bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification through bioinformatics of cDNAs encoding human thymic shared Ag-1/stem cell Ag-2. A new member of the human Ly-6 family.
Authors: Capone M C , Gorman D M , Ching E P , Zlotnik A 
Published: December 2022

Abstract
The Ly-6 family of cell surface molecules includes many members that have been characterized in the mouse. Until recently, very few Ly-6 family members had been described in the human. A significant development with important implications for novel gene discovery has been the growth of the public Expressed Sequence Tag (EST) database. Here we report that, through the application of bioinformatics analysis to the dbEST database, we obtained the sequence of human TSA-1/SCA-2, a new member of the human Ly-6 family. In addition, we identified full-length clones encoding this molecule as well as expression data in various tissues. Sequencing of the clones identified this way confirmed the sequence predicted through bioinformatics. This study constitutes an example of the application of bioinformatics to the analysis of the recently expanded databases for the identification of genes of potential importance in the immune system.
Ligation of MHC class I molecules on peripheral blood T lymphocytes induces new phenotypes and functions.
Authors: Bregenholt S , Röpke M , Skov S , Claesson M H 
Published: December 2022

Abstract
Microgram concentrations of immobilized anti-MHC class I (MHC-I) Ab induced proliferation of resting CD3+ T cells from peripheral blood. In contrast, soluble Ab did not activate T cells. Exposure of T cells to immobilized anti-MHC-I Ab for only 24 h was followed by proliferation and development of T cell-mediated cytotoxicity. Immediately following MHC-I ligation, the T cells responded with increased protein tyrosine phosphorylation, with new bands appearing in the SDS-PAGE. Exposure of T cells to immobilized anti-MHC-I Ab for 24 h induced an increased surface expression of the TCR/CD3 and CD28 molecules. MHC-I-induced proliferation of purified T cells was dependent on cellular interactions with non-T cells. Under certain conditions, in which MHC-I was ligated by picogram concentrations of immobilized anti-MHC-I Ab, anti-TCR/CD3 Ab-induced proliferation of T cells was strongly inhibited. These data clearly demonstrate that ligation of the MHC-I complex on T cells may induce both positive and negative signals. Since the physiologic ligands for MHC-I molecules are TCR and the CD8 molecules, our data may suggest that MHC-I molecules are instrumental in cellular interactions between T cells.
Murine T lymphocytes modulate activity of an ATP-activated P2Z-type purinoceptor during differentiation.
Authors: Chused T M , Apasov S , Sitkovsky M 
Published: December 2022

Abstract
Murine T, but not B, lymphocytes constitutively express a membrane receptor for adenosine nucleotides that opens a nonspecific pore that admits Ca2+ and ethidium (314 Da), but not propidium (415 Da) ions. ATP, ADP, and AMP show decreasing potency; UTP and adenosine are inactive. Nonhydrolyzable ATP analogues are completely ineffective. Oxidized ATP inhibits the response. Activity is detectable at ATP concentrations of 125 microM and peaks at 1 mM. The intracellular free Ca2+ ([Ca2+]i) rise is not reversed by removing ATP by centrifugation or apyrase. The kinetics, agonist and antagonist profiles, and the passage of ions as large as ethidium are the characteristics of a P2z-type purinoceptor. No expression of classical P2x-, P2u-, or P2Y-type purinoceptors can be detected. The [Ca2+]i elevating activity of the ATP receptor is modulated during T cell differentiation. CD4+8+ double-positive thymocytes are the least responsive. CD4-8+ single-positive thymocytes, CD8+ splenic T cells, CD4+8- single-positive thymocytes, and CD4+ splenic T cells show increasing reactivity. Measurement of P2Z expression by the rate of ethidium ion uptake correlates with the [Ca2+]i. The trimodal expression of P2Z by splenic CD4+ T cells correlates with the subsets defined by CD44 and CD45RB, differentiation Ags that distinguish memory cells: P2Zlow cells are CD44brightCD45RBbright; P2Zint are CD44dullCD45RBint; P2Zhigh are CD44brightCD45RBdull. It is suggested that P2Z receptor-mediated signaling could be involved in the regulation of differentiation and cell death in the thymus and peripheral T lymphocytes.
Activated B cells express CD28/B7-independent costimulatory activity.
Authors: Ding L , Shevach E M 
Published: December 2022

