bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Ca2+ current in Jurkat T cells following the depletion of Ca2+ stores by microsomal Ca(2+)-ATPase inhibitors.
Authors: Premack B A , McDonald T V , Gardner P 
Published: December 2022

Abstract
The mechanism of TCR-stimulated Ca2+ influx was studied in the Jurkat human T cell line using Ca2+ indicator dyes and whole-cell patch clamp. Ca2+ influx induced by inositol 1,4,5-triphosphate (IP3)-coupled surface receptors (either the TCR or a heterologous muscarinic receptor) was compared with Ca2+ influx induced by inhibitors of the microsomal Ca(2+)-ATPase (thapsigargin, cyclopiazonic acid, di-tert-butylhydroquinone), which release stored Ca2+ without production of IP3. The same Ca2+ influx pathway could be activated by IP3-dependent or IP3-independent means, and therefore appeared to be regulated by the fullness of the microsomal Ca2+ stores rather than by the direct action of IP3. Depletion of stored Ca2+ by either receptor stimulation or microsomal Ca(2+)-ATPase inhibition activated a low conductance, Ca(2+)-selective, non-voltage-activated membrane current. Ca2+ currents induced by receptor stimulation and Ca(2+)-ATPase inhibition were not additive. Several properties of the depletion-activated Ca2+ current suggest that it is carried by a novel type of Ca2+ channel rather than an electrogenic carrier or pump. The conductance saturated when external Ca2+ was raised (Kd approximately 2 mM) and became highly permeable to monovalent cations when external Ca2+ was lowered to below 100 nM, much as has been observed for some voltage-gated Ca2+ channels. The Ca2+ current was reversibly blocked by &gt; 90% with 0.3 mM Cd2+, whereas the same concentration of Ni2+ or Co2+ blocked only 50 to 60% of the current. However, the absence of voltage-dependent activation, relative conductance sequence for divalent cations (Ca2+ &gt; Ba2+ approximately Sr2+ &gt; Mn2+), and lack of inhibition by nifedipine, D600, diltiazem, delta-conotoxin, or aga-IVa were unlike that of voltage-gated Ca2+ channels.
Unique antigen recognition by a herpesvirus-specific TCR-gamma delta cell.
Authors: Sciammas R , Johnson R M , Sperling A I , Brady W , Linsley P S , Spear P G , Fitch F W , Bluestone J A 
Published: December 2022

Abstract
TCR-gamma delta cells, a T cell subset present in the epithelial and lymphoid tissues, have been implicated in viral and bacterial infections. We have identified a TCR-gamma delta clone (TgI4.4) that, unlike TCR-alpha beta cells, recognizes a herpes simplex virus type 1 transmembrane glycoprotein, gI, in an MHC class I- and class II-independent fashion. The TCR of TgI4.4 is composed of rearranged V delta 8 (a V alpha 2 family member) and V gamma 1.2 variable genes, a heterodimeric pair not previously described. Furthermore, anti-V alpha 2 mAbs are sufficient to block recognition of the gI ligand. Strikingly, anti-gI Abs also are capable of blocking recognition, a phenomena that is very rare in TCR-alpha beta Ag recognition. Therefore, to dissect the mechanism involved in this unique form of Ag recognition, we constructed a mutant of gI, gIt, that lacks cell surface expression upon transfection into APCs. This form of gI was not sufficient for Ag presentation. In contrast, wild-type gI expressed in the Ag-processing mutant cell, RMA-S, is recognized by TgI4.4, suggesting that gI presentation occurs independently of classical Ag-processing pathways. In fact, through the use of a soluble recombinant gI molecule, gI-Ig, we show that TgI4.4 can recognize whole, unprocessed gI protein in the absence of any APCs. These results suggest that there exist alternate and novel forms of TCR Ag recognition, and that the TCR-gamma delta clone, TgI4.4, may represent a novel T cell subset that, during pathogenic challenge, may respond directly to Ags on the surfaces of bacteria and viruses.
Both naive and memory CD4 T cell subsets become anergic during MAIDS and each subset can sustain disease.
Authors: Koch S , Muralidhar G , Swain S L 
Published: December 2022

