bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGF-beta induced by oral tolerance ameliorates experimental tracheal eosinophilia.
Authors: Haneda K , Sano K , Tamura G , Sato T , Habu S , Shirato K 
Published: January 2023

Abstract
Induction of peripheral tolerance is one of the feasible approaches for the control of autoimmunities and allergies. Therapeutic applications of oral tolerance to autoimmunities are in progress both experimentally and clinically, while those to allergies have been poorly investigated. We examined the induction of CD4+ T cells with suppressive properties by oral tolerance and the mechanism by which these cells down-regulated Ag-induced eosinophilia in the trachea. Feeding of mice transgenic for anti-OVA TCR with high doses of OVA inhibited the airway eosinophilic inflammation induced by the intratracheally administered Ag. This inhibition reflected the mechanism of active suppression, since the inhibitory effect was adoptively transferred by splenic CD4+ T cells from the transgenic mice fed with high doses of OVA. The Ag specificity of the suppressor T cells was documented by the failure of spleen cells from mice that were orally tolerant of OVA to suppress irrelevant Ag, KLH-specific airway eosinophilic inflammation. The suppressive effect of the transferred T cells on eosinophil recruitment was neutralized by anti-TGF-beta mAb, but not anti-IFN-gamma mAb, indicating that the suppression is due to the inhibitory effect by secreted TGF-beta, but not to the dominance of the transferred Th1 cells over Th2 cells. This is the first study to reveal a link between oral tolerance and the regulation of Th2-mediated experimental tracheal eosinophilia through TGF-beta. Our experimental model suggests possible therapeutic applications of oral tolerance for the treatment of allergic disorders such as bronchial asthma.
Mechanism of suppression of macrophage nitric oxide release by IL-13: influence of the macrophage population.
Authors: Bogdan C , Thüring H , Dlaska M , Röllinghoff M , Weiss G 
Published: January 2023

Abstract
IL-13 is a cytokine produced by T lymphocytes, mast cells, basophils, and certain B cell lines that up-regulates or inhibits various macrophage functions. In the present study we analyzed the mechanisms of suppression of nitric oxide (NO) release by IL-13 in the macrophage cell line J774A.1 and in thioglycolate-elicited mouse peritoneal macrophages. In both cell types efficient reduction (&gt;80%) of NO production required treatment of the macrophages with IL-13 for at least 7 h before stimulation with IFN-gamma and LPS. In J774A.1 cells, increasing concentrations of IFN-gamma partially antagonized the suppression mediated by IL-13, whereas in peritoneal macrophages, the inhibitory effect of IL-13 was largely independent of the concentrations of IFN-gamma and LPS. In J774A.1 cells, IL-13 strongly reduced both the mRNA and protein levels of inducible nitric oxide synthase (iNOS, NOS-2), as determined by Northern blot analysis and immunoprecipitation. In peritoneal macrophages, in contrast, IL-13 decreased iNOS protein and enzyme activities after 8 to 48 h of stimulation, without altering the expression of iNOS mRNA. Pulse labeling with [35S]methionine revealed that IL-13 caused a 4.7-fold reduction of the de novo synthesis of iNOS protein in these cells. These data demonstrate for the first time that IL-13 is capable of regulating iNOS at both the mRNA and translational levels and underline the important influence of the macrophage population when studying mechanisms of cytokine functions.
Distinct CD4+ T cell helper requirements in Theileria parva-immune and -naive bovine CTL precursors.
Authors: Taracha E L , Awino E , McKeever D J 
Published: January 2023

