bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-10 Is Critical in the Regulation of Autoimmune Encephalomyelitis as Demonstrated by Studies of IL-10- and IL-4-Deficient and Transgenic Mice
Authors: Bettelli Estelle , Prabhu Das Mercy , Howard Edward D. , Weiner Howard L. , Sobel Raymond A. , Kuchroo Vijay K. 
Published: December 2022

AbstractExperimental autoimmune encephalomyelitis (EAE) and other organ-specific autoimmune diseases are induced by autoantigen-specific Th1 cells. In contrast, transfer of autoantigen-reactive Th2 cells that produce IL-4 and IL-10 can prevent and/or reverse EAE. The relative roles of these two Th2 cytokines in the regulation of EAE has not been evaluated. Utilizing IL-4 and IL-10 knockout mice deficient for these cytokines and IL-10 and IL-4 transgenic mice overexpressing these cytokines, we demonstrate that IL-10-deficient mice (IL-10−/−) are more susceptible and develop a more severe EAE when compared with IL-4-deficient mice (IL-4−/−) or wild-type mice. T cells from IL-10−/− mice exhibit a stronger Ag-specific proliferation, produce more proinflammatory cytokines (IFN-γ and TNF-α) when stimulated with an encephalitogenic peptide, and induce very severe EAE upon transfer into wild-type mice. In contrast, while IL-4 transgenic mice develop similar disease compared with their nontransgenic littermates, mice transgenic for IL-10 are completely resistant to the development of EAE. Taken together, our data suggest that IL-10 plays a more critical role in the regulation of EAE by regulating autopathogenic Th1 responses.
Neonatal Murine B Lymphocytes Respond to Polysaccharide Antigens in the Presence of IL-1 and IL-6
Authors: Chelvarajan Ralph L. , Gilbert Nikole L. , Bondada Subbarao 
Published: December 2022

AbstractUnlike adults, neonates are unable to respond to polysaccharide Ags, making them especially vulnerable to pathogenic encapsulated bacteria. Since the Ab response to polysaccharides in adult mice requires certain cytokines, it was hypothesized that neonatal murine B cells may be competent to respond to such Ags, but may fail to do so due to a deficiency of cytokines. Neonatal splenocyte cultures, which were otherwise unresponsive to trinitrophenyl (TNP)-Ficoll, a haptenated polysaccharide Ag, mounted an adult-like Ab response when supplemented with IL-1. However, IL-1 failed to induce such a response to TNP-Ficoll when purified B cells were used instead. Although IL-6 alone did not induce a response in whole spleen cells or purified B cells from neonates, it synergized with IL-1 in inducing purified neonatal B cells to respond to TNP-Ficoll. The avidity of the cytokine-induced neonatal anti-TNP Abs was comparable to that of Abs made by adult splenocyte cultures. One effect of IL-1 may be at the level of clonal expansion, since it induced neonatal B cells to proliferate in response to anti-IgM, which was further enhanced by IL-6. The spontaneous secretion of IL-1 by neonatal splenocytes was below the detection limit, while adult splenocytes secreted 30.8 ± 5.2 U/ml, which is of the same order of magnitude as what was required to stimulate neonatal B cells to respond to TNP-Ficoll. Thus, the neonatal unresponsiveness to polysaccharide Ags could be due to the inability of a non-B cell population resident in the neonatal spleen to secrete sufficient quantities of IL-1.
Expression and Function of CTLA-4 in Th1 and Th2 Cells
Authors: Alegre Maria-Luisa , Shiels Helena , Thompson Craig B. , Gajewski Thomas F. 
Published: December 2022

