bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of tolerance in freshly isolated alloreactive T cells by activated T cell stimulators is not due to the absence of CD28-B7 interaction.
Authors: Satyaraj E , Rath S , Bal V 
Published: December 2022

Abstract
Human T cells express MHC class II molecules on activation, and this makes them potential APCs for responder CD4 T cells. We have shown earlier that MHC class II-expressing human T cell APCs induce specific tolerance in freshly isolated alloreactive responder CD4 T cells. In this study, we show that this induction of tolerance does not depend on the expression of a specific coreceptor on the stimulator T cell APCs, because both CD4 and CD8 T cell stimulators efficiently induce tolerance. Such a tolerant cell population responds significantly better to IL-2 than unprimed cells, indicating the physical presence of T cells expressing higher levels of IL-2 receptors. The addition of exogenous IL-2 during priming with activated T cell APCs effectively blocks the induction of tolerance and permits successful priming of alloreactive responder cells. We have investigated the possible role of the CD28/CTLA4-B7 family interaction in this model of induction of T cell anergy in T-T interactions. The freshly activated T cell APCs used in this study express CTLA4-binding ligand(s). Furthermore, cross-linking CD28 on responder T cells does not enable activated T cell APCs to elicit a primary proliferative alloresponse, nor does it prevent the induction of tolerance in responder T cells. The CD28/CTLA4-B7 family interaction is thus unlikely to be involved in the induction of T cell anergy by T cell APCs.
Mapping of receptor binding sites on IL-1 beta by reconstruction of IL-1ra-like domains.
Authors: Boraschi D , Bossù P , Ruggiero P , Tagliabue A , Bertini R , Macchia G , Gasbarro C , Pellegrini L , Melillo G , Ulisse E , Visconti U , Bizzarri C , Del Grosso E , Mackay A R , Frascotti G , Frigerio F , Grifantini R , Grandi G 
Published: December 2022

Abstract
Upon structure comparison between IL-1 beta and its antagonist IL-1ra, single or multiple residues along the IL-1 beta sequence were replaced with the corresponding amino acids present in the IL-1ra protein, in the attempt to identify sites important for receptor binding and for biologic activity on the two molecules. Ten of fifteen mutant proteins had activity comparable to that of wild-type IL-1 beta in three different biologic assays and in receptor binding, indicating that the introduced changes did not influence the functional structure of the protein. Conversely, three mutants (SMIL-9: 127/263 R/T--&gt;W/Y; SMIL-10: 125/127/263/265 T/R/T/Q--&gt;R/W/Y/E; SMIL-15:222/227 I/E--&gt;S/S) showed an increased binding capacity for IL-1RI, not paralleled by increased agonist activity, indicating that the introduced IL-1ra residues could be involved in the nonagonist IL-1RI binding site. On the other hand, two mutants showed diminished binding capacity with concomitant decrease in biologic activity. Both mutants (SMIL-1, five substitutions in the loop 202-214; and SMIL-3, total replacement of the loop 164-173 with the IL-1ra stretch 52-55) included substitutions of residues allegedly important for agonist binding to IL-1RI. Mutant SMIL-3 showed the most profound reduction in binding capacity for IL-1RI (CDw121a) and a more than 1,000-fold reduced biologic activity both in vitro and in vivo, but it retained full capacity of binding to IL-1RII (CDw121b) and acted as a selective antagonist of IL-1RII. From these results the following conclusions can be drawn. IL-1 beta binds to IL-1RI and to IL-1RII through different sites, and the loop 164-173 appears as one of the areas involved in the selective interaction with IL-1RI. Agonist (IL-1 beta) and nonagonist (IL-1ra) binding to IL-1RI occur through distinct sites, with loops 164-173 and 202-214 of IL-1 beta identified as two of the sites selectively involved in agonist binding to the activating receptor.
Parasite strain specificity of bovine cytotoxic T cell responses to Theileria parva is determined primarily by immunodominance.
Authors: Taracha E L , Goddeeris B M , Teale A J , Kemp S J , Morrison W I 
Published: December 2022