Abstract
There is strong evidence that class I MHC-restricted parasite-specific CD8+ CTL protect cattle against the protozoan parasite Theileria parva. As part of an effort to develop a subunit vaccine for the induction of these responses, we have investigated the factors involved in the generation of T. parva-specific CTL in cattle. Purified populations of bovine immune and naive CD8+ T cells were cocultured with autologous T. parva-infected lymphoblasts (TpL) in the presence or absence of immune CD4+ T cells or cytokine preparations. Neither population developed CTL activity when cultured with TpL alone, whereas incorporation of immune CD4+ T cells in the cultures supported the generation of parasite-specific CTL from both immune and naive CD8+ precursors. The helper function of parasite-specific CD4+ T cells for immune, but not naive, CTL precursors could be replaced by CD4+ T cells responding to an unrelated Ag or by the addition of T cell growth factors or recombinant bovine IL-2. In experiments with two-chamber culture plates, in which cocultures of CD4+ and CD8+ T cells with TpL were separated by a semipermeable membrane, CTL activity was observed to develop only in immune precursor populations. Hence, although bovine T. parva-specific CD8+ memory T cells need no helper signals other than IL-2 for activation, their naive counterparts require close contact with responding parasite-specific CD4+ T cells. This may reflect essential receptor-ligand interactions, or alternatively, a requirement for more stringent microenvironmental cytokine conditions.
CD40 ligand expressed on B cells in the BXSB mouse model of systemic lupus erythematosus.
Authors: Blossom S , Chu E B , Weigle W O , Gilbert K M 
Published: January 2023

Abstract
Male BXSB mice, unlike female BXSB, develop a severe early onset lupus-like disease that has been linked to an intrinsic B cell defect. In investigating this B cell defect the present study showed that male, but not female, BXSB contained a higher percentage of large, activated splenic B cells that were more responsive to anti-CD40 mAb-induced proliferation. The hyperactivity of the large B cells from the male mice was also observed in the absence of anti-CD40 mAb or any other stimuli. In examining the mechanism of the B cell hyperactivity, it was found that 20% of unstimulated large B cells from male mice, unlike large B cells from female mice, expressed CD40 ligand (CD40L), a molecule normally expressed on activated CD4+ cells. The percentage of large B cells from the male BXSB that expressed CD40L was increased to 43% by stimulation with LPS. A functional role for CD40L expression on B cells was confirmed by showing that CD40-Ig blocked the spontaneous proliferation of the large B cells from male mice. In addition, the stimulatory capacity of the large B cells from the male mice was demonstrated by their ability to induce DNA synthesis in small B cells in a CD40L-dependent manner. These results demonstrated that large B cells from male BXSB expressed functionally active CD40L. It is likely that the B cell CD40L expression and increased susceptibility to CD40 signaling due to an intrinsic B cell hyperactivity promotes autoimmune disease in BXSB mice.
Fas ligand expression and function in systemic lupus erythematosus.
Authors: McNally J , Yoo D H , Drappa J , Chu J L , Yagita H , Friedman S M , Elkon K B 
Published: January 2023

Abstract
Mutations in the Fas receptor or its ligand (FasL) lead to lupus-like systemic autoimmune diseases in mice and in some humans. To determine whether a significant number of patients with systemic lupus erythematosus (SLE) have impaired FasL function, we compared T cell effector function by superantigen-activated CD4+ T cell lines or by anti-CD3- and IL-2-generated cytotoxic T cells. No differences were observed between SLE and normal control superantigen-derived CD4+ T cells in either the ability of these cells to up-regulate Fas expression or to induce apoptosis of the Fas-sensitive target B cells. When anti-CD3/IL-2-activated T cells were examined, SLE T cells had a modest reduction (-8%) in T cell cytotoxicity compared with normal controls, but the reduction was similar to the rheumatoid arthritis disease controls. A modest reduction in cytotoxicity was evident in both the Fas and perforin/granzyme pathways as determined by testing Fas-positive and -negative targets as well as by selective blockade of the perforin/granzyme pathway with concanamycin. These results indicate that no specific defects in FasL function are evident in the majority of SLE patients under the in vitro conditions tested. The proportional reduction in FasL and perforin/granzyme function in SLE and rheumatoid arthritis patients following anti-CD3/IL-2 stimulation most likely reflects subtle differences in activation in patient-derived vs normal control T cells.
Spontaneous Inflammatory Disease in HLA-B27 Transgenic Mice Is Independent of MHC Class II Molecules: A Direct Role for B27 Heavy Chains and Not B27-Derived Peptides
Authors: Khare Sanjay D. , Bull Michael J. , Hanson Julie , Luthra Harvinder S. , David Chella S. 
Published: January 2023

