bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of anergy in human T helper 0 cells by stimulation with altered T cell antigen receptor ligands.
Authors: Tsitoura D C , Holter W , Cerwenka A , Gelder C M , Lamb J R 
Published: December 2022

Abstract
CD4+ T cells may become profoundly unresponsive to antigenic restimulation following ligation of TCR by immunogenic peptides bound to MHC class II molecules in the absence of costimulation. Furthermore, it has been reported that anergy can be induced as a consequence of engagement of TCR by analogues of antigenic peptides presented by live APCs. In this study, based on resolution of the crystal structure of an influenza virus hemagglutinin (HA) peptide (HA 306-318) bound to HLA-DRB1*0101, we investigated the potential of analogues with amino acid substitutions at those positions predicted to form interactions with TCR to differentially activate and/or anergize HA-specific human Th0 cells restricted by DR1 class II molecules. For some analogues altering the affinity of peptide/TCR interactions revealed a direct positive correlation between antigenicity and their ability to induce anergy. Nevertheless, certain HA peptide analogues functioned as partial agonists, which although they failed to stimulate clonal expansion, were capable of rendering the Th0 cells unresponsive to immunogenic rechallenge. Furthermore, differences were noticed in the characteristics of the anergic phenotype induced by selected analogues. Restimulation with the native peptide of Th0 cells pre-exposed to the HA analogues in the absence of costimulatory signals failed to uncouple IL-4 and IFN-gamma secretion; however, in some instances, dissociation of proliferation from cytokine production was observed. The ability to differentially signal T cells through changing the affinity of peptide/TCR interactions may have implications in the potential use of altered TCR ligands in immunotherapy.
Very late antigen-4/vascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway is involved in the transendothelial migration of lymphocytes in bancroftian filariasis.
Authors: Freedman D O , Parker-Cook S , Maia e Silva M C , Braga C , Maciel A 
Published: December 2022

Abstract
The role of endothelial vascular cell adhesion molecule-1 (VCAM-1) in the trafficking of lymphocytes from the vascular circulation through endothelium and into sites of filarial inflammation was investigated in asymptomatic microfilaremic (MF; n = 16) and in patients with filaria-associated lymphatic pathology (LP; n = 23). When compared, by human umbilical vein endothelial cell ELISA, with PBMC supernatants generated from MF patients, filarial Ag (Brugia malayi adult Ag (BmA))-stimulated supernatants from LP patients stimulated over 50% more VCAM-1 (lymphatic pathology (LP) = 0.377 relative ELISA units vs MF = 0.246; p = 0.02). No difference was seen between patient groups with nonfilarial Ag (streptolysin O)-stimulated supernatant (LP = 0.160 relative ELISA units vs MF = 0.166). BmA-stimulated supernatants from LP patients stimulated significantly more T cell migration (percentage of relative migration LP = 79.9% vs MF = 25.8%; p = 0.01) through tightly confluent human umbilical vein endothelial cell monolayers cultured on collagen gels. Anti-VCAM-1 inhibited the increased T cell migration induced by BmA-stimulated supernatants by 97.7%, anti-VLA-4 by 74.7%, and blockade of NF-kappa B-dependent VCAM-1 transcription with 50 microM pyrrolidine dithiocarbamate resulted in 87.7% inhibition. Biopsies from 87.5% of the LP patients, but only 38.5% of the MF patients, demonstrated VCAM-1 on vascular endothelium. BmA-stimulated supernatants pretreated with anti-IL-1 alone resulted in VCAM-1 expression that was 23.7% of that with untreated supernatants while anti-IL-4, anti-IFN-gamma, or anti-TNF alone had essentially no effect on VCAM-1 expression.
Tumor rejection requires a CTLA4 ligand provided by the host or expressed on the tumor: superiority of B7-1 over B7-2 for active tumor immunization.
Authors: Gajewski T F , Fallarino F , Uyttenhove C , Boon T 
Published: December 2022