Abstract
Infection of C57BL/6 mice with the LP-BM5 mixture of retroviruses causes a severe murine acquired immunodeficiency syndrome (MAIDS). After infection, the entire CD4 T cell population shifts to a memory/activated phenotype and the CD4 cells become anergic to further stimulation. This drastic shift in phenotype could result either from a response of naive cells to the virus or its products and/or from the selective expansion of cells already having a memory phenotype. We have investigated whether both naive and memory CD4 T cells can be anergized during BM5 infection and whether each subset is sufficient for disease development. We show that V beta 3/V alpha 11 TCR transgenic mice that have &gt; 98% CD4 T cells with naive phenotype develop MAIDS. Their spleens and lymph nodes become enlarged, their CD4 population expressing the TCR transgene shifts to a memory/activated phenotype, and the CD4 cells neither proliferate nor secrete IL-2 in response to specific Ag, a fragment of pigeon cytochrome C, or to mitogens. Adult thymectomized mice, having memory but not naive CD4 T cells, also developed MAIDS and anergy of the CD4 T cell population at a rate and extent comparable to normal control mice. Furthermore, CD4 T cells from mice primed with keyhole limpet hemocyanin 6 wk before infection with BM5 also became unresponsive to KLH during MAIDS. Thus, both naive and memory CD4 T cells are rendered anergic by the BM5 virus infection and it is likely that each subset is sufficient to sustain the development of MAIDS.
Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide.
Authors: Wucherpfennig K W , Zhang J , Witek C , Matsui M , Modabber Y , Ota K , Hafler D A 
Published: December 2022

Abstract
TCR rearrangements were used to probe the clonal origin of myelin basic protein (MBP)-reactive T cells from patients with multiple sclerosis (n = 7) and normal subjects (n = 3). The majority of MBP-specific T cell lines were specific for the immunodominant MBP(84-102) and MBP(143-168) peptides and were restricted by HLA-DR molecules. In two patients with the DR2 haplotype, the T cell response to MBP was focused on the MBP(84-102) peptide. In both patients, in vivo expanded population(s) (three expanded populations in the first patient, one expanded population in the second patient) dominated the response to the MBP(84-102) peptide. Two MBP(84-102)-specific T cell clones from a normal subject with the DR2 haplotype were also found to have identical TCR sequences. Clonality was proven by demonstrating that independent clones had identical TCR alpha- and TCR beta-chain sequences as well as identical sequences of a TCR gamma-chain or of a second TCR alpha-chain rearrangement. Repeated analysis of one patient after 13 mo demonstrated that the three expanded clones had persisted in vivo. A representative of one of the expanded clones was again obtained after 31 mo by IL-2 stimulation suggesting that this clone was activated in vivo. These data suggest that the response to human MBP is dominated in at least some subjects by expanded clones that may persist in vivo for relatively long periods of time.
Thiol-mediated redox regulation of lymphocyte proliferation. Possible involvement of adult T cell leukemia-derived factor and glutathione in transferrin receptor expression.
Authors: Iwata S , Hori T , Sato N , Ueda-Taniguchi Y , Yamabe T , Nakamura H , Masutani H , Yodoi J 
Published: December 2022

Abstract
The proliferative response of PBMC to PHA, Con A, OKT3 mAb and IL-2-dependent proliferation of PHA-blasts was examined in a thiol-free environment (cultured in a L-cystine- and GSH-free medium). [3H]TdR incorporation assay and cell cycle analysis revealed that stimulated PBMC could not enter the S phase when deprived of these thiol compounds. In thiol-free cultures, an increase in intracellular free Ca2+ concentration and IL-2R alpha-chain/p 55 (Tac) induction was still observed, whereas transferrin receptor induction was markedly reduced, suggesting that the proliferative response of mitogenically stimulated PBMC was arrested in the late G1 phase in which transferrin receptor is induced. In GSH-depleted cultures, a similar reduction of the proliferative response of PBMC and PHA-blasts was observed when the concentration of L-cystine was lowered, in a dose-dependent manner. Each reduction or loss of proliferative response was partially restored by supplementation of 2-ME or adult T cell leukemia-derived factor (ADF)/human thioredoxin which is considered to be an endogenous dithiol-reducing factor. L-Cystine transport analysis showed that mitogenically stimulated PBMC and PHA blasts incorporated L-cystine, whereas resting PBMC did not. Furthermore, ADF as well as 2-ME exhibited an enhancing activity on the L-cystine transport in PHA blasts. Together with the fact that L-cystine transport is a limiting step in glutathione synthesis, these findings suggest that GSH and ADF might cooperate in the thiol-mediated redox regulation process and might also play key roles in cell cycle (late G1 to S) progression of activated lymphocytes.
TCR-dependent and -independent signaling mechanisms differentially regulate lymphokine gene expression in the murine T helper clone D10.G4.1.
Authors: Naora H , Altin J G , Young I G 
Published: December 2022

