bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice.
Authors: Wiley J A , Harmsen A G 
Published: December 2022

Abstract
The role of the CD40-CD40 ligand (CD40L) interaction in resolution of Pneumocystis carinii (PC) pneumonia (PCP) was assessed in a PC-infected severe combined immunodeficiency (SCID) mouse reconstitution model using an anti-CD40L mAb to block CD40L. SCID mice infected with PC were reconstituted with unfractionated spleen cells from immunocompetent donors and given either anti-CD40L mAb or an irrelevant control mAb. Mice given the control mAb resolved the PC infection, whereas those given the anti-CD40L mAb did not. That anti-CD40L mAb also inhibited PC-specific IgG production is consistent with the possibility that cognate CD4+ T cell-B cell interactions are important in PCP resolution. The experiment was then repeated, except that the PC-infected SCID mice were reconstituted with purified CD4+ T cells only. Again, the control mAb-treated group resolved the PCP, whereas mice treated with anti-CD40L mAb did not. In the second experiment, inhibition of resolution of PCP in the anti-CD40L mAb group was not the result of blocking CD4+ T cell-dependent activation of PC-specific B cells. The results are consistent with the possibility that resistance to PCP may involve interaction between B cells and CD4+ T cells via the CD40-CD40L pathway. However, results additionally indicate that inhibition of CD40-CD40L interaction ablates resistance to PCP by inhibiting the interaction of T cells with some cell other than B cells.
Superantigen-induced collagenase gene expression in human IFN-gamma-treated fibroblast-like synoviocytes involves prostaglandin E2. Evidence for a role of cyclooxygenase-2 and cytosolic phospholipase A2.
Authors: Mehindate K , al-Daccak R , Dayer J M , Kennedy B P , Kris C , Borgeat P , Poubelle P E , Mourad W 
Published: December 2022

Abstract
MHC class II molecules expressed in lymphoid and nonlymphoid cells act as signal-transducer molecules. We demonstrate that engagement of MHC class II molecules on human IFN-gamma-treated fibroblast-like synoviocytes by their natural ligand, the staphylococcal enterotoxin A (SEA), selectively induces the production of interstitial collagenase over the expression of the tissue inhibitor of metalloproteinase (TIMP). Collagenase gene expression required de novo protein synthesis and was accompanied by high levels of PGE2 production, suggesting its implication in this response. Two inhibitors that affect prostaglandin biosynthesis, indomethacin and arachidonyl-trifluoromethyl-ketone, inhibited both PGE2 production and collagenase gene expression. The addition of exogenous PGE2 to inhibitor-treated cells partially restored the SEA-induced collagenase, indicating a role for PGE2 in this response. As cyclooxygenases (COX-1 and -2), cytosolic phospholipase A2 (cPLA2), and secreted PLA2 (sPLA2) are the enzymes potentially implicated in prostaglandin synthesis, their involvement in SEA-induced collagenase was investigated. The mRNA levels of COX-2 and cPLA2 rapidly increased following ligation of MHC class II molecules, while COX-1 and sPLA2 mRNA levels were unchanged and transiently depressed, respectively. SEA-induced COX-2 mRNA was translated adequately to protein, whereas cPLA2 protein level was not enhanced, but rapidly phosphorylated, a process previously linked to the enzyme activation. In conclusion, this work demonstrates a selective induction of collagenase gene expression over its natural inhibitor TIMP in human IFN-gamma-treated fibroblast-like synoviocytes mediated, at least in part, by PGE2, and provides evidence that signaling via MHC class II molecules induces the production of PGE2 through enhanced production of COX-2 and possibly activation of the cPLA2.
Molecular characterization of fusion regulatory protein-1 (FRP-1) that induces multinucleated giant cell formation of monocytes and HIV gp160-mediated cell fusion. FRP-1 and 4F2/CD98 are identical molecules.
Authors: Ohgimoto S , Tabata N , Suga S , Nishio M , Ohta H , Tsurudome M , Komada H , Kawano M , Watanabe N , Ito Y 
Published: December 2022