Abstract
Resting and activated B cells display distinct phenotypes and functional properties. Resting B cells are incompetent accessory cells whereas activated B cells are capable of triggering T cell activation. The up-regulation of expression of the B7 family of molecules has been considered to be the primary reason for this functional conversion of activated B cells. We report here that activation of B cells induces a novel costimulatory activity for induction of T cell proliferation, which is independent of the CD28/B7 costimulatory pathway. B cells activated by different stimuli expressed comparable levels of many of the known counter-receptors for costimulation and intercellular adhesion (B7-1, B7-2, HSA, ICAM-1), but differed markedly in their capacity to activate CD4+ T cells from CD28-deficient (-/-) mice. Activation of B cells via CD40, and to a lesser extent with LPS, induced potent B7/CD28-independent costimulatory activity that resulted in marked augmentation of IL-2-mediated proliferative responses of CD4+ T cells from CD28 -/- mice. The B7/CD28-independent costimulatory pathway was capable of triggering the activation of naive CD4+ T cells, as both sorted CD45RBhigh and isolated high density naive CD4+ T cells from CD28 -/- mice responded vigorously to the costimulation provided by CD40L-activated B cells.
Inhibition of transcription factor Stat1 activity in mononuclear cell cultures and T cells by the cyclic AMP signaling pathway.
Authors: Ivashkiv L B , Schmitt E M , Castro A 
Published: December 2022

Abstract
Activation of T cells results in a cascade of gene activation and subsequent proliferation and differentiation into effector phenotypes. The regulation of transcription factors belonging to the signal transducer and activator of transcription (STAT) family was analyzed in PHA-activated mononuclear cells and in purified T cells activated by cross-linking cell surface CD3. Cell activation resulted in a delayed induction of STAT DNA-binding activity, which was sustained for several days, was composed predominantly of Stat1 and Stat3, and was blocked by cycloheximide and actinomycin D. Increased Stat1 and Stat3 mRNA and protein levels were detected, respectively 4 and 24 h after activation. Stimulation of the cAMP signal transduction pathway, which skews cytokine production toward a Th2 pattern, resulted in the preferential suppression of Stat1 activity. cAMP inhibited the induction of expression of IL-2 receptor components, but did not inhibit IL-4 receptor alpha-chain and CD69 expression or the induction of activator protein 1 transcription factors. cAMP signaling inhibited Stat1 at several different levels, including suppression of DNA binding and down-regulation of Stat1 protein and mRNA levels. Our results demonstrate the regulation of STAT activity by a signaling pathway that regulates the T cell functional phenotype and is distinct from the cytokine-activated Janus kinase-STAT signaling pathway.
CD40 ligation results in protein kinase C-independent activation of ERK and JNK in resting murine splenic B cells.
Authors: Li Y Y , Baccam M , Waters S B , Pessin J E , Bishop G A , Koretzky G A 
Published: December 2022

Abstract
CD40 is a 45- to 50-kDa transmembrane glycoprotein that plays an important role in B cell proliferation, survival, memory, and Ig isotype switching. How CD40 engagement couples to these distal events in B cell activation remains poorly understood. In this study, we have examined signal transduction events mediated by CD40 cross-linking in resting murine splenic B cells. In comparison to signaling via the B cell Ag receptor (BCR), CD40 cross-linking was less effective at activating protein tyrosine kinases. Interestingly, however, CD40 engagement resulted in the phosphorylation of both extracellular signal-regulated protein kinase (ERK) and the Ras guanine nucleotide exchange factor, Son of sevenless. In addition, both ERK and c-Jun NH2-terminal kinase activities were increased after both CD40 and BCR ligation. Overnight treatment of cells with phorbol ester as well as pharmacologic inhibitors of protein kinase C abrogated these signaling events after BCR treatment; however, no effect was seen on CD40-mediated activation of ERK or c-Jun NH2-terminal kinase, suggesting that the BCR and CD40 differentially utilize protein kinase C to couple with these signaling pathways.
Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome.
Authors: Razanajaona D , van Kooten C , Lebecque S , Bridon J M , Ho S , Smith S , Callard R , Banchereau J , Brière F 
Published: December 2022