Abstract
The signaling mechanisms that regulate lymphokine gene expression in the murine Th2 clone D10.G4.1 were investigated by comparing the steady state mRNA levels of six lymphokine genes in response to cellular treatment with various activators and inhibitors of several key signaling pathways. A surprising degree of differential regulation was found. All of the genes studied (IL-3, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage (GM)-CSF) were induced by the lectin Con A and the TCR idiotype-specific mAb 3D3. However, the induction of the IL-3, IL-4, and GM-CSF genes, but not the IL-5, IL-6, and IL-10 genes, was strongly inhibited by cyclosporin A. Furthermore, IL-5, IL-6, and IL-10 genes were independently induced by IL-1 alpha, the phorbol ester PMA, and by forskolin, an activator of adenylate cyclase. Results of studies performed with use of the Ca2+ ionophore A23187 indicated that elevation of intracellular Ca2+ levels is sufficient to fully induce IL-3 and IL-4 gene expression. Protein kinase C activation was also required for full induction of the GM-CSF gene and seemed to be obligatory for maximal IL-5 gene expression. The patterns of mRNA induction by the different stimuli broadly correlated with increased rates of transcription. In addition to their induction by IL-1 alpha, the IL-5, IL-6, and IL-10 genes were also induced by mAbs to CD2 and to CD45. In contrast, adding CD45 mAb strongly inhibited the induction of IL-3, IL-4, and GM-CSF genes through TCR stimulation. These results indicate that distinct groups of lymphokine genes may be differentially regulated by signaling pathways that are activated by stimulation of the TCR and other cell surface molecules.
Inhibition of the transendothelial migration of human T lymphocytes by prostaglandin E2.
Authors: Oppenheimer-Marks N , Kavanaugh A F , Lipsky P E 
Published: December 2022

Abstract
To determine whether part of the anti-inflammatory effects of prostaglandin E2 (PGE2) was related to inhibition of T cell interactions with endothelial cells (EC), the effects of PGE2 and other cAMP-elevating agents on the transendothelial migration of human T cells was examined. Although PGE2 did not effect T cell binding to EC, concentration-dependent inhibition of the transendothelial migration of T cells through unstimulated or IL-1-activated EC was observed. PGE2 inhibited the function of both T cells and EC, with maximal inhibition observed when both T cells and EC were treated with PGE2. However, the inhibitory action of PGE2 could not be ascribed to an effect on the adhesion receptor pair, CD11a/CD18-CD54. The inhibitory effect of PGE2 seemed to relate to its capacity to elevate cellular cAMP levels, because 3-isobutyl-1-methylxanthine enhanced PGE2 activity and dibutyryl cAMP and forskolin also inhibited transendothelial migration. The inhibitory effect of PGE2 and the other cAMP-elevating agents on the function of T cells related in part to suppression of their intrinsic locomotory behavior as random migration in the absence of EC was blocked. In EC, PGE2 and the other cAMP-elevating agents increased the barrier function of EC as evidenced by a decrease in the diffusion of [3H]mannitol through the endothelium. These results indicate that part of the anti-inflammatory action of PGE2 relates to its capacity to suppress the transendothelial migration of T cells by cAMP-mediated alterations in the function of both T cells and EC.
Control of T lymphocyte activation and IL-2 receptor expression by endogenously secreted lymphokines.
Authors: Pimentel-Muiños F X , Muñoz-Fernández M A , Fresno M 
Published: December 2022