AbstractCTLA-4 is expressed on T cells after activation and shares homology with the CD28 costimulatory receptor. In contrast to CD28, CTLA-4 is thought to be a negative regulator of T cell activation. Cross-linking of CTLA-4 during activation of peripheral T cells reduces IL-2 production and arrests T cells in G1. Much less is known about the function of CTLA-4 in differentiated T cells. We have investigated the expression and function of CTLA-4 in established Th1 and Th2 clones and in bulk populations of Th1 and Th2 cells freshly derived in vitro from TCR transgenic splenocytes. We found that CTLA-4 was induced under similar conditions and with similar kinetics following activation of both Th1 and Th2 clones. However, CTLA-4 expression was much higher in Th2 than Th1 clones and lines. This was confirmed by flow cytometry, confocal microscopy, and Northern blot analysis. The ratio of surface to intracellular expression of CTLA-4 and its rate of endocytosis were similar in Th1 and Th2 clones. Inhibition of binding of CTLA-4 to its ligands using soluble anti-CTLA-4 mAb during stimulation with Ag increased the production not only of IL-2 by Th1 clones, but also that of IL-3 and IFN-γ by Th1 clones and of IL-3, IL-4, IL-5, and IL-10 by Th2 clones. In contrast, when anti-CTLA-4 was coimmobilized with anti-CD3 and anti-CD28 mAbs, a decrease in the production of multiple cytokines was observed. We conclude that CTLA-4 can function to suppress the production of cytokines produced by both Th1 and Th2 cells.
Caspase-Independent Cell Death Induced by Anti-CD2 or Staurosporine in Activated Human Peripheral T Lymphocytes
Authors: Déas Olivier , Dumont Céline , MacFarlane Marion , Rouleau Matthieu , Hebib Chafika , Harper Francis , Hirsch François , Charpentier Bernard , Cohen Gerald M. , Senik Anna 
Published: December 2022

AbstractWe examined the effects of the cell-permeable, broad spectrum peptide caspase inhibitors, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (Z-VAD.fmk), and BOC-Asp(OMe)-fluoromethyl ketone (BOC-D.fmk), on apoptosis induced by anti-CD2, anti-Fas, and the protein kinase inhibitor staurosporine in activated human peripheral T lymphocytes. We monitored ultrastructural, flow cytometric, and biochemical apoptotic changes, including externalization of phosphatidylserine, cleavage of poly(ADP-ribose) polymerase (PARP) and lamins, activation of caspase-3 and caspase-7, decrease in mitochondrial membrane potential, and DNA fragmentation. Z-VAD.fmk and BOC-D.fmk completely inhibited all the biochemical and ultrastructural changes of apoptosis in anti-Fas-treated cells. In marked contrast, neither Z-VAD.fmk nor BOC-D.fmk inhibited CD2- or staurosporine-mediated cell shrinkage, dilatation of the endoplasmic reticulum (seen in anti-CD2-treated cells), externalization of phosphatidylserine, and loss of mitochondrial membrane potential that accompanied cell death. However, these inhibitors did inhibit the cleavage of PARP and lamins and the formation of hypodiploid cells, and partially inhibited chromatin condensation. These results demonstrate that in activated T cells, anti-CD2 and staurosporine induce a caspase-independent cell death pathway that exhibits prominent cytoplasmic features of apoptosis. However, caspase activation is required for the proteolytic degradation of nuclear substrates such as PARP and lamins together with the DNA fragmentation and extreme chromatin condensation that occur in apoptotic cells.
γ3 Gene-Disrupted Mice Selectively Deficient in the Dominant IgG Subclass Made to Bacterial Polysaccharides Undergo Normal Isotype Switching After Immunization with Polysaccharide-Protein Conjugate Vaccines
Authors: Shapiro David A. , Threadgill Deborah S. , Copfer M. Janna , Corey Deborah A. , McCool Tera L. , McCormick Laura L. , Magnuson Terry R. , Greenspan Neil S. , Schreiber John R. 
Published: December 2022