Abstract
Fusion regulatory protein (FRP)-1 regulates virus-mediated cell fusion and fusion of monocytes. Eleven of fifteen N-terminal amino acids of FRP-1 were the same as the amino acid sequence of 4F2/CD98 heavy chain. FRP-1 molecules were detected in Con A- or IL-2-stimulated lymphocytes, while FRP-1 was rare on resting lymphocytes. These properties of FRP-1 are similar to those of 4F2/CD98. Treatment of monocytes with anti-4F2/CD98 mAbs resulted in cell fusion, and other mAbs directed against 4F2/CD98 induced formation of multinucleated giant cells of Cd+U2ME-7 cells, a CD4+U937 cell line transfected with the HIV gp160 gene. Both anti-4F2/CD98 and anti-FRP-1 mAbs reacted with murine L929 cells expressing human 4F2/CD98 transiently or constitutively. When Newcastle disease virus (NDV)-infected L929 cells expressing human FRP-1/CD98 were incubated with mAb 4-5-1, an anti-FRP-1 mAb, multinucleated giant cells were induced; thus, FRP-1/CD98 molecules expressed in L929 cells are functional for fusion regulatory activity.
Two structurally distinct kappa B sequence motifs cooperatively control LPS-induced KC gene transcription in mouse macrophages.
Authors: Ohmori Y , Fukumoto S , Hamilton T A 
Published: December 2022

Abstract
The mouse KC gene is an alpha-chemokine gene whose transcription is induced in mononuclear phagocytes by LPS. DNA sequences necessary for transcriptional control of KC by LPS were identified in the region flanking the transcription start site. Transient transfection analysis in macrophages using deletion mutants of a 1.5-kb sequence placed in front of the chloramphenicol acetyl transferase (CAT) gene identified an LPS-responsive region between residues -104 and +30. This region contained two kappa B sequence motifs. The first motif (position -70 to -59, kappa beta 1) is highly conserved in all three human GRO genes and in the mouse macrophage inflammatory protein-2 (MIP-2) gene. The second kappa B motif (position -89 to -78, kappa B2) was conserved only between the mouse and the rat KC genes. Consistent with previous reports, the highly conserved kappa B site (kappa B1) was essential for LPS inducibility. Surprisingly, the distal kappa B site (kappa B2) was also necessary for optimal response; mutation of either kappa B site markedly reduced sensitivity to LPS in RAW264.7 cells and to TNF-alpha in NIH 3T3 fibroblasts. Although both kappa B1 and kappa B2 sequences were able to bind members of the Rel homology family, including NF kappa B1 (P50), RelA (65), and c-Rel, the kappa B1 site bound these factors with higher affinity and functioned more effectively than the kappa B2 site in a heterologous promoter. These findings demonstrate that transcriptional control of the KC gene requires cooperation between two kappa B sites and is thus distinct from that of the three human GRO genes and the mouse MIP-2 gene.
Simultaneous cross-linking by two nontriggering bivalent ligands causes synergistic signaling of IgE Fc epsilon RI complexes.
Authors: Posner R G , Subramanian K , Goldstein B , Thomas J , Feder T , Holowka D , Baird B 
Published: December 2022

Abstract
We have used two bivalent ligands that bind IgE to study the relationship between the aggregation of receptors with high affinity for IgE (Fc epsilon RI) and the responses (receptor immobilization, Ca2+ influx, and degranulation) of rat basophilic leukemia (RBL-2H3) cells. One of these is a symmetric bivalent ligand, N,N'-bis[[epsilon-[(2,4-dinitrophenyl)amino]caproyl]-L-tyrosyl]-L- cystine ((DCT)2-cys), which binds specifically to the combining sites of a mAb anti-DNP IgE and efficiently cross-links cell surface IgE, but does not trigger significant degranulation or increases in intracellular Ca2+. Several lines of evidence, including lateral mobility measurements, indicate that this ligand preferentially forms stable cyclic complexes containing two (DCT)2-cys and two IgE. The second ligand is a mAb anti-IgE, B1E3, which causes lateral mobility changes consistent with dimerized IgE-Fc epsilon RI and also does not trigger increases in intracellular Ca2+ or degranulation. The two ligands together trigger robust responses. In the presence of B1E3, (DCT)2-cys causes immobilization of IgE-Fc epsilon RI in a broad concentration range; in a more narrow concentration range, it is a potent stimulant of changes in both degranulation and Ca2+. We have compared the dose-response curves for cellular activation to simulated IgE aggregation curves, i.e., curves that predict the equilibrium IgE aggregate size distribution as a function of the (DCT)2-cys concentration. Our results indicate that maximal cellular activation occurs at a much higher (DCT)2-cys concentration than maximal IgE aggregation. When IgE aggregation is maximal, almost all aggregated IgE is in cyclic dimers. Thus, cyclic dimers appear to be functionally ineffective, even after they have been cross-linked by B1E3. Aggregated IgE-Fc epsilon RI that is effective in stimulating a cellular response may have particular structural or dynamic properties that allow critical interactions for initiating the signaling cascade.
Influence of heavy chain constant regions on antigen binding and HIV-1 neutralization by a human monoclonal antibody.
Authors: Cavacini L A , Emes C L , Power J , Desharnais F D , Duval M , Montefiori D , Posner M R 
Published: December 2022

