bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune protection and control of inflammatory tissue necrosis by gamma delta T cells.
Authors: Fu Y X , Roark C E , Kelly K , Drevets D , Campbell P , O'Brien R , Born W 
Published: December 2022

Abstract
Host defenses against experimental listeriosis in mice involve neutrophils, macrophages, NK cells, and alpha beta T cells. Recently gamma delta T cells have also been implicated in antilisterial resistance. However, their specific role has remained unclear. Here we show that efficient resistance to infection by this bacterium depends on the functions of both alpha beta and gamma delta T cells in both primary and secondary responses. We also present evidence that these functions are complementary. In the livers of alpha beta T cell-depleted mice, bacteria grow to large numbers within hepatocytes but are infrequently found extracellularly. Granulomatous lesions are more frequent and somewhat larger than in normal controls, but remain focal. Neutrophils are absent from liver lesions in these mice. In contrast, the livers of gamma delta T cell-depleted mice contain many extracellular bacteria, but do not show hepatocytes containing large numbers of Listeria. Liver lesions in gamma delta T cell-depleted mice are far more extensive than in normal controls or in alpha beta T cell-depleted mice, and contain large numbers of neutrophils. Particularly in secondary listeriosis, gamma delta T cell-depleted mice show vast coalescent areas of necrotic liver parenchyma within 48 h after infection. Because the bacterial numbers in gamma delta T cell-depleted mice remain lower than in alpha beta T cell-depleted mice, increased mortality in the former may be in part caused by liver failure. We conclude that gamma delta T cells are required to control inflammatory reactivity and to prevent excessive liver damage during the immune response to Listeria monocytogenes.
IL-10 mediates susceptibility to Trypanosoma cruzi infection.
Authors: Reed S G , Brownell C E , Russo D M , Silva J S , Grabstein K H , Morrissey P J 
Published: December 2022

Abstract
IL-10 has been shown to inhibit some aspects of macrophage activation, including the in vitro IFN-gamma-mediated intracellular killing of the protozoan parasite Trypanosoma cruzi. We have previously shown that genetically susceptible mice produced more IL-10 during T. cruzi infection than resistant mice, suggesting an association between IL-10 production and disease susceptibility. In the present study, such an association was documented. IL-10 mRNA was present in the spleens of susceptible C57BL/6 mice, but not in resistant (C57BL/6 x DBA/2) F1 mice, as early as 2 days after infection with T. cruzi. In susceptible mice, IL-10 mRNA was found in enriched populations of splenic T cells and peritoneal macrophages by 4 days after infection. By 14 days after infection, IL-10 mRNA was detected in enriched populations of splenic T cells and peritoneal macrophages, as well as by splenic B cells and macrophages. In SCID mice infected with T. cruzi, IL-10 mRNA was detected in peritoneal cells 2 days after infection. The IL-10 mRNA production was not abolished by treatment with anti-asialo GM-1 Ab before infection, which is consistent with its production by macrophages. Finally, the role of endogenous IL-10 production in the susceptibility to T. cruzi infection was demonstrated by the protection of highly susceptible C57BL/6 mice against acute disease and death from T. cruzi by the administration of neutralizing anti-IL-10 mAb. This study demonstrated an important and perhaps essential role of IL-10 in mediating in vivo susceptibility to T. cruzi infection.
P-selectin interacts with a beta 2-integrin to enhance phagocytosis.
Authors: Cooper D , Butcher C M , Berndt M C , Vadas M A 
Published: December 2022

Abstract
P-selectin is an adhesion molecule for myeloid cells that seems to be essential for the development of cellular inflammatory responses. We show that adhesion of neutrophils to purified and recombinant P-selectin enhances the phagocytosis of unopsonized zymosan particles as judged by the number of cells ingesting particles (30.2 +/- 5.8 vs 14.5 +/- 4.0, p = 0.002) and the number of particles ingested per cell (percentage increase 58.3 +/- 4.4%. p = 0.0002). The enhanced phagocytosis was inhibited by Abs to CD18 or CD11b, suggesting that P-selectin alters beta 2-integrin function. The enhancement was only seen in the presence of cations allowing the integrin to assume a particular extracellular conformation. Furthermore, P-selectin, although not altering the total expression of CD18 on neutrophils, significantly increased the binding of mAb 24, which detects an activation-dependent epitope. Our results support a signaling role for P-selectin in influencing beta 2-integrin function.
Asbestos stimulates IL-8 production from human lung epithelial cells.
Authors: Rosenthal G J , Germolec D R , Blazka M E , Corsini E , Simeonova P , Pollock P , Kong L Y , Kwon J , Luster M I 
Published: December 2022