Abstract
The parasite strain specificity of CTL responses to Theileria parva varies among cattle immunized with the same parasite stock. We have investigated the influence of class I MHC on the strain specificity of CTL responses to T. parva in 19 cattle of defined class I phenotype immunized with either of two T. parva populations, in which protection to subsequent reciprocal challenge correlated with CTL strain specificity. In the majority of animals the response was restricted by the products of one MHC haplotype and there was a consistent bias to some haplotypes in preference to others. In 10 of 13 cattle expressing the molecularly defined MHC specificities A10 and KN104 on one haplotype, the CTL response was restricted entirely by this haplotype, thus allowing a precise analysis of the MHC restriction specificities. The MHC restriction specificity and the parasite population used for immunization both influenced the strain specificity of the response. By examining responses in identical twins immunized with different parasites or in animals before and after challenge with heterologous parasites, animals that mounted a strain-specific response to primary infection were shown to be capable of responding to Ags shared by the two parasite populations. These findings indicate that the strain specificity of CTL responses to T. parva is not determined primarily by immune response genes that define the inherent capacity to respond, but rather is a consequence of the response in individual animals being biased toward a limited number of immunodominant peptide-MHC determinants.
Cyclic nucleotide phosphodiesterase type IV participates in the regulation of IL-10 and in the subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages.
Authors: Kambayashi T , Jacob C O , Zhou D , Mazurek N , Fong M , Strassmann G 
Published: December 2022

Abstract
We have recently shown that PGE2 inhibits the release of TNF-alpha from LPS-stimulated murine peritoneal macrophages via a feedback mechanism involving IL-10. Here we demonstrate that a rolipram-sensitive phosphodiesterase (PDE) type IV participates in the regulation of IL-10 synthesis. Selective PDE IV inhibitors (rolipram and RO-20-1724), but not selective inhibitors of other types of PDE, significantly augment marcrophage IL-10 production and contribute to the inhibition of TNF-alpha and IL-6 release. The addition of rolipram to LPS-stimulated macrophages results in the accumulation of cAMP and in the significant augmentation of IL-10 release. Competitive PCR analysis reveals that the drug dramatically increases IL-10 mRNA, but does not affect TNF-alpha mRNA. The inhibitory effect of rolipram on TNF-alpha can be significantly but incompletely reversed by anti-IL-10 Ab, whereas the effect of the drug on IL-6 can be completely reversed by anti-IL-10. In endotoxemic mice, the administration of rolipram increases serum IL-10 and reduces TNF-alpha and IL-6 levels. Northern blot analysis of spleens from these mice shows that rolipram increases IL-10 mRNA, whereas TNF-alpha mRNA remains largely unchanged. These results suggest that a rolipram-sensitive PDE type IV is involved in the production of IL-10 and in turn contributes to the inhibition of TNF-alpha and IL-6 release.
Identification of messenger RNA for IL-4 in human eosinophils with granule localization and release of the translated product.
Authors: Moqbel R , Ying S , Barkans J , Newman T M , Kimmitt P , Wakelin M , Taborda-Barata L , Meng Q , Corrigan C J , Durham S R , Kay A B 
Published: December 2022

Abstract
Human eosinophils are cytokine-producing cells that are prominent in IgE-dependent allergic tissue reactions. IL-4 promotes the development of the Th2-type phenotype in T cells and is an essential cofactor for IgE production by B cells. We detected mRNA for IL-4 by reverse transcription-PCR in blood eosinophils from atopic asthmatics. By specific ELISA, 108 +/- 20 pg of IL-4 protein/10(6) cells could be extracted from whole cells, and approximately 30% of the IL-4 was released after incubation with serum-coated particles. Using immunocytochemistry, eosinophils from atopic asthmatics and nonatopic controls showed IL-4 immunoreactivity using an anti-IL-4 mAb. IL-4 was located predominantly in the eosinophil granules, as shown by both immunogold electron microscopy and a cell fractionation technique that dissociated cell granules from membrane and cytosolic components. IL-4 mRNA colocalized with eosinophils (using sequential immunocytochemistry with an eosinophil-specific (EG2) mAb and in situ hybridization using an IL-4-specific antisense riboprobe) in both cell cytospins from bronchoalveolar lavage fluid from asthmatics as well as skin biopsies obtained from allergen-induced late phase (6-h) reactions in atopic subjects. Using double immunocytochemistry on skin biopsies with eosinophil- and IL-4-specific mAb, 83.5 +/- 3.5% of eosinophils were IL-4+. Conversely, eosinophils accounted for 46.5 +/- 3.9% of the total cells expressing IL-4 immunoreactivity. Thus, human eosinophils express mRNA for IL-4, and the translated product is contained within the crystalloid granule from which it is released after stimulation with serum-coated particles. These observations are consistent with the hypothesis that eosinophils contribute to the development of the Th2 phenotype by T cells infiltrating atopic allergic reactions as well as to IgE synthesis.
Follicular dendritic cells, interdigitating cells, and cells of the monocyte-macrophage lineage are the C1q-producing sources in the spleen. Identification of specific cell types by in situ hybridization and immunohistochemical analysis.
Authors: Schwaeble W , Schäfer M K , Petry F , Fink T , Knebel D , Weihe E , Loos M 
Published: December 2022

