vivo skin test reactivities and serum Ab levels.
Activation of nuclear factor-kappaB via T cell receptor requires a Raf kinase and Ca2+ influx. Functional synergy between Raf and calcineurin.
Authors: Kanno T , Siebenlist U 
Published: December 2022

Abstract
Signals transduced via the TCR activate the transcription factor nuclear factor-kappaB (NF-kappaB), which, in turn, is critical to the transcriptional induction of many genes important for the proliferation and expression of a differentiated phenotype. Treatment of T cells with the protein kinase C activator PMA in combination with Ca2+ ionophores mimics this process, and the two agents are often substituted for TCR stimulation, bypassing the TCR. Here we identify intracellular signaling components involved in activation of NF-kappaB following TCR stimulation. TCR signaling was triggered by treating Jurkat T cells with PHA or anti-CD3 Abs, and NF-kappaB activation was monitored by electrophoretic mobility shift assays and/or by kappaB-dependent reporter assays. Contrary to the idea that protein kinase C is involved in TCR-mediated activation of NF-kappaB, high doses of staurosporine did not interfere with activation of NF-kappaB by PHA, while the same dose of staurosporine completely blocked activation by PMA. PHA-induced kappaB-dependent reporter activity was, however, effectively blocked by a dominant negative form of Raf-1, suggesting a critical role for a Raf kinase. The TCR-mediated activation of NF-kappaB was also dependent on a Ca2+ influx, because the Ca2+ channel blocker, SK&F 96365, as well as other agents that prevented the Ca2+ influx, inhibited NF-kappaB activation. Cotransfection of a constitutively active form of calcineurin largely substituted for the Ca2+ requirement and reversed the blockade by SK&F 96365. Consistent with these observations, coexpression of constitutively active forms of Raf-1 and calcineurin synergistically induced kappaB-dependent reporter activity, suggesting a physiologically relevant functional interaction between the kinase and the phosphatase.
IL-2 induces beta2-integrin adhesion via a wortmannin/LY294002-sensitive, rapamycin-resistant pathway. Phosphorylation of a 125-kilodalton protein correlates with induction of adhesion, but not mitogenesis.
Authors: Nielsen M , Svejgaard A , Skov S , Dobson P , Bendtzen K , Geisler C , Odum N 
Published: December 2022

Abstract
Besides its function as a growth factor, IL-2 induces beta2-integrin-dependent, homotypic adhesion of IL-2R-positive T cells. In this study, we investigated how IL-2R are functionally and biochemically linked to the beta2-integrin adhesion pathway. After a lag period of 15 to 20 min, IL-2 induces beta2-integrin-dependent, homotypic adhesion in Ag-specific, human T cell lines. The IL-2 adhesion response is blocked by wortmannin and LY294002, inhibitors of phosphatidylinositol-3 (PI-3) kinase activity. In contrast, rapamycin strongly inhibits IL-2-induced proliferation without inhibiting IL-2-induced adhesion. Herbimycin A and genestein, inhibitors of protein tyrosine kinases, inhibit cytokine-induced adhesion and mitogenesis in parallel, whereas cytochalasin E, an inhibitor of actin polymerization, almost completely blocks the adhesion response at concentrations that have little effect on mitogenesis. IL-2R ligation rapidly (&lt;5 min) induces tyrosine phosphorylation of several proteins, the most prominent being signal transducer and activator of transcription (Stat) proteins, the p85 subunit of the PI-3 kinase, and an as yet unidentified 125-kDa protein (p125). Wortmannin, LY294002, and cytochalasin E almost completely inhibit cytokine-induced tyrosine phosphorylation of p125, whereas tyrosine phosphorylation of PI-3 kinase, Janus kinases, Stat3, Stat5, and other proteins is unaffected. In contrast, rapamycin has little effect on IL-2-induced phosphorylation of p125. Taken together, these data suggest that 1) IL-2R ligation induces homotypic adhesion through a wortmannin/LY294002-sensitive, rapamycin-resistant pathway, 2) tyrosine kinases play a critical role in cytokine-induced adhesion, and 3) adhesion, but not mitogenesis, correlates with enhanced tyrosine phosphorylation of an as yet unidentified protein of 125 kDa.
A major role for the Fas pathway in acute graft-versus-host disease.
Authors: Via C S , Nguyen P , Shustov A , Drappa J , Elkon K B 
Published: December 2022

Abstract
Recent studies have suggested a role for the Fas pathway in the wasting syndrome associated with lpr--&gt;wild-type bone marrow transplants. To directly examine whether Fas ligand has a major role in the development of acute graft-vs-host disease (GVHD), Fas ligand-deficient (gld) mice were used as donors and C3H/HeJ x C57BL/6F1 as recipients in the parent-into-F1 model of acute GVHD. Transplantation of C3H/gld spleen cells induced significantly less host lymphoid depletion and was associated with less antihost cytotoxic activity in vitro when compared with wild-type C3H donor cells. The reduced depletion of host lymphocytes was explained by both impaired antihost T cell cytolytic activity and by reduced expansion of gld donor T cells in F1 recipients. These findings not only indicate that the Fas ligand is an important effector molecule in acute GVHD, but also provide in vivo evidence supporting a role for Fas/Fas ligand interactions in T cell expansion and maturation.