Abstract
Although transfection to express any of a multitude of immunomodulatory molecules can lead to the rejection of murine tumors in vivo, it is not clear which of these cofactors are truly important for the induction of tumor-specific CTL. Examination of the costimuli used by the host immune response during the normal rejection of immunogenic tumors should reveal critical cofactors for CTL differentiation in vivo. The involvement of a host B7 family costimulator molecule in the rejection of immunogenic tum- variants of the mastocytoma P815 was explored. Rejection of immunogenic P815 variants was prevented by mCTLA4 gamma 3, a fusion protein between the extracellular domain of murine CTLA4 and the Fc portion of a murine IgG3 Ab, indicating the importance of a CTLA4 ligand provided by the host in the rejection of B7- tumors. Tumor rejection also was prevented by mCTLA4 gamma 3 in the absence of CD4+ cells, suggesting that CD8+ lymphocytes may receive direct costimulation by B7 in vivo. Finally, although living transfectants of poorly immunogenic P1.HTR cells expressing B7-1 or B7-2 were equally rejected by syngeneic mice, if delivered as multiple injections of irradiated cells, only B7-1 transfectants successfully induced CTL activity and protected against living tumor challenge. Our results indicate that a CTLA4 ligand is normally involved in the generation of CD8+ CTL against tumor Ag and suggest that immunization with irradiated B7-1-transfected tumor cells may be superior to immunization with irradiated B7-2 transfectants as an approach to tumor Ag vaccination in patients.
Molecular basis of T cell dysfunction in cancer is influenced by the paracrine secretion of tumor-derived IL-2.
Authors: Salvadori S , Zier K 
Published: December 2022

Abstract
Previously we reported that T cells from mice bearing parental tumors have a variety of functional and biochemical defects when compared with T cells from mice bearing IL-2-secreting tumors. The biochemical defects included reduced levels of several cytoplasmic proteins such as p56lck, p59fyn, and zeta, all of which are known to be critical for signal transduction through the TCR. Based upon these results, we determined the consequences of these alterations on downstream signaling events. First, we showed that T cells of parental tumor-bearing mice have a reduction of total in vitro kinase activity associated with the TCR/CD3 compared with T cells from mice with IL-2-secreting tumors. Second, we observed that following activation, only T cells from IL-2-secreting tumor-bearing mice had completely phosphorylated CD3-associated zeta-chains and recruited ZAP-70 to cell surface-associated TCR. In contrast, T cells from mice with parental tumors contained incompletely phosphorylated CD3-associated zeta-chains with little or no TCR-associated ZAP-70. Third, the recruitment of ZAP-70 to the TCR/CD3 complex was seen only in animals with an increase in in vitro p56lck kinase activity after T cell activation. Finally, we report that these defects in T cell signaling were associated with generalized anergy in vivo. Our findings provide a molecular basis to explain T cell suppression of mice with parental tumors and offer a hypothesis to explain the protective effect of tumor-derived IL-2.
A triallelic Fc gamma receptor type IIIA polymorphism influences the binding of human IgG by NK cell Fc gamma RIIIa.
Authors: de Haas M , Koene H R , Kleijer M , de Vries E , Simsek S , van Tol M J , Roos D , von dem Borne A E 
Published: December 2022

Abstract
A donor-dependent difference in electrophoretic mobility of deglycosylated released Fc gamma RIIIa derived from NK cells and macrophages was observed. We investigated whether this was based on a polymorphism of the Fc gamma RIIIA gene. Cloning and sequencing of Fc gamma RIIIa-encoding cDNA derived from an apparently heterozygous donor showed one single nucleotide substitution at position 230 (T--&gt;G), which was responsible for a leucine (L)--&gt;arginine (R) substitution at position 48 in the first extracellular Ig-like domain (EC1) of Fc-gamma RIIIa and caused a higher electrophoretic mobility of Fc gamma RIIIa. An allele-specific primer annealing PCR assay was developed to amplify specifically an Fc gamma RIIIA gene-derived fragment, which was digested with AciI (recognizing G230) or MnlI (recognizing T230). MnlI restriction analysis revealed the presence of a third Fc gamma RIIIa allele with a T230--&gt;A substitution, which predicts a change of 48-leucine into 48-histidine (H). A gene frequency of 86% for the T230 (48-L) allele, 6% for G230 (48-R), and 8% for A230 (48-H) was found. A significantly different genotype distribution was found among 12 unrelated Caucasian Fc gamma RIIIB gene-deficient donors. Fc gamma RIIIa-48R and Fc gamma RIIIa-48H showed a higher binding capacity of human (h)IgG1, hIgG3, and hIgG4 compared with Fc gamma RIIIa-48L. Finally, the CD16 mAbs 1D3 and MEM154 bound more strongly and Leu11c (B73.1) bound less to the newly identified Fc gamma RIIIa isoforms.
Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis.
Authors: Blotta M H , Marshall J D , DeKruyff R H , Umetsu D T 
Published: December 2022