AbstractBacterial polysaccharides (PS) are T-independent type 2 Ags that elicit restricted Ab responses of IgM and IgG3 in mice and IgM and predominantly IgG2 in humans. Immunodeficiency in the dominant IgG subclass made to PS is associated with chronic sinus and pulmonary infections with PS-encapsulated bacteria. To elucidate the biologic role of the dominant IgG subclass in the immune response to PS and to make an animal model of human IgG subclass deficiency, we generated mice with a targeted disruption of the exon encoding the CH1 domain of the γ3 heavy-chain constant region gene. Homozygotes had no detectable serum IgG3, and their splenocytes did not produce IgG3 after LPS stimulation. IgG3−/− mice immunized with PS from Pseudomonas aeruginosa LPS O-side chain or Streptococcus pneumoniae type 19F capsule did not produce any IgG3 anti-PS Abs, in contrast to wild-type mice in which IgG3 was the major IgG subclass. Immunizing both wild-type and IgG3−/− mice with 19F PS-protein conjugate elicited IgG1 Abs. We conclude that IgG3−/− mice have a selective deficiency in the dominant murine IgG subclass made to T-independent type 2 Ags and may be a useful animal model of IgG subclass deficiency. In addition, we show that the anti-PS Ab class switching to IgG1 that occurs when mice are immunized with a PS-protein conjugate vaccine does not require sequential Ig expression or an intact, upstream γ3 heavy-chain gene.
IL-15 Promotes IL-12 Production by Human Monocytes Via T Cell-Dependent Contact and May Contribute to IL-12-Mediated IFN-γ Secretion by CD4+ T Cells in the Absence of TCR Ligation
Authors: Avice Marie-Noëlle , Demeure Christian E. , Delespesse Guy , Rubio Manuel , Armant Myriam , Sarfati Marika 
Published: December 2022

AbstractAt inflammatory sites, the number of activated bystander T cells exceeds that of Ag-activated T cells. We investigated whether IL-15, a monocyte-derived cytokine that shares several biologic activities with IL-2, may contribute to bystander T cell activation in the absence of IL-2 and triggering Ag. The addition of IL-15 to cocultures of monocytes and T cells stimulates CD4+ but not CD8+ T cells to produce IFN-γ. IFN-γ production requires endogenous IL-12, the production of which in turn is dependent upon CD40/CD154 interactions between CD4+ T cells and monocytes. Indeed, non-TCR-activated CD4+ but not CD8+ T cells express significant levels of CD154. IL-15 may enhance IFN-γ in this system by up-regulating CD40 expression on monocytes and IL-12Rβ1 expression on CD4+ T cells. Conversely, using neutralizing anti-IL-15 mAb, we show that the ability of IL-12 to augment IFN-γ secretion is partly mediated by endogenous IL-15. Finally, in the absence of monocytes, a synergistic effect between exogenous IL-12 and IL-15 is necessary to induce IFN-γ production by purified CD4+ T cells, while IL-15 alone induces T cell proliferation. It is proposed that this codependence between IL-12 and IL-15 for the activation of inflammatory T cells may be involved in chronic inflammatory disorders that are dominated by a Th1 response. In such a response, a self-perpetuating cycle of inflammation is set forth, because IL-15-stimulated CD4+ T cells may activate monocytes to release IL-12 that synergizes with IL-15 to induce IL-12 response and IFN-γ production.
Role of Nuclear Factor-κB and Mitogen-Activated Protein Kinase Signaling Pathways in IL-1β-Mediated Induction of α-PDGF Receptor Expression in Rat Pulmonary Myofibroblasts
Authors: Lindroos Pamela M. , Rice Annette B. , Wang Yi-Zhe , Bonner James C. 
Published: December 2022