Abstract
Studies have indicated that soluble products, including chemotactic factors, released by activated lung macrophages and fibroblasts are critical mediators in the pathogenesis of asbestos-induced pulmonary fibrosis. We provide evidence that mediators produced by lung epithelial cells in response to asbestos may also contribute to lung disease. In the present study, the carcinogenic and fibrogenic fibers, chrysotile and crocidolite asbestos, were shown to directly stimulate the human pulmonary type-II epithelial cell line, A549, and to a lesser degree primary human bronchial epithelial cells, to elicit the chemotactic cytokine IL-8 in the absence of endogenous stimuli such as IL-1 and TNF. That the membrane signaling events responsible for asbestos-induced IL-8 production are distinct from those responsible for IL-8 induction by cytokines was confirmed by using membrane-stabilizing agents and protein synthesis inhibitors. Stimulation was not observed with nonfibrogenic fibers, wollastonite and titanium dioxide, and was the direct result of asbestos-induced initiation of transcription. Asbestos failed to stimulate the release of TNF, IL-1 beta, or monocyte chemoattractant protein-1 in A549 or primary bronchial epithelial cells, indicating that cytokine secretion by asbestos is highly selective. However, a slight release of IL-1 alpha, probably preformed, was released in human bronchial epithelial cells. These data suggest that epithelial cells may, in addition to macrophages and fibroblasts, be an important effector cell in the immunopathogenesis of asbestos-associated diseases and in particular, in the neutrophilic infiltration that is commonly observed after asbestos exposure.
Cross-desensitization of receptors for peptide chemoattractants. Characterization of a new form of leukocyte regulation.
Authors: Tomhave E D , Richardson R M , Didsbury J R , Menard L , Snyderman R , Ali H 
Published: December 2022

Abstract
The formylpeptide (fMLP) and C5a chemoattractants were previously shown to cross-desensitize each other's ability to mobilize Ca2+ in leukocytes but not to affect nonchemoattractant Ca(2+)-mobilizing receptors, and vice versa. Our data show that all receptors studied underwent homologous desensitization. Interestingly, peptide chemoattractants (fMLP, C5a, and IL-8) desensitized each other's Ca(2+)-mobilizing responses, but had no effect on a Ca(2+)-mobilizing purinergic receptor. Lipid chemoattractant receptors (PAF and leukotriene B4) were also desensitized by peptide chemoattractants but not vice versa. In the presence of cytochalasin B, only fMLP and C5a caused the activation of phospholipase D in intact leukocytes and enhanced desensitization of IL-8 and C5a but not fMLP receptors. To measure receptor/G protein interactions, agonist-stimulated GTP gamma S binding to leukocyte membranes was measured. Whereas all peptide receptors underwent homologous desensitization, C5a and IL-8, but not fMLP, receptors were cross-desensitized by other peptide chemoattractants. Furthermore, PMA caused inhibition of C5a- and IL-8- but not fMLP-stimulated GTP gamma S binding. These data suggest that in addition to homologous desensitization, peptide chemoattractant receptors cross-desensitize one another by at least two processes. One can be detected at the level of receptor/G-protein interaction and possibly involves receptor phosphorylation by protein kinase C. The fMLP receptor is resistant to this process. The second process is distal to receptor/G-protein interaction and utilizes an undefined pathway to cross-desensitize the Ca2+ mobilization response to all peptide chemoattractants. We propose that receptor cross-desensitization in leukocytes is orchestrated at several levels by mechanisms with selectivity for types of chemoattractant receptors.
A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire.
Authors: Kuchroo V K , Greer J M , Kaul D , Ishioka G , Franco A , Sette A , Sobel R A , Lees M B 
Published: December 2022