Abstract
F105, a neutralizing IgG1 kappa human mAb, is reactive with a discontinuous epitope within the gp120 CD4 binding site. Because isotype usage may affect Ab function, we examined the effect of isotype on Ag/Ab interactions and HIV-1 neutralization. An IgG3 kappa Ab was prepared by linking the variable regions of F105 to cloned human kappa and gamma 3 constant regions. Immunoreactivity of F105 IgG1 and IgG3 with IIIB-, MN-, and RF-infected cells was equivalent. Inhibition of binding and fusion of IIIB to uninfected cells and neutralization of IIIB virus was comparable for F105 IgG1 and IgG3, with 14 to 23 micrograms/ml required for 90% neutralization. In contrast, F105 IgG3 was marginally more effective at inhibition of MN binding/fusion and significantly more effective at neutralization of MN virus (62 micrograms/ml for IgG3 and &gt; 100 micrograms/ml for IgG1 to achieve 90% neutralization). Despite high affinity binding to RF-infected cells, F105 IgG1 minimally neutralizes free RF virus. F105 IgG3 is dramatically more effective against the RF isolate, with 2 to 20 micrograms/ml of Ab required for 50% neutralization. Both isotypes were relatively ineffective at inhibition of RF binding/fusion. Thus, whereas affinity with native Ags on the surface of HIV-1-infected cells was unaffected by heavy chain constant regions, Ab isotype can strongly influence virion neutralization. Structural changes in gp120, as a result of increased flexibility conferred by the elongated IgG3 hinge region, are suggested as a possible mechanism to increase neutralization of selected HIV-1 isolates. These results may have significant implications in the design of immunotherapeutic and vaccine agents.
Laser light suicide of proliferating virus-specific CD8+ T cells in an in vivo response.
Authors: Tripp R A , Lahti J M , Doherty P C 
Published: December 2022

Abstract
Virus-specific CD8+ CTL precursor (CTLp) frequencies are a function of rates of clonal expansion and loss, both of which are difficult to assess in vivo. Proliferating T cells incorporate the nucleoside analogue 5-bromo-2'-deoxyuridine (BrdU), making them sensitive to light-induced apoptotic cell death (suicide). Mice were infected with an influenza A virus, then given 50 mg of BrdU 24 h before sampling. Exposure of freshly isolated, CD8-labeled T cells to the laser beam of the flow cytometer resulted in the elimination of &gt; 90% of the responding CTLp. The effect was obvious for the regional lymph node from day 6 to day 12 after priming, indicating continued cycling over a 7-day interval. Thus, as CTLp frequencies remain fairly constant from 7 to 30 days after infection, the persistent increase (&gt; 30x) in numbers must be accompanied by a very substantial loss of virus-specific CD8+ T cells.
Rapid rejection of H2k and H2k/b bone marrow cell grafts by CD8+ T cells and NK cells in irradiated mice.
Authors: Davenport C , Kumar V , Bennett M 
Published: December 2022

Abstract
Acute rejection of transplanted bone marrow cell (BMC) grafts can occur within 48 h in unsensitized, lethally irradiated mice, and NK cells have been implicated as the effector cells. Recently, we observed that both CD8+ TCR-alpha beta+ T and NK cells of irradiated mice could rapidly reject allogeneic lymph node cell grafts. In this study, we evaluated the ability of NK and CD8+ T cells to mediate rejection of H2k or H2k/b BMC grafts by pretreating groups of mice with depleting mAbs. H2k BMC were transplanted into syngeneic, B6 (H2b), BALB/c (H2d), NZB (H2d), and (NZB x B6)F1 (NZB6F1, H2d/b) hosts. Proliferation measured 5 days after cell transfer indicated that syngeneic, B6, and BALB/c hosts accepted H2k BMC grafts. However, CD8+ T cells from NZB and poly I:C-treated BALB/c hosts, and NK cells from poly I:C-treated NZB6F1, hosts, rejected H2k BMC grafts. In NZB6F1 hosts, there was an added effect of anti-TCR-alpha beta and anti-NK1.1 mAbs. It is possible that T and NK cells cooperate in rejecting H2k or H2k/b BMC grafts in certain hosts. Transplantation of H2k/b, but not H2k/d, BMC into similar recipients had the same fate as H2k BMC. Thus, certain CD8+ T cells may share a similar recognition system with NK cells.
Effect of gene-targeted mutation in TNF receptor (p55) on contact hypersensitivity and ultraviolet B-induced immunosuppression.
Authors: Kondo S , Wang B , Fujisawa H , Shivji G M , Echtenacher B , Mak T W , Sauder D N 
Published: December 2022