Abstract
X-linked hyper-IgM (HIGM-1) syndrome is a rare disorder resulting from mutations in the CD40-ligand (CD40L) gene. This defect is associated with normal or elevated serum levels of IgM, and with low to undetectable levels of serum IgG, IgA, and IgE. We analyzed the somatic mutation status in Ig V genes from three unrelated HIGM-1 patients by reverse-transcription PCR and sequence analysis. Two patients (B.S. and P.S.) expressed unmutated VH6 genes. In contrast, one patient (A.T.) was found to express mutated VH6 genes. Whether the presence of somatic mutations in this patient was related to a functional CD40L was assessed by deriving T cell clones from his peripheral blood cells. Upon activation, these T cell clones expressed weakly and transiently surface CD40L, and were able to induce limited isotype switch of normal native B cells, indicating residual CD40L function. Altogether, our results 1) confirm the central role played by CD40L in the generation of somatic mutation (patients B.S. and P.S.), 2) provide an unusual illustration of the relative dissociation between somatic mutation and isotype switching (patient A.T.), and 3) demonstrate a further complexity of the X-linked HIGM syndrome that may occur despite a partially functional CD40L.
The transcription factor B-cell-specific activator protein is not involved in the IL-4-induced activation of the human IgE germline promoter.
Authors: Albrecht B , Peiritsch S , Messner B , Woisetschläger M 
Published: December 2022

Abstract
Transcriptional activity of the human IgE germline gene is a prerequisite for a subsequent deletional rearrangement of the Ig heavy-chain locus, the hallmark of isotype switching to IgE. The B-cell-specific transcription factor B cell-specific activator protein (BSAP) was described for being critically involved in the IL-4 up-regulation of the murine IgE germline gene. Our study was initiated to evaluate the regulatory role of BSAP in the human IgE germline promoter. It is shown that BSAP binds to a DNA element located immediately upstream of the most 5' transcriptional start site. The authenticity of BSAP was determined by electrophoretic mobility shift assays in which oligonucleotides corresponding to published BSAP binding sites efficiently competed for binding to the novel identified sequence. In addition, recombinant purified BSAP protein bound this motif and comigrated with the band seen with nuclear extracts. Finally, a polyclonal anti-BSAP antiserum specifically prevented interaction of the protein with its DNA recognition sequence. The affinity of BSAP for its recognition sequence was low compared with the sites identified in the CD19, the blk gene, and an LR1 transcription factor binding sequence located in the Ig gamma 1 switch region. Reporter gene constructs in which binding of BSAP was abolished by site-directed mutagenesis responded to IL-4 stimulation better than the wild-type construct in both cell lines tested. In addition, the basal activity of the mutated promoter did not change significantly despite the close proximity of the BSAP motif to the transcriptional start site. It is concluded that BSAP plays no direct regulatory role in the cytokine-induced response of the human IgE germline promoter.
Stat1 alpha expression is involved in IFN-gamma induction of the class II transactivator and class II MHC genes.
Authors: Lee Y J , Benveniste E N 
Published: December 2022

Abstract
Class II MHC Ags are critical in the regulation of immune responses by presenting Ag to T lymphocytes, resulting in their activation and differentiation. Class II expression is rare in the normal central nervous system, but elevated expression on glial cells has been observed in several neurologic diseases. We have previously demonstrated that IFN-gamma-induced class II expression in glial cells involves activation of both tyrosine kinase and protein kinase C. IFN-gamma induces tyrosine phosphorylation of the tyrosine kinases Jak1 and Jak2 and of Stat1 alpha. In addition, IFN-gamma enhances expression of Stat1 alpha mRNA and protein. We utilized antisense oligonucleotides against Stat1 alpha to determine directly whether IFN-gamma-induced activation and/or enhancement of Stat1 alpha is involved in class II expression. Antisense oligonucleotides complementary to Stat1 alpha mRNA were introduced in CH235-MG astroglioma cells by transient transfection; such treatment inhibited both constitutive and IFN-gamma-enhanced expression of Stat1 alpha. IFN-gamma-induced class II MHC expression was also inhibited in cells exposed to Stat1 alpha antisense oligonucleotides. The fact that the class II promoter does not contain IFN-gamma-activated sequences for binding Stat1 alpha suggests that Stat1 alpha must activate another protein that is directly involved in class II expression. A likely candidate is the class II MHC transactivator (CIITA). IFN-gamma induction of CIITA mRNA was also inhibited in cells treated with antisense oligonucleotides against Stat1 alpha. These findings demonstrate that Stat1 alpha is involved in IFN-gamma induction of CIITA expression, resulting in class II MHC expression.
Induction of autoimmunity in the absence of CD28 costimulation.
Authors: Bachmaier K , Pummerer C , Shahinian A , Ionescu J , Neu N , Mak T W , Penninger J M 
Published: December 2022