AbstractInduction of the α-platelet-derived growth factor receptor (PDGF-Rα) by IL-1β in lung myofibroblasts enhances mitogenic and chemotactic responses to PDGF, and this could be a mechanism of myofibroblast hyperplasia during lung fibrogenesis. Since the regulation of many genes by IL-1β involves activation of NF-κB and mitogen-activated protein (MAP) kinases, we examined these signaling pathways in the control of PDGF-Rα expression by IL-1β in cultured rat lung myofibroblasts. Treatment of cells with pyrrolidine dithiocarbamate (PDTC), an antioxidant that inhibits NF-κB activation, completely blocked PDGF-Rα up-regulation by IL-1β as assayed by [125I]PDGF-AA binding and PDGF-Rα mRNA expression, suggesting a role for NF-κB. However, while IL-1β and TNF-α both induced nuclear binding of the Rel proteins p50 and p65 to an NF-κB consensus oligonucleotide in gel shift assays and caused transient degradation of inhibitor of NF-κB-α (IκB-α) in the cytoplasm of myofibroblasts, only IL-1β up-regulated PDGF-Rα. These results suggest that NF-κB activation alone is not sufficient for up-regulation of PDGF-Rα. An investigation of MAP kinase signaling pathways revealed that IL-1β or PDTC activated extracellular signal-regulated kinase-2 (ERK-2) and c-jun NH2 terminal kinase-1 (JNK-1) phosphorylation of PHAS-1 and c-Jun substrates, respectively. Pretreatment of cells with the MAP kinase kinase-1 (MEK1) inhibitor PD 98059 blocked IL-1β-induced activation of ERK-2 by more than 90% but enhanced IL-1β-stimulated induction of PDGF-Rα expression fourfold. Taken together, these data suggest that IL-1β activates both positive and negative signaling pathways that control the expression of PDGF-Rα. IL-1β appears to mediate its negative effects on PDGF-Rα expression via MAP kinase activation, while the factor(s) that mediate induction of PDGF-Rα remain to be elucidated.
Specific Antagonism of Type I IL-4 Receptor with a Mutated Form of Murine IL-4
Authors: Schnare Markus , Blum Horst , Jüttner Stefan , Röllinghoff Martin , Gessner André 
Published: December 2022

AbstractIL-4 is a pleiotropic cytokine that is essential for the differentiation of Th2 cells and is critically involved in the pathogenesis of certain infectious and allergic diseases. We have produced and functionally characterized a mutant of murine IL-4 (IL-4.Y119D) as a potential antagonist of IL-4. The analysis of IL-4R binding revealed no differences between wild-type and mutated IL-4. Despite this finding, IL-4.Y119D was unable to induce proliferation of several IL-4-responsive T cell lines mediated via the type I IL-4R (IL-4Rα/common γ chain (γc chain)) and specifically inhibited the proliferative effect of wild-type IL-4. In contrast, with IL-4.Y119D we found induction of MHC class II and CD23 molecules on resting splenic B cells as well as proliferation of B9 plasmocytoma cells. In addition, IL-4.Y119D induced mRNA for soluble IL-4R, leading to the release of soluble IL-4R protein by spleen cells. In macrophages, mutated IL-4 in combination with IFN-γ induced TNF-α-dependent killing of Leishmania major parasites such as wild-type IL-4. The agonistic effects of IL-4.Y119D were observed on cells expressing the IL-13R α-chain, including an IL-13R α-chain transfected T cell line, but were absent in T cells that lack this molecule, indicating that IL-4.Y119D conveys its activity via the type II IL-4R (IL-4Rα/IL-13Rα). The described IL-4 mutant, therefore, represents a new tool to use in dissecting different IL-4 functions that are mediated by either type I or type II IL-4R complexes.
The Molecular and Functional Characterization of a Dominant Minor H Antigen, H60
Authors: Malarkannan Subramaniam , Shih Patty P. , Eden Peter A. , Horng Tiffany , Zuberi Aamir R. , Christianson Greg , Roopenian Derry , Shastri Nilabh 
Published: December 2022