Abstract
In a mouse model, we have shown previously that macrophages are the principal source of complement C1q. Furthermore, spleen, heart, and brain were found to contain substantial levels of murine C1q-specific mRNA, whereas liver, kidney, lung, and small intestine contained only trace amounts of C1q-specific mRNA. This work addresses the identification of C1q-expressing spleen cells in the rat, using Northern blotting and in situ detection of rat C1q mRNA combined with immunohistochemical analysis. The complete sequence of mRNA encoding the B chain of rat C1q was established. The cloned cDNA was found to hybridize primarily with spleen-derived mRNA of 1.2 kb, and additionally with a novel mRNA species of 3 kb. In situ hybridization together with immunohistochemistry revealed most of the C1q-expressing cells to be located in the red pulp of the spleen, and to be mainly of the monocyte-macrophage lineage, as indicated by coexpression of ED-1, an established marker for this type of cell. In addition, C1q was expressed in S-100-positive but ED-1-negative cells, in germinal center follicular dendritic cells, and in some interdigitating dendritic cells of the periarteriolar lymphatic sheath (PALS). These results indicate that the spleen, containing the above APCs that are all involved to a major extent in the adaptive immune response and are all capable of synthesizing C1q that is involved intimately in the innate immune response, may provide the site at which the innate and adaptive immune systems merge.
B7 costimulation is necessary for the activation of the lytic function in cytotoxic T lymphocyte precursors.
Authors: Guerder S , Carding S R , Flavell R A 
Published: December 2022

Abstract
B7-CD28 costimulation is essential for the activation of CD4+ T helper cells, mainly by regulating IL-2 and other cytokine production. The requirement for this costimulatory pathway in the activation of CD8+ T cells, however, is still poorly understood. Here we analyzed the role of B7-CD28 costimulation in the differentiation of Ag-specific CTL precursor. We found that the activation of not only IL-2 production but also cytotoxic function in CD8 T cells requires B7 costimulation. The costimulatory signal, which cannot be replaced by exogenous IL-2, is directly implicated in the activation of the lytic machinery in CD8 T cells. Moreover, B7-CD28 costimulation appears to play a critical role in the accumulation of mRNA encoding at least one of the granzymes required for cytolytic function, granzyme B or CTLA-1. The production of IFN-gamma by CD8 T cells, however, does not appear to require costimulation.
Activation of human epidermal Langerhans cells by engagement of the high affinity receptor for IgE, Fc epsilon RI.
Authors: Jürgens M , Wollenberg A , Hanau D , de la Salle H , Bieber T 
Published: December 2022

Abstract
Human epidermal Langerhans cells (LCs) bind IgE via the high affinity receptor (Fc epsilon RI), and therefore are suspected to be involved in the genesis of atopic diseases. In this study, we report that surface expression of Fc epsilon RI is increased dramatically on LCs from patients with atopic dermatitis (AD) when compared with nonatopic individuals. Cross-linking of Fc epsilon RI on LCs from nonatopic individuals and patients with AD leads to a rapid tyrosine phosphorylation of several proteins, including p72, p77, and p95. However, upon receptor ligation, calcium mobilization is only detected in LCs freshly isolated from patients with AD (responder LCs), but not in those from normal skin of healthy individuals (nonresponder LCs). The beta-chain of Fc epsilon RI is not detected in normal LCs and only in a minority of LCs from atopic individuals, indicating that it is not related to the capacity of LCs to respond to Fc epsilon RI-mediated activation. In contrast, LCs from both nonatopic and atopic individuals internalize Fc epsilon RI by receptor-mediated endocytosis as a prerequisite for Ag focusing. Therefore, LCs from normal individuals and individuals with AD differ functionally by their Fc epsilon RI expression and by a distinct ability to respond to Fc epsilon RI-mediated activation.
A metalloprotease inhibitor blocks shedding of the IL-6 receptor and the p60 TNF receptor.
Authors: Müllberg J , Durie F H , Otten-Evans C , Alderson M R , Rose-John S , Cosman D , Black R A , Mohler K M 
Published: December 2022

