bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-4 Is an Endogenous Inhibitor of Neutrophil Influx and Subsequent Pathology in Acute Antibody-Mediated Inflammation
Authors: Saleem Sohail , Dai Zhenhua , Coelho Sandra N. , Konieczny Bogumila T. , Assmann Karel J. M. , Baddoura Fady K. , Lakkis Fadi G. 
Published: January 2023

Abstract
IL-4 is an immunoregulatory cytokine that has in vitro and in vivo anti-inflammatory actions. In this study we investigated whether endogenously produced IL-4 modulates inflammatory processes that occur after Abs bind to target tissue by comparing the severity of glomerulonephritis induced by heterologous anti-glomerular basement membrane Abs in wild-type (IL-4+/+) mice to that of glomerulonephritis induced in homozygous IL-4 gene knockout (IL-4−/−) mice. Two hours after Ab injection, IL-4−/− mice had significantly higher intrarenal intercellular adhesion molecule-1 mRNA expression and intraglomerular neutrophil accumulation than the IL-4+/+ group. Treatment of IL-4−/− mice with recombinant murine IL-4 at the time of disease induction reduced intercellular adhesion molecule-1 expression and neutrophil influx to levels observed in IL-4+/+ kidneys. Four days after Ab administration, untreated IL-4−/− mice developed significantly greater urinary protein excretion, intracapillary fibrinogen deposits, and glomerular hypercellularity than IL-4+/+ mice. These results demonstrate that endogenous IL-4 suppresses neutrophil influx and limits tissue damage in Ab-induced glomerulonephritis, suggesting that IL-4 is an important regulator of acute inflammatory processes.
Activation of Human T Cells with Superantigen (Staphylococcal Enterotoxin B) and CD28 Confers Resistance to Apoptosis via CD95
Authors: McLeod Julie D. , Walker Lucy S. K. , Patel Yusuf I. , Boulougouris George , Sansom David M. 
Published: January 2023

AbstractAg recognition is an essential component for an effective T cell response. However, T cell activation is also subject to additional regulation by accessory molecules. CD28 provides essential costimulatory signals that allow T cells to proliferate, whereas molecules such as CTLA-4 and CD95 (Fas) appear to be negative regulators. Currently, which outcome predominates under conditions of antigenic challenge is poorly understood. In particular it has been suggested that one consequence of antigenic activation of T cells is the up-regulation of both CD95 and CD95 ligand, thereby exposing activated T cells to apoptotic death. We have investigated this possibility in normal human peripheral blood T cells triggered by the superantigen SEB either in the presence of endogenous APCs or transfectants expressing DR4 and CD80. In either case, we find that such activation does not expose the majority of T cells to anti-CD95-induced apoptosis as detected by annexin V externalization and DNA fragmentation. Furthermore, by phenotypically identifying, by flow cytometry, those cells that received both antigenic and costimulatory signals from those cells that did not, we observed that CD95-induced apoptosis was not seen in activated T cells receiving Ag and costimulatory signals via CD28. However, while not all T cells were stimulated by superantigen, CD95 expression was found to be homogeneously up-regulated, suggesting a mechanism whereby bystander cells might be made susceptible to CD95-induced death. We conclude that antigenic activation of T cells via the TCR and CD28 engagement provides protection from CD95-induced apoptosis.
A Novel Role for TGF-β and IL-10 in the Induction of Immune Privilege
Authors: D’Orazio Thomas J. , Niederkorn Jerry Y. 
Published: January 2023

Abstract
Immune privilege within the eye is due in large part to Ag-specific, systemic down-regulation of Th1 immune responses, a phenomenon termed anterior chamber-associated immune deviation (ACAID). Since the cytokine milieu influences Th cell differentiation, we hypothesized that TGF-β, an immunosuppressive cytokine secreted by ocular cells, determines the nature of the immune response to Ags introduced into the anterior chamber. Accordingly, an in vitro model of the eye was used to determine the cytokine profile of ocular APC. TGF-β preferentially induced APC to secrete a Th2-type cytokine, IL-10, and concomitantly suppressed the production of the Th1-inducing cytokine, IL-12. APC incubated with TGF-β and anti-IL-10 Ab lost their ability to induce ACAID. In the absence of TGF-β, Ag-pulsed APC preferentially secreted IL-12 and elicited Ag-specific Th1 responses (i.e., delayed-type hypersensitivity (DTH)). However, APC pulsed with Ag and exogenous IL-10 behaved in a manner similar to ocular APC and induced Ag-specific suppression of DTH. The role of IL-10 in ACAID was confirmed in IL-10 knockout mice. Anterior chamber injection of OVA into IL-10 knockout mice elicited normal DTH responses rather than ACAID. Moreover, Ag-pulsed APC from IL-10 knockout mice were unable to induce ACAID following in vitro treatment with TGF-β. Thus, TGF-β predisposes ocular APC to secrete IL-10 during Ag processing. This, in turn, directs the immune response away from a Th1 pathway and toward a Th2-like response in which DTH is suppressed.
Structural Dichotomy of Staphylococcal Enterotoxin C Superantigens Leading to MHC Class II-Independent Activation of T Lymphocytes
Authors: Lamphear James G. , Bohach Gregory A. , Rich Robert R. 
Published: January 2023