Abstract
The relative contribution of endogenously secreted lymphokines, TNF-alpha and IL-2, to T cell activation has been studied. Interestingly, a neutralizing anti-TNF-alpha mAb strongly inhibited the proliferation, IL-2R alpha expression, and activation of the nuclear factor (NF)-kappa B induced on human purified T lymphocytes by an immobilized anti-CD3 mAb (imm.anti-CD3). Furthermore, the addition of exogenous TNF-alpha to T cells activated by imm.anti-CD3 or phorbol esters strongly stimulated all those activities. Similarly, neutralizing anti-IL-2R alpha Abs inhibited the cell proliferation and the IL-2R alpha expression induced by imm.anti-CD3, whereas exogenous addition of IL-2 enhanced both activities. However, exogenous addition of IL-2 did not affect NF-kappa B activation. Cyclosporin A, which prevented lymphokine mRNA transcription, inhibited more than 90% of the IL-2R alpha and NF-kappa B levels induced by TCR/CD3-mediated activation. Exogenous TNF-alpha and IL-2 were equally important to the partial recovery of this IL-2R alpha inhibition, and high doses of both lymphokines together completely abolished the inhibitory effect of cyclosporin A. However, only TNF-alpha (but not IL-2) efficiently recovered the nuclear NF-kappa B levels. Those results indicate that the autocrine secretion of TNF-alpha and IL-2, and not the primary stimulus itself, contribute mostly to the regulation of IL-2R; thereby playing a very important role in quantitative control of T cell proliferation and leaving to the specifically TCR/CD3-derived signals the triggering role in T cell activation.
Identification of a novel 33-kDa C1q-binding site on human blood platelets.
Authors: Peerschke E I , Reid K B , Ghebrehiwet B 
Published: December 2022

Abstract
The constitutive expression of a 60-kDa platelet membrane protein (cC1qR) recognizing the collagen-like amino terminal of C1q was previously described. Recently, a novel 33-kDa C1q receptor (gC1qR) that interacts with the globular head region of C1q was identified on Raji cells, as well as PBLs, neutrophils, and eosinophils. The present study demonstrates that polyclonal Abs directed against this novel C1q-binding protein also recognize a 33-kDa platelet membrane constituent on Western blots. Interestingly, Ab reactivity with platelets in suspension was minimal, but increased nearly 10-fold after platelet adhesion to collagen, fibrinogen, or fibronectin-coated surfaces. Similar increases in Ab reactivity were not achieved after platelet stimulation in suspension, even with strong agonists such as thrombin or A23187. Platelet function studies, however, demonstrated that both the globular C-terminal domain of C1q and the collagen-like N-terminal region participate in platelet aggregation in response to C1q multimers. Moreover, a synthetic 18 amino acid peptide (X18) corresponding to the amino terminal sequence of the cloned Raji cell gC1qR inhibited both platelet adhesion to immobilized C1q and aggregated C1q-induced platelet aggregation. Aggregated C1q-induced platelet aggregation was also inhibited by a mAb (1B4) directed against the recombinant gC1qR. The data support the involvement of both carboxy- and amino-terminal regions of C1q in platelet-C1q interactions, and suggest a role for the gC1qR in this process.
High expression of V gamma 8 is a shared feature of human gamma delta T cells in the epithelium of the gut and in the inflamed synovial tissue.
Authors: Söderström K , Bucht A , Halapi E , Lundqvist C , Grönberg A , Nilsson E , Orsini D L , van de Wal Y , Koning F , Hammarström M L 
Published: December 2022

Abstract
We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a new mAb (B18) specific for V gamma 8 of human TCR-gamma delta+ T cells. The B18+ population constituted a minor subset of the gamma delta T cells in peripheral blood (PB) of healthy persons (6 +/- 5%) and only 1 of 35 gamma delta T cell clones analyzed was positive. In contrast, the B18+ subset was a dominant gamma delta T cell population among intraepithelial lymphocytes (IEL) derived from the human intestine (74 +/- 29, p &lt; 0.002), and two of three IEL clones from patients with coeliac disease were B18+. Interestingly, a higher proportion of B18+ gamma delta T cells was found in the synovial fluid of patients with rheumatoid arthritis (RA) (21 +/- 18%, 0.02 &lt; p &lt; 0.05) compared with normal PB. Furthermore, the B18+ subset was more frequent among IL-2-expanded gamma delta T cells (42 +/- 20%) derived from synovial tissue than among IL-2-expanded cells derived from synovial fluid (p &lt; 0.002) and PB from RA patients (p &lt; 0.02) as well as normal PB (p &lt; 0.002). The V-gene usage of 13 gamma delta T cell clones from the synovial fluid of arthritic patients was analyzed. All B18+ clones (n = 7) expressed mRNA for V gamma 8 together with mRNA for V delta 1 (n = 5) or mRNA for V delta 3 (n = 2). None of the B18- clones expressed V gamma 8 (n = 6). We conclude that the gamma delta T cell that expresses V gamma 8, together with mainly V delta 1, is a major gamma delta T cell subset among the IEL of the gut and a highly frequent subset in the synovial tissue of patients with RA. This subset may correspond to the mouse V gamma 7+ IEL, which has a high degree of amino acid sequence homology with the human V gamma 8 protein.
Extrathymic expression of the intracellular hepatitis B core antigen results in T cell tolerance in transgenic mice.
Authors: Milich D R , Jones J E , Hughes J L , Maruyama T , Price J , Melhado I , Jirik F 
Published: December 2022