Abstract
Although there is good evidence that the induction of IL-4 synthesis in CD4+ T lymphocytes is favored by Ag presentation by B cells and not macrophages, the precise molecular signals provided by B cells to T cells that enhance IL-4 synthesis are not clear. To examine this issue, we established an APC-independent system to activate highly purified T cells and induce cytokine synthesis, using immobilized mAbs against several T cell surface molecules, including CD3, CD28, and the CD40 ligand (CD40L). The counter-receptors for all three of these molecules are expressed on B cells, and include CD40, which is expressed primarily on B cells, but also on dendritic cells and thymic epithelium. We found that IL-4 synthesis was greatly enhanced by triggering of CD40L on the T cell surface in conjunction with ligation of CD3/TCR and CD28, whereas ligation of CD3/TCR and CD28 in the absence of CD40L triggering resulted in little or no IL-4 synthesis. CD40L costimulation greatly enhanced IL-4 synthesis both in T cells from normal nonallergic adult subjects as well as in naive T cells from cord blood. Furthermore, we demonstrated that IL-4 synthesis was optimally enhanced when the strength of the CD3/TCR signal was limiting, while IL-4 synthesis was inhibited when CD3/TCR stimulation was maximal. These studies confirm that IL-4 synthesis can be induced in normal T lymphocytes in the absence of exogenous IL-4, and demonstrate that CD40L costimulation is of fundamental importance in regulation of IL-4 production. In addition, these findings provide a mechanism by which B cells preferentially enhance IL-4 synthesis in T cells at low Ag concentrations.
Salmonella typhimurium aroA- infection in gene-targeted immunodeficient mice: major role of CD4+ TCR-alpha beta cells and IFN-gamma in bacterial clearance independent of intracellular location.
Authors: Hess J , Ladel C , Miko D , Kaufmann S H 
Published: December 2022

Abstract
Due to the dependency on aromatic precursors, the growth of Salmonella typhimurium aroA- is limited in immunocompetent mice. Here we show that H-21-A beta-/- mice (lacking MHC class II molecules and thus devoid of mature CD4+ TCR-alpha beta cells), TCR-beta-/- mice (devoid of TCR-alpha beta cells), and IFN-gamma R-/- mice (unresponsive to IFN-gamma) are highly susceptible to S. typhimurium aroA- infection compared with heterozygous controls. In contrast, beta 2m-deficient mice (lacking surface MHC class I and thus devoid of conventional CD8+ T cells) or TCR-delta-/- mice (devoid of TCR-gamma delta cells) were equally as resistant to S. typhimurium aroA- infection as their heterozygous littermates. These findings emphasize the vital role of CD4+ TCR-alpha beta cells and IFN-gamma in resistance against S. typhimurium aroA-. Sublethal inocula of S. typhimurium aroA- led to permanent infection in H-21-A beta-/- mice, suggesting that bacterial starvation is insufficient for sterile clearance in immunocompetent mice and that MHC class II-dependent immune mechanisms are required for pathogen eradication. The TCR-beta-/- mice suffered from salmonellosis more severely than the MHC class II-deficient mutants, suggesting an auxiliary function of CD8+ T cells. Recombinant S. typhimurium aroA-, secreting listeriolysin (Hly) of Listeria monocytogenes, are capable of escaping from the phagosome into the cytosol of the host cell. However, the course of infection of these recombinant S. typhimurium SL7207 Hlys and control strains did not differ in beta 2m-/- mutants. This finding argues against direct correlation of cytosolic location of S. typhimurium SL7207 Hlys with CD8+ T cell dependency of protection.
CD40-mediated stimulation contributes to lymphocyte proliferation, antibody production, eosinophilia, and mastocytosis during an in vivo type 2 response, but is not required for T cell IL-4 production.
Authors: Lu P , Urban J F , Zhou X D , Chen S J , Madden K , Moorman M , Nguyen H , Morris S C , Finkelman F D , Gause W C 
Published: December 2022

Abstract
CD40/CD40 ligand interactions are required for the development of T cell-dependent Ab responses in vivo. The role of these cell surface molecules in contributing to T cell cytokine production and the development of effector populations other than B cells and T cells is, however, less well defined. We have examined the in vivo effects of blocking CD40/CD40 ligand interactions on the type 2 mucosal immune response that follows oral inoculation of mice with the nematode parasite, Heligmosomoides polygyrus. Administration of anti-gp39 (CD40L) mAb (MR1) blocked H. polygyrus-induced elevations in serum IgG1 levels and inhibited elevations in blood eosinophils and mucosal mast cells at day 14 after inoculation. Anti-gp39 mAb markedly inhibited B cell blastogenesis 8 days after H. polygyrus inoculation but did not inhibit elevations in B cell class II MHC expression. Maximal elevations in B7-2 expression required signaling through both CD40 and the IL-4R. Elevations in T cell cytokine gene expression and elevations in the number of IL-4-secreting cells were unaffected by treatment with anti-gp39 mAb, although IL-4 production was inhibited by anti-IL-4R mAb. These results suggest that CD40/CD40L interactions are not required to activate T cells to produce cytokines but are required for the activation and proliferation of other effector cells associated with the type 2 response.
Receptor binding and internalization of a water-soluble (1--&gt;3)-beta-D-glucan biologic response modifier in two monocyte/macrophage cell lines.
Authors: Müller A , Rice P J , Ensley H E , Coogan P S , Kalbfleish J H , Kelley J L , Love E J , Portera C A , Ha T , Browder I W , Williams D L 
Published: December 2022