AbstractWe have recently characterized an MHC class II-deficient human cell line, SW480, that supports the proliferation of purified human T cells in the presence of the staphylococcal enterotoxin and superantigen SEC1, but not the closely related isotypes SEC2 or SEC3. We now investigate the structural basis of this dichotomy and explore possible mechanisms that may account for it. Differences in activity between SEC1 and SEC2 were not attributable to differences in biochemical modification, to differences in Vβ specificity, or to the potential to induce anergy. SEC2 inhibited SEC1-mediated T cell activation in the presence of SW480 cells, suggesting that SEC2 could compete with SEC1 for binding to the TCR but was unable to productively signal through the TCR. Utilizing a panel of hybrid enterotoxins we identified specific amino acids near the NH2-terminus of SEC1 that abrogated MHC class II-independent T cell activation, yet did not alter potency in the presence of class II+ APC. These residues mapped to the putative TCR binding domain of SEC1, and suggest that subtle differences in TCR binding affinity or the topology of the SEC1-TCR interaction can compensate for the lack of MHC class II and hence promote T cell proliferation.
Differential Coupling of Membrane Ig and CD40 to the Extracellularly Regulated Kinase Signaling Pathway
Authors: Purkerson Jeffrey M. , Parker David C. 
Published: January 2023

AbstractCoupling of membrane Ig (mIg) and CD40 to the extracellularly regulated kinase (ERK) signal transduction pathway was examined in the WEHI-231 B lymphoma and normal mouse B cells. Cross-linking mIg induces ERK activation in both WEHI-231 and normal B cells. In contrast, CD40 cross-linking failed to induce ERK activation in WEHI-231, but signals through CD40 were more effective than mIg as a stimulus for ERK activation in normal B cells. However, several lines of evidence suggest that CD40 and the B cell Ag regulate ERK through distinct pathways that converge at the level of MEK-1, mitogen-activated protein kinase kinase. Abs to mIg or CD40 induced MEK-1 activation with different kinetics. Cross-linking of mIg, but not CD40, induced tyrosine phosphorylation of the SHC adapter molecule that couples receptors to Ras-dependent signaling pathways. Finally, agents that elevate cAMP, causing protein kinase A-mediated inhibition of Raf-1, inhibited activation of ERK in response to mIg cross-linking, but had no affect on ERK activation in response to anti-CD40 or Jun N-terminal kinase activation by signals through either receptor. Thus, CD40 uses an unidentified protein kinase A-insensitive MEK kinase, rather than Raf-1, to regulate ERK activity.
Expression of the Costimulatory Receptor CD30 Is Regulated by Both CD28 and Cytokines
Authors: Gilfillan Molly C. , Noel Patricia J. , Podack Eckhard R. , Reiner Steven L. , Thompson Craig B. 
Published: January 2023

AbstractCostimulation was originally defined and characterized during primary T cell activation. The signaling events that regulate subsequent antigen encounters by T cells are less well defined. In this study we examined the role of CD30 in T cell activation and defined factors that regulate expression of CD30 on T cells. We demonstrate that CD30 expression is restricted to activated T cells and regulated by CD28 signal transduction. In contrast to CD28-expressing TCR Tg cells, CD28-deficient TCR Tg cells did not express CD30 when cultured with peptide and APCs. However, rIL-4 reconstituted CD30 expression on CD28-deficient TCR Tg cells. Blockade of CD28 interactions or depletion of IL-4 inhibited the induction of CD30, suggesting that both CD28 and IL-4 play important roles in the induction of CD30 expression on wild-type cells. However, CD28 signaling did not up-regulate CD30 expression solely through its ability to augment IL-4 production because IL-4-deficient T cells stimulated with anti-CD3 and anti-CD28 expressed CD30. Induction of CD30 in the absence of IL-4 was not due to the IL-4-related cytokine IL-13. CD30, when expressed on an activated T cell, can act as a signal transducing receptor that enhances the proliferation of T cells responding to CD3 crosslinking. Collectively, the data suggest that T cell expression of CD30 is dependent on the presence of CD28 costimulatory signals or exogenous IL-4 during primary T cell activation. Once expressed on the cell surface, CD30 can serve as a positive regulator of mature T cell function.
Corticosteroids Enhance the Capacity of Macrophages to Induce Th2 Cytokine Synthesis in CD4+ Lymphocytes by Inhibiting IL-12 Production
Authors: DeKruyff Rosemarie H. , Fang Yu , Umetsu Dale T. 
Published: January 2023