Abstract
Previously, six T cell clones, which are specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) peptide residues 139 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use diverse TCR genes. To design TCR antagonist peptides that could interfere with the activation of these clones in vitro and inhibit experimental allergic encephalomyelitis (EAE) in vivo, we first determined the TCR and MHC contact residues of the encephalitogenic peptide. The analysis indicated that residues 144 (tryptophan) and 147 (histidine) were the TCR binding sites and that residues 145 (leucine) and 148 (proline) were important for MHC class II (IAs) binding. On the basis of this information, a peptide analogue (leucine 144/arginine 147), in which both of the major TCR contact residues were substituted, was synthesized. This analogue acts as a TCR antagonist for the panel of PLP 139-151-specific T cell clones, does not cause EAE by itself, blocks the induction of disease by the native 139-151 peptide, and prevents clinical disease progression if administered at the first signs of disease. Thus, although multiple TCR genes are used by PLP 139-151-specific clones, a single peptide analogue can interfere with the disease process. This approach should be feasible for designing peptide analogues that can be tested for therapeutic efficacy in human autoimmune diseases in which the pathogenic Ags are known and TCR use is diverse.
Protective influences on experimental autoimmune encephalomyelitis by MHC class I and class II alleles.
Authors: Mustafa M , Vingsbo C , Olsson T , Issazadeh S , Ljungdahl A , Holmdahl R 
Published: December 2022

Abstract
Experimental autoimmune encephalomyelitis (EAE) is influenced by polymorphism of the MHC. We have previously found that Lewis rats with certain MHC haplotypes are susceptible to disease induced with the myelin basic protein (MBP) peptide 63-88, whereas Lewis rats with other MHC haplotypes are resistant. Interestingly, rats with the MHC u haplotype develop an immune response to the MBP 63-88, but do not get EAE. In this study we have used intra-MHC recombinant rat strains to compare the influences of the MHC u with the a haplotype. We discovered the following: 1) The class II region of the MHC a haplotype permits EAE and a Th1 type of immune response as measured by IFN-gamma production after in vitro challenge of in vivo-primed T cells with MBP 63-88. 2) The class II region of the u haplotype is associated with a disease-protective immune response characterized by production of not only IFN-gamma, but also of IL-4 mRNA expression by the MBP 63-88-activated cells. 3) The class I region upstream of the class II region of the u haplotype is associated with a disease-protective effect and the expression of mRNA for TGF-beta after MBP 63-88-induced activation. Thus, such a TGF-beta response occurs in all strains expressing the class I Au allele. Treatment with Abs to CD8+ cells abrogates peptide-induced TGF-beta mRNA expression, and aggravates disease in strains with the class I Au allele.
Up-regulation of murine neonatal T helper cell responses by accessory cell factors.
Authors: Adkins B , Ghanei A , Hamilton K 
Published: December 2022

Abstract
We previously found that lymph node T cells from 4-day-old, naive neonatal mice show diminished Th1-like responses. Neonatal T cells produced low levels of IL-2 and proliferated poorly in response to soluble anti-CD3 stimulation. However, neonatal T cells resembled Th2 cells (or primed adult T cells) in that they produced large amounts of IL-4. Here, we have investigated the importance of accessory cell signals in the diminished Th1-like responses of neonatal T cells. Anti-CD28 mAb greatly augmented IL-2 production by neonatal T cells in response to plate-bound anti-CD3 Ab. In response to soluble anti-CD3 mAb plus accessory cells, exogenous accessory cell-derived cytokines were sufficient to restore neonatal responses to adult-like levels. In the presence of exogenous IL-6, IL-4 production by neonatal T cells was largely unchanged whereas IL-2 production was dramatically increased, reaching the high levels produced by adult T cells. In addition, the presence of exogenous IL-6 enhanced the proliferation of neonatal T cells to adult levels. IL-6 also had marked effects on the capacity of neonatal T cells to respond to secondary stimuli. In the absence of exogenous IL-6, neonatal T cells responded poorly to secondary stimulation. This lack of responsiveness was not overcome by the addition of IL-2 or by stimulation with phorbol ester and calcium ionophore. When IL-6 was present during the primary stimulation, neonatal T cells, like adult T cells, produced high levels of IL-4 and proliferated extensively in response to secondary stimuli. Thus, IL-6 was sufficient to restore both the primary and secondary responses of neonatal T cells to mature, adult-like levels. These results imply that neonatal T cells have a greater requirement for accessory cell signals than do adult T cells and may have important bearing in overcoming neonatal T cell immunodeficiencies in vivo.
Free recirculation of memory B cells versus antigen-dependent differentiation to antibody-forming cells.
Authors: Bachmann M F , Kündig T M , Odermatt B , Hengartner H , Zinkernagel R M 
Published: December 2022