Abstract
Although association of HLA-B27 with human spondyloarthropathies has been known for several years, its role in disease pathogenesis is not understood. Recently, a few investigators have proposed that presentation of B27-derived peptides by MHC class II molecules may be the underlying mechanism. HLA-B27 transgenic rat and mouse models have provided a new tool for understanding the exact role of B27 in disease pathogenesis. HLA-B27 mice lacking endogenous β2-microglobulin (B27+β2mo) develop disease after they are transferred from the barrier facility to the conventional colony. This model was utilized to test the hypothesis that B27-derived peptide presented by MHC class II molecules is the cause of the disease. The MHC class II knockout gene, Aβo, was bred into our B27+β2mo mice, and disease manifestation was monitored. These mice develop spontaneous disease, demonstrating that MHC class II molecules do not play a major role in B27-related disease. Thus, the disease is not manifested by presentation of B27-derived peptides by class II molecules, since these mice are devoid of H2-A and H2-E molecules. Furthermore, in vivo treatment with mAb against the heavy chain of B27 reduced the incidence of disease in B27+β2mo mice. Our results clearly demonstrate that B27 heavy chains are directly involved in the disease process.
Long-Lived B Cells Are Distinguished by Elevated Expression of A1
Authors: Tomayko Mary M. , Cancro Michael P. 
Published: January 2023

Abstract
Only 5% of the 15 million B cells formed daily reach the long-lived peripheral B cell pool, presumably reflecting both negative and positive selection. These selective events occur primarily during late stages of differentiation in the marrow and periphery, when newly formed B cells bear surface IgM (sIgM), but differ from mature B cells in their expression of heat-stable Ag (CD24), B220 (CD45), and sIgD. Because genes of the Bcl-2 family influence longevity, we compared the expression of Bcl-2, Bax, and A1 among immature vs mature peripheral B cells using semiquantitative reverse-transcriptase PCR. While the levels of both Bcl-2 and Bax mRNA remain constant in these two populations, A1 expression is strikingly up-regulated among mature B cells. In addition, A1 expression is low among pro- and pre-B cells, as well as in immature (sIgM+) marrow B cells. Together, these data indicate that A1 mRNA expression is low at all stages of B cell development before final maturation in the periphery and, unlike other Bcl-2 family members whose expression changes little after marrow egress, A1 is up-regulated 10-fold as cells are recruited into the long-lived peripheral B cell pool.
Post-Thymic Maturation of Migrating Human Thymic Single-Positive T Cells: Thymic CD1a− CD4+ T Cells Are More Susceptible to Anergy Induction by Toxic Shock Syndrome Toxin-1 than Cord Blood CD4+ T Cells
Authors: Imanishi Ken’ichi , Seo Kazuhiro , Kato Hidehito , Miyoshi-Akiyama Tohru , Zhang Rui-Hua , Takanashi Yoshinori , Imai Yasuharu , Uchiyama Takehiko 
Published: January 2023