Abstract
Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic proinflammatory cytokine. TNF-alpha has been implicated in the pathogenesis of delayed-type hypersensitivity reactions such as allergic contact hypersensitivity and has been suggested as a mediator of ultraviolet B (UVB)-induced immunosuppression. Conflicting reports, however, exist concerning the effects of TNF-alpha on contact hypersensitivity (CHS). To determine the role of TNF-alpha in the generation and regulation of CHS, gene-targeted mutant mice lacking TNF-receptor (p55) gene (TNF-R1(-) mice) were treated with dinitrofluorobenzene (DNFB) to induce CHS. TNF-R1(-) mice showed significant hyperresponsiveness in CHS (152.8 +/- 20.9%, p &lt; 0.025) compared with normal syngeneic mice (C57BL/6) assessed by ear swelling. To determine whether UVB can induce suppression in TNF-R1(-) mice, mice were irradiated on the shaved abdomen with 96 mj/cm2 UVB and 3 days later they were painted with 0.5% DNFB (sensitization dose), followed 5 days later with 0.2% DNFB to the left ear (challenge dose). Significant suppression of CHS was observed both locally (sensitization on irradiated site) and systemically (sensitization on unirradiated site) in UVB-irradiated TNF-R1(-) mice as well as in normal mice. To rule out possible signaling through p75 TNF-R, the mice were treated with anti-TNF-alpha Ab (V1q), which can neutralize any TNF effects through either receptor. V1q had no effect on these phenomena observed in TNF-R1(-) mice. These results suggest that TNF-alpha plays a regulatory role in CHS but is not required to induce UVB-mediated immunosuppression.
IFN-gamma receptor-deficient mice are hypersensitive to the anti-CD3-induced cytokine release syndrome and thymocyte apoptosis. Protective role of endogenous nitric oxide.
Authors: Matthys P , Froyen G , Verdot L , Huang S , Sobis H , Van Damme J , Vray B , Aguet M , Billiau A 
Published: December 2022

Abstract
Mice with a disruption of the IFN-gamma receptor alpha-chain gene (IFN-gamma R alpha o/o mice) were found to be significantly more sensitive than their wild-type counterparts to induction of the anti-CD3-induced disease syndrome. Specifically, when given a selected dose of anti-CD3 Ab, IFN-gamma R alpha o/o mice developed severe hypothermia and hypoglycemia, leading to 100% mortality within 72 h. In contrast, wild-type mice failed to develop overt pathologic manifestations and survived. Histologic examination revealed apoptosis in thymuses and spleens, which were significantly more pronounced in the mutant than in the wild-type mice, as confirmed by flow cytometric and DNA electrophoretic analysis. Apoptosis affected mainly CD4+CD8+ and CD4+CD8- thymocytes. Other histologic alterations were steatosis in livers, and erythrocyte extravasation and infiltration of apoptotic cells in lungs, all of which were exclusively observed in IFN-gamma R alpha o/o mice. Blood levels of TNF, IL-2, IL-6, and IL-10 were slightly more elevated in IFN-gamma R alpha o/o mice, but insufficiently so to explain increased disease severity. Thus, even more elevated cytokine levels in wild-type mice receiving high doses of anti-CD3 Ab were not associated with morbidity or apoptosis. Blood levels of IFN-gamma were barely detectable in anti-CD3-challenged wild-type mice, but were relatively high in the mutant mice. Increased susceptibility of IFN-gamma R alpha o/o mice was associated with impaired nitric oxide (NO) production, as indicated by significantly lower plasma nitrite levels and by more transient expression of spleen inducible NO synthase mRNA. Moreover, treatment of wild-type mice with the NO synthase inhibitor N-nitro-L-arginine methylester resulted in increased anti-CD3-induced morbidity and mortality. The data indicate that IFN-gamma R alpha o/o mice produce less NO and are therefore more sensitive than wild-type mice to the deleterious effect of anti-CD3 Ab.
Murine CD4+ T cells undergo TCR-activated adhesion to extracellular matrix proteins but not to nonantigenic MHC class II proteins.
Authors: O'Rourke A M , Lasam M C 
Published: December 2022