Abstract
Glucan phosphate, a water-soluble, chemically defined (1--&gt;3)-beta-D-glucan biologic response modifier, has been reported to exert antisepsis activity and accelerate wound healing. In this study we describe the specific binding of glucan phosphate to human and murine monocyte/macrophage cell lines, U937 and J774A.1, respectively. At 37 degrees C, equilibrium binding was rapidly achieved, i.e., within 1 min. In U937 cells, binding occurred with an affinity (Kd) of 37 microM and a Bmax of 65 x 106 binding sites/cell at 37 degrees C. In J774A.1 cells, glucan phosphate bound with an affinity (Kd) of 24 microM and a Bmax of 53 x 106 binding sites/cell at 37 degrees C. In both cases there was insignificant nonspecific binding. We further demonstrated that bound glucan phosphate cannot be displaced by a 50-fold excess of unlabeled ligand, suggesting internalization of glucan phosphate. Transmission electron microscopy showed significantly increased cytoplasmic vacuolization and significantly decreased mitotic activity in glucan phosphate-treated U937 cells compared with that in untreated cells. Pullulan, a random coil alpha-(1--&gt;4)-(1--&gt;6)-linked glucose polymer that served as a control, did not compete for the same binding site as glucan phosphate in either cell line, indicating the specificity of the binding site for (1--&gt;3)-beta-D-glucans. We conclude that water-soluble pharmaceutical grade (1--&gt;3)-beta-D-glucan phosphate specifically binds to and is internalized by U937 and J774A.1 cells.
Pathologic leukocyte infiltration of the rabbit aorta confers a vasomotor effect to chemotactic peptides through cyclooxygenase-derived metabolites.
Authors: Petitclerc E , Levesque L , Grose J H , Poubelle P E , Marceau F 
Published: December 2022

Abstract
We determined the effect of chemotactic peptides FMLP and C5a, postulated to be relatively selective activators of phagocytes, on the thoracic aorta of rabbits subjected to experimental pathologies that allowed infiltration by leukocytes, i.e., dietary atherosclerosis and serum sickness. Aortic ring tissues isolated from hypercholesterolemic rabbits, precontracted or not by phenylephrine, exhibited a rapid and relatively sustained (10 to 20 min) contractile response when challenged by FMLP (10 nM and above); precontracted tissues also responded to C5a (2.5 nM and above). Aortic rings from rabbits with serum sickness (13 days post-BSA injection) exhibited brief contractions that were often followed by a relaxation in phenylephrine-precontracted tissues. In both models, tissues from normal weight-matched animals were not consistently responsive to these peptides. The cyclooxygenase inhibitor indomethacin extensively reduced the contractile effect of either peptide on precontracted aortic rings in both models. Chemotactic peptide-induced increased prostanoid secretion was evident only in the fluid bathing atherosclerotic aortic rings. Morphologic correlations included the demonstration of cells positive for the RAM-11 macrophage marker and the C5a receptors in tissues from rabbits with hypercholesterolemia (numerous clusters of cells) or serum sickness (modest infiltration). Control aortic rings responded to FMLP by a significant contraction if cultured for 2 h in the presence of resident peritoneal cells (84% macrophages), but not in the presence of a high density of PBL (less than 0.5% monocytes). Infiltrating or adherent macrophages in the blood vessel wall confer to some phagocyte activating peptides the role of eicosanoid-dependent vasoconstrictor agents.
Inhibition of TNF-alpha expression by adenosine: role of A3 adenosine receptors.
Authors: Sajjadi F G , Takabayashi K , Foster A C , Domingo R C , Firestein G S 
Published: December 2022