Abstract
Ag-specific activation of T lymphocytes requires two signals, one by the TCR and a second by costimulatory molecules. In a CD4+ T helper cell-dependent experimental autoimmune myocarditis model, we provide genetic evidence that cardiac myosin-induced autoimmune myocarditis and the production of IgG auto-Abs is dependent on functional T cells and did not occur in mice lacking the tyrosine kinase p56lck or the tyrosine phosphatase CD45. By contrast, animals lacking the T cell-costimulatory molecule CD28 (CD28 -/-) developed autoimmune heart disease, although at significantly lower severity than in heterozygous littermates, and produced IgG auto-Abs depending on the concentration of the autoantigen administered. In addition, the isotypes of IgG auto-Abs specific for cardiac myosin differed between CD28 +/- and CD28 -/- mice. Whereas CD28 +/- mice predominantly produced Th2-mediated IgG1 auto-Abs, CD28 -/- mice produced predominantly IgG2a. These data suggest that CD28 costimulation plays a crucial role in induction and maintenance of autoimmune heart disease and that CD28 expression is required for predominant Th2-IgG1 responses in an autoimmune setting.
Pathogenesis of post-thymectomy autoimmune gastritis. Identification of anti-H/K adenosine triphosphatase-reactive T cells.
Authors: Suri-Payer E , Kehn P J , Cheever A W , Shevach E M 
Published: December 2022

Abstract
Autoimmune gastritis spontaneously develops following thymectomy of 3-day-old BALB/c mice (d3Tx). These mice develop autoantibodies to the gastric parietal cell proton pump, H/K ATPase, and aberrant expression of the H/K ATPase in the neonatal thymus prevents the induction of disease post-thymectomy. To characterize the effector cells mediating autoimmune gastritis, we isolated H/K ATPase-enriched preparations of parietal cell microsomes and further purified the enzyme by lectin affinity chromatography. Both preparations induced significant proliferative responses of gastric lymph node cells, which were mediated by CD4+, MHC class II-restricted T cells. Surprisingly, T cells reactive to the Ag could only be demonstrated in lymph nodes in the immediate proximity of the stomach; little or no response was seen when mesenteric or peripheral lymph nodes were tested. It is likely that the H/K ATPase-reactive T cells are actually the effector cells in this disease, as they could only be detected in mice that developed gastritis, as indicated by anti-parietal cell Ab, gastric inflammation, and the presence of cells capable of transferring disease into nu/nu mice. H/K ATPase-specific T cell proliferative responses could first be detected 5 wk post-thymectomy and were accompanied by high background responses at this time point. These latter responses may represent enhanced syngeneic MLRs, which we have previously shown to be elevated in d3Tx mice. Characterizations of the H/K ATPase-reactive and self-reactive T cell populations may reveal the factors that break peripheral T cell tolerance and lead to the development of organ-specific autoimmune disease.
Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions.
Authors: Lundqvist C , Melgar S , Yeung M M , Hammarström S , Hammarström M L 
Published: December 2022

Abstract
The functional properties of intraepithelial lymphocytes (IEL) in normal human jejunum, ileum, and colon were investigated. Cytokine mRNA expression in IEL and enterocytes was determined by reverse transcriptase-PCR and IFN-gamma+ IEL by immunohistochemistry. Polyclonal activators were used to study proliferation and IFN-gamma secretion of IEL, and an anti-CD3-mediated redirected cytotoxicity assay was used to determine the lytic potential of IEL. Freshly isolated IEL at all three gut levels expressed mRNA for IL-1 beta, IL-2, IL-8, IFN-gamma, and TNF-alpha. Approximately 10% of IEL produced IFN-gamma, suggesting that IEL are immunologically active in vivo, performing similar functions along the intestine. IEL could be stimulated further in vitro to express IL-10, TNF-beta, and TGF-beta 1, while no Th2-type cytokines were induced, suggesting suppressive and cytolytic functions for IEL. All three jejunal IEL subpopulations (CD4-CD8-TCR-gamma delta+, CD4+TCR-alpha beta+, CD8+TCR-alpha beta+) expressed the same four cytokines, IL-2, IL-8, IFN-gamma, and TNF-alpha, indicating that CD4+TCR-alpha beta+ IEL are Th1 cells and that TCR-gamma delta+ IEL and CD8+TCR-alpha beta+ IEL include cytotoxic effector cells. Indeed, freshly isolated jejunal IEL displayed cytolytic activity. IEL were induced to proliferation by anti-CD3/TCR complex mAbs and leukoagglutinin, but not by Con A. There was no correlation between the magnitude of the proliferative response and the amounts of secreted IFN-gamma. Enterocytes expressed IL-1 beta and IL-8, and sometimes TNF-alpha. Although jejunal enterocytes express HLA-DR and hsp60, Ag presentation by these cells may induce anergy since their cytokine profile is different from that of classical APCs.
Switching on of the proliferation or apoptosis of activated human T lymphocytes by IFN-gamma is correlated with the differential expression of the alpha- and beta-chains of its receptor.
Authors: Novelli F , Bernabei P , Ozmen L , Rigamonti L , Allione A , Pestka S , Garotta G , Forni G 
Published: December 2022