Abstract
Engagement of the TCR modulates the avidity of several receptors that play key roles in lymphocyte adhesion and/or signal transduction, including CD8, CD11a/CD18 (LFA-1), CD2, and several beta 1-integrins. Here, we investigated whether CD4+ T cells similarly undergo TCR-regulated adhesion to isolated MHC class II proteins through CD4. Strong adhesion of a number of CD4+ T cell clones to immobilized antigenic peptide/class II complexes was readily detectable. Adhesion to antigenic class II proteins was CD4 dependent and inhibited by pretreatment of T cells with the protein tyrosine kinase inhibitor herbimycin A, suggesting that adhesion requires TCR- and/or CD4-derived signal transduction. Treatment of T cells with anti-TCR Ab strongly increased subsequent adhesion to the extracellular matrix proteins, fibronectin and vitronectin, but, significantly, not to immobilized nonantigenic class II proteins. Suboptimal densities of antigenic peptide/class II complexes also activated adhesion of T cells to coimmobilized fibronectin or vitronectin, and this resulted in production of IFN-gamma to levels exceeding those stimulated by optimal densities of antigenic class II complexes alone. However, no augmentation of adhesion or cytokine secretion occurred when self or third party class II proteins were coimmobilized with antigenic class II complexes. The present results, therefore, suggest fundamental differences in the mechanism by which the TCR regulates coreceptor adhesion in CD4+ and CD8+ T cells.
Inhibition of T cell costimulation by VCAM-1 prevents murine graft-versus-host disease across minor histocompatibility barriers.
Authors: Schlegel P G , Vaysburd M , Chen Y , Butcher E C , Chao N J 
Published: December 2022

Abstract
Activation of T cells leading to graft-vs-host disease (GVHD) requires two signaling events: the Ag-specific signal generated through the engagement of the TCR/CD3 complex with antigenic peptide fragments presented by MHC molecules on APCs and the second signal provided through additional costimulatory ligands. T cells have preferential costimulatory requirements depending on their state of activation-induced maturation. In the present study, we investigated the role of the receptor-ligand pair VLA-4 (alpha 4 beta 1) and VCAM-1 in allogeneic T cell responses in vitro and in vivo. Anti-VCAM-1 mAb effectively inhibited mixed lymphocyte culture (MLC) across several major MHC barriers and secondary MLC across minor histocompatibility Ags (95.5% and 90.0% inhibition, respectively). In contrast, anti-VLA-4 mAb inhibited a CD8(+)-mediated primed CTL response in vitro by 100%, yet had little effect on proliferative responses. In the B10.D2/nSnJ--&gt;BALB/c (both H-2d) system of GVHD, BALB/c received anti-VCAM-1, or anti-VLA-4 or controls NS-1 or Y13-259 for the first 5 wk after transplant. Anti-VLA-4 mAb delayed the onset of GVHD, but failed to reduce incidence, severity or GVHD-related mortality. In contrast, anti-VCAM-1 reduced the incidence of GVHD from 100% (18/18) in control animals to 53.3% (8/15) (p &lt; 0.01) on day 70 post-transplant and significantly decreased GVHD-related mortality. Sixty percent (9/15) of anti-VCAM-1 recipients survived more than 180 days after transplant. Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by PCR analysis of a microsatellite region in the IL-1 beta gene.
Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis.
Authors: Taub D D , Sayers T J , Carter C R , Ortaldo J R 
Published: December 2022

Abstract
Chemokines have been shown to play an important role in both the adhesion and migration of numerous leukocytic cell types, including granulocytes, monocytes, mast cells, and T lymphocytes. However, the biologic effects of chemokines on NK cells remain to be defined. Chemotaxis studies using purified human NK cells and a panel of human recombinant chemokines revealed that macrophage inflammatory protein (MIP)-1 alpha and IFN-inducible protein-10 (IP-10) are potent NK cell chemoattractants in vitro. Modest but significant chemotactic (not chemokinetic) responses were also observed in response to RANTES, MCP-1, MCP-2, MCP-3, and MIP-1 beta. Chemokine receptor expression on human NK cells was determined through displacement and Scatchard analyses, using a panel of radiolabeled chemokines, and revealed the presence of both distinct and shared chemokine receptors with affinities similar to those previously described for other cell types. Functional studies have also revealed that the beta chemokines and IP-10 are capable of augmenting NK- but not LAK- or ADCC-specific cytolytic responses in both a dose- and donor-dependent fashion. Neutralization analysis using Abs specific for various adhesion molecules revealed that NK:tumor cell conjugate formation is required for chemokine-induced NK killing. In addition, NK cells incubated in the presence of beta chemokines and IP-10 for 4 h induced the release of granule-derived serine esterases, suggesting a possible mechanism for chemokine-mediated NK killing. These results suggest that chemokines not only play an important role in the recruitment of NK cells, but also may be important mediators of NK cell degranulation augmenting local tumor cell destruction.