Abstract
This study investigated whether or not the localization of persisting Ag influenced the localization of memory B and/or of Ab-forming cells (AFC). As a model Ag, we used vesicular stomatitis virus, which does not measurably replicate extraneuronally in adult mice after peripheral infection. Our results show that memory B cells and AFC are induced at the site where Ag is present; induced memory B cells then recirculate throughout the lymphoid system independently of Ag localization. In contrast, AFC are induced only at the sites of Ag persistence. These triggered Ab producing cells do not recirculate through the lymphoid tissue but migrate to the bone marrow.
Modulation of antigen- and mitogen-induced proliferative responses of peripheral blood mononuclear cells by nonselective and isozyme selective cyclic nucleotide phosphodiesterase inhibitors.
Authors: Essayan D M , Huang S K , Undem B J , Kagey-Sobotka A , Lichtenstein L M 
Published: December 2022

Abstract
Cyclic nucleotide phosphodiesterase (PDE) enzymes are felt to play a role in the regulation of inflammatory responses through their effects on cAMP. In this study, we investigated the effects of nonselective and isozyme selective PDE inhibitors on the proliferative responses of peripheral blood mononuclear cells (PBMCs) to ragweed (RW, a Th2 stimulus), tetanus toxoid (TT, a Th1 stimulus), and phytohemagglutinin in ragweed-allergic patients. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) produced nearly identical concentration-dependent inhibition for PBMCs cultured with either Ag (RW and TT) or mitogen (phytohemagglutinin). Neither the type V inhibitor, zaprinast, nor the type III inhibitor, siguazodan, was effective at inhibiting antigen- or mitogen-driven proliferative responses of human PBMCs. The type IV inhibitor, rolipram, was unique in its ability to inhibit the RW-driven proliferative response and, to a lesser extent, the TT-driven proliferative response. However, rolipram was ineffective at inhibiting the mitogen-driven proliferative response. Only with a combination of type III and type IV inhibitors could the efficacy on the TT response be made to approximate that of the type IV inhibitor alone in the RW-driven system. Although the efficacies of IBMX and rolipram were identical in the RW-driven system, the IC50 value of the latter was 10-fold lower, similar to the difference noted in the TT-driven system between IBMX alone and the combination of rolipram with siguazodan. Dose-response curves generated by using the D- or L-isomers of rolipram were not appreciably different from each other or from the curve generated with racemic rolipram. The addition of supraphysiologic doses of human rIL-2 and rIL-4 was unable to counteract the inhibitory effect of IBMX or rolipram. These data support the hypothesis that modulation of proliferation of PBMCs by selective PDE inhibitors varies in sensitivity with the type of stimulus used, and that the type IV PDE exerts the predominant cAMP-associated regulatory effect on allergen-driven proliferation. Finally, the inhibitory effect induced by rolipram is independent of its stereochemistry and cannot be exclusively attributed to deficits in IL-2 or IL-4.
Simultaneous activation of Ig and Oct-2 synthesis and reduction of surface MHC class II expression by IL-6.
Authors: Natkunam Y , Zhang X , Liu Z , Chen-Kiang S 
Published: December 2022

Abstract
Terminal differentiation of B cells to plasma cells in vivo is characterized by secretion of Ig and extinction of MHC class II expression on the cell surface. We show that IL-6 signaling leads to marked increases in the synthesis and secretion of Ig in clonal human B cell lines and newly isolated polyclonal B lymphocytes in vitro. The IL-6-induced cells resemble plasma cells in ultrastructure and in reduced expression of surface MHC class II. Enhanced Ig synthesis is a result of coordinated transcriptional activation of Ig genes without promoter or isotype specificity, and differential accumulation of the mRNA encoding the secreted form of Ig heavy chain. It is saturable and subject to negative control when IL-6 stimulation is prolonged. Coordinate with temporal changes in Ig synthesis, the DNA-binding activity and the synthesis of the B cell-enriched transcription factor Oct-2 are regulated. Thus, differentiation of B cells with IL-6 in vitro recapitulates the hallmarks of terminal B differentiation in vivo; Oct-2 may have a role in this process.
The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization.
Authors: Maliszewski C R , Delespesse G J , Schoenborn M A , Armitage R J , Fanslow W C , Nakajima T , Baker E , Sutherland G R , Poindexter K , Birks C 
Published: December 2022