AbstractWe investigated the effects of corticosteroids on IL-12 production by mouse splenic adherent cells and the subsequent capacity of these cells to induce cytokine production by CD4+ T cells. To distinguish the effects of corticosteroids on APCs from those on T cells, only the APCs and not the T cells were exposed to corticosteroids. Treatment of splenic adherent cells with dexamethasone greatly inhibited production of IL-12, a cytokine known to enhance IFN-γ synthesis and decrease IL-4 synthesis by CD4+ T cells. The reduction in IL-12 production by corticosteroid-treated macrophages decreased their ability to induce IFN-γ and increased their ability to induce IL-4 synthesis in Ag-primed CD4+ T cells. Splenic adherent cells from mice treated in vivo with dexamethasone also displayed a reduced capacity to produce IL-12. These results help to resolve previous conflicting observations regarding the effects of corticosteroids on cytokine production by T cells, and indicate that while corticosteroids may directly inhibit Th1 and Th2 cytokine production in T cells, corticosteroids, by reducing IL-12 production in APCs, have the potential to indirectly enhance Th2 cytokine synthesis. Therefore, treatment of diseases such as allergy with chronic corticosteroids may indirectly exacerbate the course of the disease, which is caused primarily by the overproduction of Th2 cytokines in allergen-specific CD4+ T cells.
Activation of IL-8 Gene Expression byHelicobacter pyloriIs Regulated by Transcription Factor Nuclear Factor-κB in Gastric Epithelial Cells
Authors: Sharma Smita A. , Tummuru Murali K. R. , Blaser Martin J. , Kerr Lawrence D. 
Published: January 2023

AbstractIn vivo, gastric infection with Helicobacter pylori leads to substantial production of the inflammatory cytokines IL-1, IL-6, TNF-α, and IL-8. H. pylori strains that contain the cag pathogenicity island (cag+) and are associated with ulceration and gastric carcinoma induce greater cytokine production than cag− strains. Expression of these cytokines is often regulated by the transcription factor complex, nuclear factor-κB (NF-κB) through κB-binding elements in the enhancer/promoter regions of their genes. We report that more virulent cag+ H. pylori strains induce increased NF-κB-DNA binding activity, which elevates IL-8 expression in AGS gastric epithelial cells. The cag+ H. pylori strains induce significant stimulation of IL-8 promoter-driven reporter activity, while cag− strains do not. Furthermore, mutation of specific genes within the cag island (picA1 and picB) ablates enhanced NF-κB activation and IL-8 transcription. Increased IL-8 expression is inhibited by mutation in either the NF-κB or NF-IL-6 binding element. The cag+ strains, compared with the cag− strains, induce enhanced nuclear localization of a RelA-containing NF-κB binding complex, but no increase in NF-IL-6 binding activity. These studies demonstrate that the ability of different types of H. pylori strains to activate NF-κB correlates with their ability to induce IL-8 transcription and indicate a mechanism for the heightened inflammatory response seen in subjects infected with cag+ H. pylori strains.
The House Dust Mite Allergen,Dermatophagoides pteronyssinus, Promotes Type 2 Responses by Modulating the Balance Between IL-4 and IFN-γ
Authors: Comoy Emmanuel E. , Pestel Joel , Duez Catherine , Stewart Geoffrey A. , Vendeville Catherine , Fournier Charles , Finkelman Fred , Capron André , Thyphronitis Georges 
Published: January 2023

AbstractA common property of allergens is their potential to generate type 2 cytokine responses. To understand the mechanisms involved in this phenomenon, we have evaluated the polarizing potential of a major allergen, Dermatophagoides pteronyssinus 1 (Der p 1), in an heterologous immunization system using the glutathione S-transferase of the parasite Schistosoma mansoni (Sm28-GST) as immunogen. In previous studies, we showed that immunization with the Sm28-GST emulsified in CFA induced a nonpolarized immune response. In contrast, when alum was used as adjuvant, a type 2 immune response was induced against Sm28-GST. Using this experimental model, we examined whether the administration of Der p 1 together with Sm28-GST influenced the nonpolarized and/or the Th2 profiles induced by the CFA or the alum immunization, respectively. Our results showed that the introduction of Der p 1 in the CFA immunization protocol was associated with diminished anti-Sm28-GST IgG2a Ab titers, reduced IFN-γ mRNA expression, and frequency of IFN-γ-producing cells. In contrast, the introduction of Der p 1 in the alum protocol did not affect IL-4 or Ig isotype responses. The effect of Der p 1 was specific, since coimmunization with tetanus toxin fragment C did not affect the profile of the response against Sm28-GST. Furthermore, inactivation of Der p 1 reduced its ability to modify the immune response profile, suggesting that its protease activity played an important role in deviating the immune response. Our results suggest that the Der p 1 has the ability to modify the profile of an immune response by modulating the balance between the polarizing cytokines IL-4 and IFN-γ.
Fas/Fas Ligand Signaling During Gestational T Cell Development
Authors: Fleck Martin , Zhou Tong , Tatsuta Toru , Yang Pingar , Wang Zheng , Mountz John D. 
Published: January 2023