AbstractMinor histocompatibility (H) Ags elicit T cell responses and thereby cause chronic graft rejection and graft-vs-host disease among MHC identical individuals. Although numerous independent H loci exist in mice of a given MHC haplotype, certain H Ags dominate the immune response and are thus of considerable conceptual and therapeutic importance. To identify these H Ags and their genes, lacZ-inducible CD8+ T cell hybrids were generated by immunizing C57BL/6 (B6) mice with MHC identical BALB.B spleen cells. The cDNA clones encoding the precursor for the antigenic peptide/Kb MHC class I complex were isolated by expression cloning using the BCZ39.84 T cell as a probe. The cDNAs defined a new H locus (termed H60), located on mouse chromosome 10, and encoded a novel protein that contains the naturally processed octapeptide LTFNYRNL (LYL8) presented by the Kb MHC molecule. Southern blot analysis revealed that the H60 locus was polymorphic among the BALB and the B6 strains. However, none of the H60 transcripts expressed in the donor BALB spleen were detected in the host B6 strain. The expression and immunogenicity of the LYL8/Kb complex in BALB.B and CXB recombinant inbred strains strongly suggested that the H60 locus may account for one of the previously described antigenic activity among these strains. The results establish the source of an immunodominant autosomal minor H Ag that, by its differential transcription in the donor vs the host strains, provides a novel peptide/MHC target for host CD8+ T cells.
Therapeutic Preparations of Normal Polyspecific IgG (IVIg) Induce Apoptosis in Human Lymphocytes and Monocytes: A Novel Mechanism of Action of IVIg Involving the Fas Apoptotic Pathway
Authors: Prasad Nagendra K. A. , Papoff Giuliana , Zeuner Ann , Bonnin Emmanuelle , Kazatchkine Michel D. , Ruberti Giovina , Kaveri Srini V. 
Published: December 2022

AbstractTherapeutic preparations of normal human IgG for i.v. use (IVIg) exhibit a broad spectrum of immunoregulatory activities in vitro and in vivo. IVIg has been shown to inhibit the proliferation of activated B and T lymphocytes and of several autonomously growing cell lines. In this study, we demonstrate that IVIg induces apoptosis in leukemic cells of lymphocyte and monocyte lineage and in CD40-activated normal tonsillar B cells, involving, at least in part, Fas (CD95/APO-1) and activation of caspases. IVIg-induced apoptosis was higher in Fas-sensitive HuT78 cells than in Fas-resistant HuT78.B1 mutant cells, and soluble Fas inhibited IVIg-induced apoptosis. IVIg immunoprecipitated Fas from Fas-expressing transfectants and recognized purified Fas/glutathione-S-transferase fusion proteins upon immunoblotting. Affinity-purified anti-Fas Abs from IVIg induced apoptosis of CEM T cells at a 120-fold lower concentration than unfractionated IVIg. Inhibitors of cysteine proteases of the caspase family, caspase 1 (IL-1β-converting enzyme) and caspase 3 (Yama/CPP32b), partially inhibited IVIg-induced apoptosis of CEM cells. Furthermore, cleavage of poly(A)DP-ribose polymerase into an 85-kDa signature death fragment was observed in CEM cells following IVIg treatment. Thus, normal IgG induces apoptosis in lymphocytes and monocytes. Our results provide evidence for a role of Fas, bring new insights into the mechanisms of action of IVIg in autoimmune diseases, and suggest a role of normal Ig in controlling cell death and proliferation.
Cutting Edge: Anti-CD1 Monoclonal Antibody Treatment Reverses the Production Patterns of TGF-β2 and Th1 Cytokines and Ameliorates Listeriosis in Mice
Authors: Szalay Gudrun , Ladel Christoph H. , Blum Carmen , Brossay Laurent , Kronenberg Mitchell , Kaufmann Stefan H. E. 
Published: December 2022

AbstractProtection against intracellular bacteria by T cells is regulated by Ag-presenting molecules, which comprise classical MHC class I molecules, MHC class II molecules, and nonclassical MHC class Ib molecules. The role of CD1 molecules, which are structurally similar to classical MHC class I gene products, but less polymorphic, is not understood so far. We show that CD1 surface expression increased on APC in Listeria-infected mice. The in vivo treatment with anti-CD1 mAb reduced TGF-β2 levels and concomitantly increased secretion of the proinflammatory cytokine TNF, the Th1 cell promoting cytokine IL-12, and the Th1 cell cytokine IFN-γ at the onset of listerial infection. These findings point to a regulatory role of CD1-reactive cells in the immune response against listeriosis.
Cutting Edge: Silencing Virus-Specific Cytotoxic T Cell-Mediated Immune Recognition by Differential Splicing: A Novel Implication of RNA Processing for Antigen Presentation
Authors: Kienzle Norbert , Sculley Tom B. , Greco Sonia , Khanna Rajiv 
Published: December 2022