Abstract
Many cytokines and soluble cytokine receptors are generated by limited proteolysis of membrane-bound precursors. We have examined the ability of the recently described metalloprotease inhibitor, TNF-alpha protease inhibitor (TAPI), and other protease inhibitors to modulate shedding. The membrane-bound forms of the ligands TNF-alpha and CSF-1, the p60 TNFR and the IL-6R, were expressed in COS-7 cells. As expected, TAPI blocked the spontaneous and PMA-induced release of TNF-alpha from transfected cells. Interestingly, TAPI also inhibited the release of soluble forms of p60 TNFR and IL-6R in COS-7 cells. However, the processing of CSF-1, which also requires proteolytic cleavage of a membrane protein, was not affected. The ability of TAPI to inhibit shedding was unique, since several other classes of protease inhibitors, including three other metalloprotease inhibitors, did not inhibit shedding of IL-6R. To determine whether TAPI would prevent shedding under more physiologic conditions, we demonstrated that TAPI was able to prevent unstimulated and PMA-induced release of the soluble forms of TNF-alpha, p60 TNFR, and IL-6R from the monocytic cell line, THP-1, and from human peripheral blood monocytes. In addition, TAPI was able to inhibit LPS-induced shedding of the p60 TNFR and TNF-alpha from monocytes. In summary, our results indicate that a metalloprotease or group of related metalloproteases is responsible for the proteolytic cleavage of several cell surface proteins.
Mouse lymphotoxin-beta receptor. Molecular genetics, ligand binding, and expression.
Authors: Force W R , Walter B N , Hession C , Tizard R , Kozak C A , Browning J L , Ware C F 
Published: December 2022

Abstract
Lymphotoxin (LT) -alpha beta heterotrimer is a membrane-anchored ligand expressed by activated T cells which binds specifically to the LT beta receptor (LT beta R), a member of the TNFR family. The LT beta R is implicated as a critical element in controlling lymph node development and cellular immune reactions. To address this hypothesis we have isolated a mouse cDNA encoding a single transmembrane protein of 415 amino acids with 76% identity to human LT beta R. The receptor function of this molecule was demonstrated by the ability of the extracellular domain, constructed as a chimera with the Fc region of IgG7, to bind to LT alpha beta complexes expressed on the surface of activated T cells or insect cells infected with baculoviruses containing LT alpha and LT beta cDNAs. The gene encoding mouse LT beta R, Ltbr, contains 10 exons spanning 6.9 kb and maps to mouse chromosome 6, which is closely linked to Tnfr1, consistent with the tight linkage of the human homologue of these genes on chromosome 12p13. Mouse LT beta R mRNA is expressed by cell lines of monocytic and epithelial origin but not by a CTL line, and in vivo it is constitutively expressed in visceral and lymphoid tissues. The delineation of the structure of the mouse LT beta R will aid investigations into the role of this cytokine-receptor system in immune function and development.
Molecular cloning and functional characterization of a novel member of the C-C chemokine family.
Authors: Hara T , Bacon K B , Cho L C , Yoshimura A , Morikawa Y , Copeland N G , Gilbert D J , Jenkins N A , Schall T J , Miyajima A 
Published: December 2022

Abstract
Chemokines play an important role in immune and inflammatory responses by inducing migration and adhesion of leukocytes. We have isolated a novel chemokine cDNA, designated CCF18, from a cDNA library of an IL-3-dependent murine pro-B cell line, Ba/F3. The cDNA encodes a protein structurally related to the C-C chemokine members. Among this family, C10 shows the highest homology to CCF18, and MIP-1 alpha also has a significant homology but to a lesser extent. CCF18 produced from COS cells induced chemotaxis and Ca2+ flux in CD4+ T cell clones. Moreover, prior administration of MIP-1 alpha desensitized the cells to CCF18. The CCF18 gene (Scya10) was mapped to a middle region of murine chromosome 11, where other genes for several C-C chemokine members are localized. These results clearly indicate that CCF18 is a new member of the C-C chemokine family. Since a high level of CCF18 mRNA is constitutively expressed in macrophage and myeloid cell lines, CCF18 may play a role in inflammatory processes.
CD66 family members are associated with tyrosine kinase activity in human neutrophils.
Authors: Skubitz K M , Campbell K D , Ahmed K , Skubitz A P 
Published: December 2022