Abstract
To find out how physiologically secreted IFN-gamma controls either the proliferation or the apoptosis of human T lymphocytes, the kinetics of expression of the alpha- and beta-chains of its receptor (IFN-gamma R) were sequentially followed on T lymphocytes first activated with PHA and then cultured in the presence of IL-2, and related to the kinetics of expression of Fas, Bcl-2, and IL-2R p55 chain. Both IFN-gamma R chains were poorly expressed on the membrane of resting T lymphocytes. Following their stimulation with PHA, IFN-gamma R alpha but not IFN gamma R beta-chain up-modulated before T lymphocyte entry into the S phase, and then IFN-gamma R alpha down-modulated when they passed through the S and G2/M. The ensuing proliferative response was inhibited by an anti-IFN-gamma R alpha mAb that impeded the binding of IFN-gamma. When PHA-activated T lymphoblasts were cultured for 16 days with IL-2, IFN-gamma R alpha expression increased, whereas that of the beta-chain remained barely detectable. Fas and Bcl-2 were both highly expressed. When these T lymphoblasts were restimulated by PHA, OKT3, or Staphylococcus enterotoxin beta-pokeweed mitogen, both chains up-modulated and most cells underwent apoptosis in a way apparently independent of Bcl-2, but not of Fas. This apoptosis, too, was prevented by the anti-IFN-gamma R alpha mAb. Physiologically secreted IFN-gamma is thus involved in the activation of resting T lymphocytes and in the apoptosis of reactivated lymphoblasts. However, high expression of IFN-gamma R beta took place when IFN-gamma induced apoptosis, but not when it induced proliferation. In conclusion, a correlation exists between differential expression of the IFN-gamma R beta-chain and the delivery by IFN-gamma of proliferative or apoptotic signals.
Induction of "infectious" tolerance to MHC-incompatible cardiac allografts in CD4 monoclonal antibody-treated sensitized rat recipients.
Authors: Onodera K , Lehmann M , Akalin E , Volk H D , Sayegh M H , Kupiec-Weglinski J W 
Published: December 2022

Abstract
LBNF1 heart grafts are rejected in an accelerated manner within 36 h by LEW rats that have been sensitized with Brown Norway rat skin grafts on day -7. Treatment with RIB-5/2, a CD4-nondepleting mAb (10 doses of 5 mg/rat/day, i.v., from day -7 to day +21) abrogated rejection at &lt;36 h and produced indefinite (&gt;200 days) cardiac allograft survival. Transplantation tolerance in this model developed within several weeks, and during the maintenance phase (&gt;100 days) it was associated with diminished host circulating allo-Ab responses and induction of peripheral allospecific T cell unresponsiveness both in vitro and in vivo. Tolerant cells in mAb-treated hosts could disable naive or alloimmune cells, so that they failed to trigger graft rejection. Moreover, donor-specific and organ-nonspecific tolerance could be adoptively transferred by spleen cells alone into new sets of primary (100%) and secondary (&gt;40%) test recipients. CD4+ T cells were instrumental for the induction of such readily transferable tolerance. The first and second generation suppressive regulatory cells were also critical for the inhibition of allograft recognition by normal or even alloimmune cells. Hence, the features of an "infectious" tolerance pathway to minor histocompatibility-mismatched skin grafts, originally described in thymectomized mice, may be applied to the euthymic primed rats rendered tolerant to fully MHC-incompatible vascularized organ allografts. Such reprogramming of host cell-mediated regulatory mechanisms following CD4-targeted therapy adds to our appreciation of the potential utility and applicability of infectious tolerance in transplant recipients treated with a perioperative course of CD4-targeted monotherapy.