Abstract
To determine whether human CD4+ T cells undergo post-thymic maturation, we compared the susceptibility to anergy induction in human thymic CD1a− CD4+ single-positive (CD4+), cord blood (CB) CD4+, and adult peripheral blood (APB) CD4+ T cells by stimulation with toxic shock syndrome toxin-1 (TSST-1). Most TSST-1-induced T cell blasts derived from either T cell preparation expressed TCR Vβ2, which determines the potential reactivity to TSST-1. Most thymic CD4+ T cell blast preparations exhibited little or no production of IL-2 and IL-4 after restimulation with TSST-1 and only marginal responses after stimulation with rIL-2 or a combination of PMA and calcium ionophore, while the APB CD4+ T cell blasts showed high responses to these stimuli. The responses of CB CD4+ T cell blasts to these stimuli varied, ranging from minimal to relatively high. Studies of DNA fragmentation showed that there was no significant cell death of thymic CD4+ T cell blasts. Most thymic CD1a− CD4+ and CB CD4+ T cells were CD38 positive. APB CD4+ T cell blasts derived from the CD38+ fraction and from the CD38− fraction exhibited equally high responses to restimulation with TSST-1. These results indicate that thymic CD1a− CD4+ and CB CD4+ T cells are inherently highly susceptible to anergy induction by bacterial superantigens and that thymic CD1a− CD4+ T cells are less mature than CB CD4+ T cells, suggesting that post-thymic maturation in thymic T cells migrating to the periphery is required for acquisition of full reactivity to antigenic stimulation.
The c-Jun N-Terminal Kinase Cascade Plays a Role in Stress-Induced Apoptosis in Jurkat Cells by Up-Regulating Fas Ligand Expression
Authors: Faris Mary , Kokot Niels , Latinis Kevin , Kasibhatla Shailaja , Green Douglas R. , Koretzky Gary A. , Nel Andre 
Published: January 2023

Abstract
T lymphocytes undergo apoptosis in response to cellular stress, including UV exposure and gamma irradiation. However, the mechanism by which stress stimuli induce apoptosis is not well understood. While stress stimuli induce the activation of the c-Jun N-terminal kinase (JNK) pathway, it is not clear whether the JNK cascade is activated as a result of cell death or whether the cascade participates in inducing apoptosis. Using a Jurkat T cell line transfected with dominant active (DA)-mitogen-activated protein kinase kinase kinase (MEKK1) in a tetracycline-regulated expression system, we found that expression of DA-MEKK1 results in the apoptosis of Jurkat cells in parallel with prolonged JNK activation. Moreover, DA-MEKK1 induced Fas ligand (FasL) cell surface and mRNA expression, as well as FasL promoter activation. Interference with Fas/FasL interaction prevented DA-MEKK1-mediated apoptosis. In comparing the effect of different stress stimuli to DA-MEKK1, we found that UV, gamma irradiation, and anisomycin prolonged JNK activation in parallel with FasL expression and onset of cell death. In addition, these stimuli also enhance cell surface expression of FasL. Interference with Fas/FasL interactions inhibited anisomycin but not UV- or gamma irradiation-induced apoptosis. Our data show that while the JNK pathway contributes to stress-induced apoptosis in T lymphocytes by regulating FasL expression, not all stress stimuli use the same cell death pathway.
Harnessing Syk Family Tyrosine Kinases as Signaling Domains for Chimeric Single Chain of the Variable Domain Receptors: Optimal Design for T Cell Activation
Authors: Fitzer-Attas Cheryl J. , Schindler Daniel G. , Waks Tova , Eshhar Zelig 
Published: January 2023