Abstract
The granulocyte activation Ags, CD66a, CD66b, CD66c, and CD66d, are expressed at low levels on resting blood granulocytes, but their surface expression is up-regulated following stimulation. CD66a, in contrast to CD66b and CD66c which are anchored to the membrane via a glycosyl-phosphatidylinositol linkage, is a transmembrane protein with a cytoplasmic domain. We have previously reported that CD66a is phosphorylated in human neutrophils, largely on tyrosine, with a lower level of phosphoserine. We have now found that CD66a undergoes a rapid increase in phosphorylation following stimulation with FMLP, platelet-activating factor, and 12-O-tetradecanoyl-phorbol-13-acetate. This increase in phosphorylation was transient, with maximal phosphorylation observed by 1 min and a return to base line by 5 min following stimulation. Protein kinase activity was detected in neutrophils associated with CD66a, CD66b, and CD66c. Most of the protein kinase activity associated with these Ags was tyrosine kinase activity, with a lesser amount of threonine and serine kinase activities. Lyn and Hck accounted for much of the associated tyrosine kinase activity. The data suggest that phosphorylation of CD66a on tyrosine by an associated tyrosine kinase may play a role in the function of CD66a. In addition, associated tyrosine kinase activity may play a role in signal transduction from CD66a, CD66b, and CD66c to regulate other cell functions.
Identification of protein tyrosine phosphatase-like IA2 (islet cell antigen 512) as the insulin-dependent diabetes-related 37/40K autoantigen and a target of islet-cell antibodies.
Authors: Bonifacio E , Lampasona V , Genovese S , Ferrari M , Bosi E 
Published: December 2022

Abstract
The majority of patients with insulin-dependent diabetes (IDDM) have Abs to 40- and/or 37-kDa tryptic fragments (37/40K-Abs) deriving from an unidentified islet cell membrane protein distinct from glutamate decarboxylase (GAD). Recently, autoantibodies against ICA512, which has identity with the protein tyrosine phosphatase-like protein IA2, were reported. In this study we have examined whether IA2/ICA512 is the Ag specificity of 37/40K-Abs, and one of the determinants of islet cell Abs (ICA) detected by immunofluorescence. Serum from 51 of 100 new onset IDDM patients immunoprecipitated 40- and/or 37-kDa insulinoma polypeptides, and 53 immunoprecipitated in vitro translated rIA2; 49 had both 37/40K-Abs and rIA2 Abs. There were strong correlations between the levels of Abs to rIA2 and both 40 kDa (r = 0.85, p &lt; 0.0001) and 37 kDa (r = 0.70, p &lt; 0.0001) insulinoma polypeptides. Trypsin treatment of immunoprecipitated rIA2 yielded 40- and 37-kDa fragments, and preincubation of sera with rIA2 completely inhibited binding to the insulinoma 40- and 37-kDa polypeptides. IA2 Ab levels also correlated with ICA titer in GAD-Ab negative sera, and preincubation with rIA2 reduced ICA staining intensity in sera with ICA and IA2 Abs, but not in sera with ICA in the absence of IA2 Abs. These results provide clear evidence for the identification of IA2/ICA512 as the precursor of the islet 40- and 37-kDa polypeptide autoantigens and as one of the ICA specificities. Combined detection of Abs to IA2 and GAD65 in a single radio-binding assay identified Abs in 88 of 100 IDDM patients, and potentially facilitates population screening for IDDM risk assessment.
Frequency of molecular mimicry among T cell peptides as the basis for autoimmune disease and autoantibody induction.
Authors: Garza K M , Tung K S 
Published: December 2022

Abstract
Experimental ovarian autoimmune disease is inducible by immunization with an ovarian peptide from zona pellucida (ZP) 3, a glycoprotein of the zona pellucida on mouse oocyte. The murine ZP3 peptide contains two nested T cell epitopes with slightly different critical residue motifs. To investigate the frequency of cross-reaction between nonovarian and ovarian peptides, we have chosen arbitrarily 16 nonovarian peptides with complete or partial homology to the critical residue motifs of the two T cell epitopes. Based on peptide induction of autoimmune oophoritis and T cell-dependent amplified autoantibody response to ovarian ZP, cross-reaction was documented for 7 (or 44%) of the 16 nonovarian peptides studied. Thus, molecular mimicry as a pathogenetic mechanism of autoimmunity should not be limited by the frequency of cross-reaction among self and nonself peptides. On the other hand, the sharing of critical residue motif per se is not sufficient for mimicry to occur, nor does it predict peptide cross-reaction.