Abstract
Persistent viruses have developed potent strategies to overcome host immune defenses. In particular, viral interference with Ag presentation by HLA class I molecules can effectively impair the host’s CTL function. Here we provide evidence for a novel aspect of differential splicing on endogenous processing of a latent viral transcript resulting in dominant protein isoforms from which the CTL determinant has been deleted. Consequently, virus-infected cells expressing these isoforms were poorly recognized by CTLs. Molecular analysis revealed that this splicing significantly reduced expression of the viral transcript encoding the relevant epitope to levels below the threshold required for CTL recognition. The importance of splicing was further reinforced by the observation of efficient CTL recognition of target cells expressing a truncated viral transcript that abolished differential splicing. Thus, differential splicing, which is a common mechanism of gene regulation in many pathogens, may unexpectedly interfere with immune recognition.
Enhancing or Suppressive Effects of Antibodies on Processing of a Pathogenic T Cell Epitope in Thyroglobulin
Authors: Dai Yang , Carayanniotis Karen A. , Eliades Petros , Lymberi Peggy , Shepherd Philip , Kong Yi-chi M. , Carayanniotis George 
Published: December 2022

AbstractThyroglobulin (Tg)-specific Abs occur commonly in thyroid disease, but it is not clear to what extent they affect Tg processing and presentation to T cells. Here we show that generation of the nondominant pathogenic Tg epitope (2549–2560), containing thyroxine (T4) at position 2553 (T4(2553)), is augmented by Tg-specific IgG mAbs that facilitate FcR-mediated internalization of Tg. However, other mAbs of the same (IgG1) subclass enhanced Tg uptake by APC but had no effect on the generation of this peptide. Treatment of APC with chloroquine or glutaraldehyde abrogated enhanced generation of T4(2553). The boosting effect was selective, since the enhancing mAbs did not facilitate generation of the neighboring cryptic (2495–2511) peptide, which is also pathogenic in mice. When Tg was simultaneously complexed to a mAb reactive with T4(2553) and to a mixture of boosting mAbs, the presentation of this epitope was totally suppressed. These results suggest that Tg-specific Abs alter Tg processing and may boost or suppress the presentation of nondominant pathogenic determinants during the course of disease.
Protein Kinase C Activation Inhibits Tyrosine Phosphorylation of Cbl and Its Recruitment of Src Homology 2 Domain-Containing Proteins
Authors: Liu Yuhong , Liu Yun-Cai , Meller Nahum , Giampa Leslie , Elly Chris , Doyle Melissa , Altman Amnon 
Published: December 2022

Abstract
One of the major proteins that is rapidly tyrosine phosphorylated upon stimulation of the TCR/CD3 complex is the 120-kDa product of the c-cbl protooncogene (Cbl). Upon activation, tyrosine-phosphorylated Cbl interacts with the Src homology 2 (SH2) domains of several signaling proteins, e.g., phosphatidylinositol 3-kinase (PI3-K) and CrkL. In the present study, we report that pretreatment of Jurkat T cells with PMA reduced the anti-CD3-induced tyrosine phosphorylation of Cbl and, consequently, its activation-dependent association with PI3-K and CrkL. A specific protein kinase C (PKC) inhibitor (GF-109203X) reversed the effect of PMA on tyrosine phosphorylation of Cbl and restored the activation-dependent association of Cbl with PI3-K and CrkL. We also provide evidence that PKCα and PKCθ can physically associate with Cbl and are able to phosphorylate it in vitro and in vivo. Furthermore, a serine-rich motif at the C terminus of Cbl, which is critical for PMA-induced 14-3-3 binding, is also phosphorylated by PKCα and PKCθ in vitro. These results suggest that, by regulating tyrosine and serine phosphorylation of Cbl, PKC is able to control the association of Cbl with signaling intermediates, such as SH2 domain-containing proteins and 14-3-3 proteins, which may consequently result in the modulation of its function.