Abstract
Adenosine agonists inhibit TNF-alpha production in macrophage and monocytes, but the mechanism is unknown. Therefore, we studied the human macrophage cell line U937 to determine the adenosine receptor subtypes responsible and the intracellular signaling mechanisms involved. The A1/A3 agonist N6-(4-amino-3-iodobenzyl)adenosine (I-ABA) decreased LPS-stimulated TNF-alpha protein production by 79 +/- 5% (p = 0.003). The mechanism was pretranslational, as adenosine receptor stimulation caused a marked decrease in TNF-alpha mRNA. IL-1 beta, IL-6, and IL-8 mRNA were not changed by adenosine agonists. The rank order of agonists as TNF-alpha inhibitors suggested that the A3 receptor might be involved (N6-(3-iodobenzyl)-9-[5-(methylcarbamoyl)-beta-D-ribofuranosyl] adenosine &gt; 2-chloroadenosine &gt; or = I-ABA &gt; N6 benzyl 5'-N-ethylcarboxamidoadenosine (NECA) &gt; NECA &gt; CGS21680 &gt; N6-cyclohexyladenosine), and this was supported by the fact that a mixed A1/A3 antagonist (xanthine amine congener) reversed the effect, whereas A1-specific (1,3-dipropyl-8-cyclopentylxanthine) and A2-specific (3,7-dimethyl-1-propargylxanthine) antagonists did not. Receptor signaling did not involve cAMP or protein kinase A, nor did it alter the activation and binding characteristics of the transcription factor NF-kappa B. However, the composition of the AP-1 transcription complex was altered by I-ABA. These data suggest that stimulation of the A3 adenosine receptor can alter the cytokine milieu by decreasing TNF-alpha. Adenosine agonists or adenosine regulating agents have potential therapeutic uses in acute and chronic inflammatory diseases.
Fas mediates apoptosis in human monocytes by a reactive oxygen intermediate dependent pathway.
Authors: Um H D , Orenstein J M , Wahl S M 
Published: December 2022

Abstract
Monocyte apoptosis has emerged as a central regulatory event in hemopoiesis and inflammation. Inflammatory cytokines can either promote or prevent monocyte apoptosis. To study the possible role of Fas Ag, a member of the TNF/nerve growth factor receptor family, in monocyte apoptosis, human peripheral blood monocytes activated by IL-1 beta or TNF-alpha were exposed to anti-Fas mAb. Engagement of the Fas Ag resulted in apoptosis of monocytes, as monitored by propidium iodide uptake, decrease in cell size, DNA fragmentation, and characteristic ultrastructural changes. The apoptotic action of Fas was abolished completely by antioxidants such as N-acetylcysteine and glutathione, suggesting a role for reactive oxygen intermediates (ROI) in the death process. Consistent with this observation, Fas stimulation enhanced the fluorescence associated with oxidation of 2',7'-dichlorofluorescein, indicating increased levels of intracellular ROI. Moreover, the exogenous addition of hydrogen peroxide or menadione, an intracellular generator of superoxide anion, was sufficient for the induction of monocyte apoptosis. These data indicate that ROI are key mediators of Fas-induced apoptosis. In contrast to IL-1 beta and TNF-alpha, LPS-treated monocytes were resistant to the apoptotic action of Fas. Under these conditions, LPS did not down-regulate Fas, but inhibited the Fas-dependent elevation of ROI. Therefore, monocytes appear to have a protective mechanism that can interfere directly with the Fas-induced pathway of cell suicide, thereby controlling their destiny.
Persistence of dominant T cell clones in synovial tissues during rheumatoid arthritis.
Authors: Alam A , Lambert N , Lulé J , Coppin H , Mazières B , de Préval C , Cantagrel A 
Published: December 2022

Abstract
In a previous study, we showed that the T cell repertoire is biased in the synovial membrane (SM) compared with peripheral blood during rheumatoid arthritis (RA). The same bias was observed in different joints from the same patient and seems to be the same over time. To discover whether this bias was due to expansion of a clonal subset resulting from activation by conventional Ag(s) or to polygonal stimulation by superantigen(s), we sequenced more than 650 TCRBV-D-J junctional regions from freshly isolated SM and peripheral blood of two DR4-RA patients. From each patient, two SM were obtained on the same day, and a third was obtained later. Several dominant clones were found in SM but not in peripheral blood. Some of them were found only at the first time point in anatomically different SM, the majority persisted over time, and others were detected only at the second time point. Analysis of the complementarity-determining region 3 (CDR3) showed a bias in TCRBD and amino acid usage. Valine, encoded by randomly inserted N nucleotides, was used by 45% of dominant clones compared with 18% in the control population (p less than 0.001). In addition, GXXG and TSG motifs were frequently observed in the CDR3 of these dominant clones. These data indicate a dynamic TCR selection process during the perpetuation phase of RA. The dynamic changes of dominant clones also suggest a determinant spreading mechanism during RA.