Abstract
CD39, a 70- to 100-kDa molecule expressed primarily on activated lymphoid cells, was previously shown to mediate B cell homotypic adhesion when ligated with a subset of anti-CD39 mAbs. In the present study, we describe the cloning and molecular characterization of human and murine CD39. The nucleotide sequence of human CD39 includes an open reading frame encoding a putative 510 amino acid protein with six potential N-linked glycosylation sites, 11 Cys residues, and two potential transmembrane regions. Murine CD39 shares 75% amino acid sequence identity with human CD39 but fails to cross-react with anti-human CD39 mAbs. Although there were no significant similarities with other mammalian genes, considerable homology was found between CD39 and a guanosine diphosphatase from yeast. A series of mouse-human hybrid molecules was constructed to determine the general topology of CD39 and the location of a biologically functional epitope. These findings and supporting evidence from an anti-CD39 mAb-selected phage peptide display library indicate a likely model wherein a short intracellular N-terminus is followed by a large extracellular loop containing the epitope recognized by stimulatory anti-CD39 mAbs, and a short intracellular C terminus. The results demonstrate that CD39 is a novel cell surface glycoprotein with unusual structural characteristics.
Serologic analysis of the mouse beta chemokine JE/monocyte chemoattractant protein-1.
Authors: Luo Y , Laning J , Hayashi M , Hancock P R , Rollins B , Dorf M E 
Published: December 2022

Abstract
Mouse monocyte chemoattractant protein-1 (MCP-1), previously termed JE, is a member of the beta chemokine gene family and a homologue of the human monocyte chemoattractant protein, MCP-1. Mouse rMCP-1 was used to immunize hamsters for the production of mAb. Seven mouse MCP-1-specific mAbs were characterized: two of these mAbs cross-reacted with the human MCP-1, as determined by ELISA. A sensitive and specific capture ELISA for MCP-1 quantitation, which allowed measurement of mouse MCP-1 levels in supernatants from cells stimulated with inflammatory agents, was developed. LPS-stimulated astrocytes produce the highest levels of MCP-1 (80 ng/ml); macrophages and mesangial cells produce lower levels of MCP-1 (2 to 14 ng/ml) after LPS stimulation. IL-1 and TNF-alpha stimulation also can induce low levels of MCP-1 production. Western blot analysis demonstrated that the predominant native form of mouse MCP-1 is a 30-kDa glycoprotein. Two mAbs (2H5 and 6C7) demonstrated dose-dependent neutralization of mouse MCP-1 chemotactic activity. To localize the epitope recognized by one of these neutralizing Abs, the mAb was used to bind a series of genetically engineered truncated variants of human MCP-1. The C-terminal residues 62 to 67 on human MCP-1 molecules seem to be critical to express the epitope recognized by the neutralizing 2H5 anti-MCP-1 mAb. However, multiple sites on the MCP-1 molecule seem to be critical for bioactivity. Thus, these Ab reagents provide a useful tool to explore the biology of the mouse MCP-1 beta chemokine.
Role of sulfhydryl groups in induction of cell surface down-modulation and shedding of extracellular domain of human TNF receptors in human histiocytic lymphoma U937 cells.
Authors: Zhang L , Aggarwal B B 
Published: December 2022

Abstract
The interaction of different polypeptide growth factors with their cell surface receptors, which are typically rich in cysteine, is modulated by sulfhydryl (SH) reagents. Because the extracellular domain of both human TNFRs are likewise rich in cysteine residues, we examined the effect of SH reagents on these receptors in human histiocytic lymphoma U937 cells, which express both p60 and p80 forms. Iodoacetamide induced down-regulation of cell surface TNFRs in a dose- and time-dependent manner. Down-regulation was complete at 10 mM IAA for 1 h at 37 degrees C. The decrease was minimal at 4 degrees C. The down-modulation was also observed with other cell-permeable and -impermeable thiol reagents. The expression of other cell surface molecules such as CD3, CD11b, CD23, and CD25 were not affected. IAA induced the down-regulation of TNFR on cells of both epithelial and myeloid origin. With the use of receptor-specific Abs, we found that the kinetics of down-modulation of the p60 and p80 receptors by IAA were very similar. We also found that down-modulation was not a result of internalization but rather of the shedding of the receptors, as ascertained by receptor-ligand cross-linking analysis, immunoassay, Western blot analysis, and ligand-blot analysis. When TNFRs with a molecular mass of 80 kDa disappeared from the cell surface, a 42-kDa polypeptide appeared in the medium. Thus, we demonstrate that SH reagents down-regulate TNFRs by inducing shedding of both receptors from the cell surface, most likely by activating an endopeptidase that cleaves the receptor.