Abstract
T cells of tumor bearers often show defective TCR-mediated signaling events and, therefore, exhibit impaired immune responses. As such, patients with heavy tumor burden are often not amenable to adoptive T cell therapy. To overcome this limitation, we have developed a chimeric receptor that joins an extracellular single chain Fv (scFv) of a specific Ab for Ag recognition to an intracellular protein tyrosine kinase (PTK) for signal propagation. Stimulation through the scFv-PTK receptor should bypass defective TCR-proximal events and directly access the T cell’s effector mechanisms. In this study we describe the optimization of a scFv-PTK configuration, leading to complete T cell activation. The cytosolic PTK Syk is superior to its family member, Zap-70, for intracellular signaling. As a transmembrane (TM) domain, CD4 performs better than CD8 when plastic-immobilized Ag serves as a stimulator. However, when APC are used to trigger chimeric receptors, the need for a flexible spacer between the scFv and TM domains becomes apparent. The CD8α-derived hinge successfully performs this task in chimeric scFv-Syk receptors regardless of its cysteine content. A cytotoxic T cell hybridoma expressing chimeric receptor genes composed of scFv-CD8hinge-CD8TM-Syk or scFv-CD8hinge-CD4TM-Syk is efficiently stimulated to produce IL-2 upon interaction with APC and specifically lyses appropriate target cells in a non-MHC-restricted manner.
Induction of Granulomatous Experimental Autoimmune Thyroiditis in IL-4 Gene-Disrupted Mice
Authors: Tang Haiwen , Sharp Gordon C. , Peterson Karin E. , Braley-Mullen Helen 
Published: January 2023

Abstract
To study the role of IL-4 in development of granulomatous experimental autoimmune thyroiditis (EAT), IL-4 gene-disrupted mice expressing the EAT-susceptible H-2k haplotype were generated and used for EAT induction. Spleen cells from mouse thyroglobulin (MTg) and LPS-primed IL-4+/+ and IL-4−/− donors could induce severe granulomatous EAT when spleen cells were activated with MTg and anti-IL-2R mAb in the presence of IL-12. Thyroid lesions had extensive follicular cell proliferation, large numbers of histiocytes, polymorphonuclear leukocytes, and multinucleated giant cells, in addition to lymphocytes and other mononuclear cells. Expression of IFN-γ gene mRNA and production of IFN-γ by effector spleen cells stimulated with MTg and IL-12 were similar for both IL-4+/+ and IL-4−/− mice. Although IL-4 was undetectable in IL-4−/− mice, expression of mRNA for IL-5, IL-10, and IL-13 and production of IL-5 by both MTg-activated spleen cells and anti-CD3-activated CD4+ T cells were comparable for cells from IL-4+/+ and IL-4−/− mice, indicating that the absence of IL-4 did not prevent production of other Th2 cytokines. Production of MTg-specific IgG1 was very low or undetectable in IL-4−/− mice. IL-4 gene mRNA and MTg-specific IgG1 could be detected in IL-4+/+ or IL-4−/− recipients only when they received effector cells from IL-4+/+ donor mice, indicating that IL-4- and IgG1-secreting cells are of donor origin. These results demonstrate that IL-4 is not essential for development of granulomatous EAT.
Regulation of TCR Signal Transduction in Murine Thymocytes by Multiple TCR ζ-Chain Signaling Motifs
Authors: van Oers Nicolai S. C. , Love Paul E. , Shores Elizabeth W. , Weiss Arthur 
Published: January 2023

Abstract
The αβ TCR is a multimeric protein complex comprising ligand-binding and signal-transducing subunits. The signal transduction processes are mediated by the immunoreceptor tyrosine-based activation motifs (ITAMs), and up to 10 ITAMs are present within a single TCR complex. This multiplicity may allow for signal amplification and/or the formation of qualitatively distinct intracellular signals. Notably, the TCR-ζ subunit contains three ITAMs, and exists as a disulfide-linked homodimer in the TCR complex. In normal murine thymocytes and peripheral T cells, a proportion of TCR-ζ molecules is constitutively tyrosine phosphorylated and associated with the ZAP-70 protein tyrosine kinase. We examined the contribution of the different TCR-ζ ITAMs in regulating the constitutive phosphorylation of the TCR-ζ subunit in thymocytes by analyzing TCR-ζ-deficient mice that had been reconstituted with either full-length or single ITAM-containing TCR-ζ subunits. We report in this work that in the absence of a full-length TCR-ζ subunit, there is no apparent constitutive phosphorylation of the remaining TCR/CD3 ITAMs. Following TCR ligation, all of the CD3 ITAMs become inducibly phosphorylated and associate with the ZAP-70 protein tyrosine kinase. Regardless of the number of TCR-ζ ITAMs present in the TCR complex, we report that a number of molecules involved in downstream signaling events, such as ZAP-70, SLP-76, and pp36, are all inducibly tyrosine phosphorylated following TCR ligation. These results support the notion that the different TCR ITAMs function in a quantitative rather than qualitative manner.
Characterization and Mapping to Human Chromosome 8q24.3 of Ly-6-Related Gene 9804 Encoding an Apparent Homologue of Mouse TSA-1
Authors: Shan Xiaochuan , Bourdeau Annie , Rhoton Angela , Wells Dan E. , Cohen Edward H. , Landgraf Bryan E. , Palfree Roger G. E. 
Published: January 2023