Abstract
We previously developed a transgenic (Tg) murine lineage (B10.S-Tg31e), which secretes the hepatitis B e Ag (HBeAg) into the serum at a concentration of 10 ng/ml. This serum concentration was sufficient to render B10.S-Tg31e mice functionally tolerant at the T cell but not B cell level. To determine the tolerogenic potential of an intracellular form of this Ag, namely the hepatitis B core Ag (HBcAg), expressed outside the thymus, the B10.S-Tg10c lineage was developed. In B10.S-Tg10c mice the HBcAg is expressed as an intracellular "self"-Ag predominantly in the liver, and cannot be detected in the serum, the thymus or in nonthymic lymphoid tissue. Despite the liver-specific and intracellular location of this transgenic self-protein, B10-STg10c mice demonstrate a significant degree of HBcAg-specific T cell tolerance at the level of T cell proliferation. Similarly, in vivo anti-HBc antibody production after HBcAg immunization is significantly reduced as compared with non-Tg littermate controls. No spontaneous anti-HBc antibody is produced in B10.S-Tg10c mice, however, adoptive transfer of HBcAg-specific T cells from non-Tg B10.S mice elicits anti-HBc specific "autoantibody" production. Interestingly, antibodies with specificity for the HBeAg as well as the HBcAg are produced. Antibody production in B10.S-Tg10c mice adoptively transferred with T cells indicates that sufficient native HBcAg can gain access to the extracellular compartment to engage HBcAg-specific B cells that are clearly not tolerant in this model. No liver injury was observed as a consequence of HBcAg expression, even in B10.S-Tg10c mice adoptively transferred with HBcAg-specific T cells. Unless HBcAg is unique in this regard, these results suggest that organ-specific, intracellular self-Ag may be released during normal cell turnover in sufficient concentrations to elicit systemic T cell tolerance. B10.S-Tg10c mice also serve as an immunologic model system for chronic infection with the HBeAg-negative mutant of the hepatitis B virus.
Urokinase receptor. An activation antigen in human T lymphocytes.
Authors: Nykjaer A , Møller B , Todd R F , Christensen T , Andreasen P A , Gliemann J , Petersen C M 
Published: December 2022

Abstract
The ability of activated T lymphocytes to extravasate and reach inflammatory and malignant foci in the tissues is a basic function of cellular immunity. Recent evidence strongly suggests that the urokinase receptor (uPAR) holds a central position in the development of human two-chain urokinase-mediated pericellular proteolysis and matrix degradation, an important element in cell migration. In this report we establish uPAR as a pan T cell activation Ag. As determined by FACS analysis, CD3+ lymphocytes from healthy donors exhibited no significant uPAR expression. In contrast, patients (e.g., HIV-positive donors) showed distinct uPAR expression, confined to HLA-DR+ cells, in up to 80% of all T cells. In vitro activation by PMA caused a rapid up-regulation of membrane uPAR in all healthy donor T cells and was accompanied by enhanced receptor synthesis and elevated uPAR mRNA levels. A similar induction resulted from activation via the TCR/CD3 complex using mitogens (PHA, and Con A), anti-CD3 antibodies, and alloantigen. Receptor expression at single cell level was also modulated by a number of cytokines. IL-2, IL-4 and IL-7 increased uPAR presentation on 20 to 50% of the T cell population, and combined stimulation of bulk cultures demonstrated an additive effect of IL-2 and IL-7, whereas the response to each of the two was inhibited by IL-4. In addition, TGF-beta 1 substantially reduced the uPAR expression in T cell cultures responding to PHA, IL-2, and IL-7. Irrespective of the activating reagent, the T cells appeared to produce the same molecular uPAR species, but the affinity of uPAR expressed in PMA blasts was decreased, presumably because of a differential location at the cell surface. All activated cultures showed co-expression of uPAR and CD25. The finding that the urokinase receptor is an activation Ag may suggest that cell-associated plasminogen activation is involved in extravasation and migration of activated T cells.