Abstract
The 9804 gene, which encodes a human Ly-6 protein most similar to mouse differentiation Ag TSA-1/Sca-2, has also been called RIG-E. Like mouse TSA-1, it has a broad tissue distribution with varied expression levels in normal human tissues and tumor cell lines. Like some members of the murine Ly-6 family, the 9804 gene is responsive to IFNs, particularly IFN-α. Overlapping genomic fragments spanning the 9804 gene (5543 bp) have been isolated and characterized. The gene organization is analogous to that of known mouse Ly-6 genes. The first exon, 2296 bp upstream from exon II, is entirely untranslated. The three coding exons (II, III, and IV) are separated by short introns of 321 and 131 bp, respectively. Primers were developed for specific amplification of 9804 gene fragments. Screening of human-hamster somatic cell hybrids and yeast artificial chromosomes (YACs) indicated that the gene is distal to c-Myc, located in the q arm of human chromosome 8. No positives were detected from the Centre d′Etude du Polymorphisme Humain mega-YAC A or B panels, nor from bacterial artificial chromosome libraries; two positive cosmids (c101F1 and c157F6) were isolated from a human chromosome 8 cosmid library (LA08NC01). Fluorescence in situ hybridization of metaphase spreads of chromosome 8, containing hybrid cell line 706-B6 clone 17 (CL-17) with cosmid c101F1, placed the 9804 gene close to the telomere at 8q24.3. This mapping is significant, since the region shares a homology with a portion of mouse chromosome 15, which extends into band E where Ly-6 genes reside. Moreover, the gene encoding E48, the homologue of mouse Ly-6 molecule ThB, has also been mapped to 8q24.
Identification of an Inhibitory MHC Receptor on Alloreactive Rat Natural Killer Cells
Authors: Naper Christian , Ryan James C. , Nakamura Mary C. , Lambracht Doris , Rolstad Bent , Vaage John T. 
Published: January 2023

Abstract
Studies of allogeneic lymphocyte cytotoxicity have shown that the rat NK allorecognition repertoire is controlled by genetic elements in both the MHC (RT1) and the NK gene complex (NKC). DA rats, possessing NK cells that are unable to lyse allogeneic lymphoblasts, were immunized with alloreactive NK cells from MHC-matched PVG.1AV1 rats, and two mAb, STOK1 and STOK2, were generated. STOK1 and STOK2 stained identical subsets of NKR-P1+ T and NK cells from certain strains of rats. Relative numbers varied markedly in a panel of MHC congenic strains, however, implicating a role for self MHC genes in their development. Both STOK1 and STOK2 immunoprecipitated a 110-kDa disulfide-linked homodimeric molecule, with extensive N-linked glycosylations, encoded by a gene that mapped to the NKC. NK cells expressing this glycoprotein displayed an increased ability to lyse allogeneic lymphoblasts, while syngeneic targets were spared. However, blockade of the STOK2 Ag with F(ab′)2 of STOK2 permitted the NK lysis of syngeneic targets, but did not affect NK allorecognition. These results indicate that mAb STOK1 and STOK2 identify an NKC-encoded MHC receptor in the rat that acts as a negative regulator of cytotoxicity.