Abstract
Most thymocytes express high levels of Fas Ag (Apo-1/CD95); however, the role of Fas/Fas ligand-mediated apoptosis in thymocyte development remains unclear. During gestational development of thymocytes in C57BL/6(B6) +/+ mice, the highest levels of Fas ligand mRNA and Fas ligand protein expression were detected at gestational day (GD) 15, and there was a ninefold decrease in Fas ligand mRNA expression between GD 15 and 17 accompanied by a sixfold increase in Fas mRNA. Apoptotic thymocytes were first detected in the medulla at GD 15, and increasing numbers of cortical clusters and scattered, single apoptotic cells were present on GD 16 and 17. Thus, early apoptosis correlated with high expression of Fas ligand. High levels of Fas ligand mRNA were maintained throughout gestational development in thymocytes of Fas-deficient B6-lpr/lpr mice, but cortical clusters and scattered apoptotic cells were decreased relative to B6 +/+ mice before GD 17. Kinetic analysis of fetal thymic organ cultures treated with anti-Fas Ab demonstrated that thymocytes become sensitive to Fas-mediated apoptosis during the transition from the CD4−CD8− to the CD4+CD8+ phenotype. More mature CD4+CD8+ thymocytes and CD4+ and CD8+ thymocytes became resistant to Fas-mediated apoptosis after GD 17, despite high expression of Fas. However, low avidity engagement of the TCR on Fas-sensitive CD4+CD8+ thymocytes before GD 17 induced resistance to Fas-mediated apoptosis. The present results indicate that Fas plays a critical role in mediating apoptosis during early gestational thymocyte development and that thymocytes that receive a survival signal through TCR/CD3 become resistant to Fas-mediated apoptosis.
Antiviral Cytotoxic Activity Across a Species Barrier in Mixed Xenogeneic Chimeras: Functional Restriction to Host MHC
Authors: Colson Yolonda L. , Tripp Ralph A. , Doherty Peter C. , Wren Sherry M. , Neipp Michael , Abou El-Ezz Ashraf Y. , Ildstad Suzanne T. 
Published: January 2023

AbstractReconstitution of lethally irradiated mice with a mixture of mouse and rat bone marrow cells (mouse + rat→mouse) results in mixed xenogeneic chimerism and donor-specific tolerance. The current study demonstrates that mouse and rat T lymphocytes that have developed in xenogeneic chimeras are restricted to Ag presentation by mouse, but not rat, APC. Restriction to host Ags results in functional immunocompetence with generation of antiviral cytotoxic activity in vivo, within and across species barriers. These data demonstrate for the first time that the host thymus is sufficient to support development and positive selection of functional cross-species T lymphocytes. The superior immunocompetence, as compared with fully xenogeneic (rat→mouse) chimeras, may prove to be of significant benefit in the clinical application of xenotransplantation to solid organ transplantation and immune reconstitution for AIDS.
Lymphocytes Produce IL-1β in Response to Fcγ Receptor Cross-Linking: Effects on Parenchymal Cell IL-8 Release
Authors: Marsh Clay B. , Lowe Melissa P. , Rovin Brad H. , Parker Jennifer M. , Liao Zhiming , Knoell Daren L. , Wewers Mark D. 
Published: January 2023

AbstractNeutrophils mediate tissue injury in response to immune complexes, although the factors that induce their recruitment are incompletely understood. We have reported that lymphocytes may be important regulators of monocyte and macrophage IL-8 release in the presence of immobilized IgG. Since tissue parenchymal cells are important local producers of IL-8 but are not directly stimulated by FcγR cross-linking, we hypothesized that lymphocytes may also regulate parenchymal IL-8 release. Supernatants from lymphocytes incubated on immobilized IgG induced primary human fibroblasts and human mesangial cells to produce IL-8 (17 ± 3.5 and 44 ± 8 ng/ml, respectively). Fibroblast and mesangial cell IL-8 mRNA levels were similarly increased by the conditioned lymphocyte supernatant. Immobilized anti-human FcγRIII, but not FcγRI or FcγRII Abs, could stimulate this IL-8-inducing activity in lymphocytes, suggesting that FcγRIII-bearing lymphocytes were responsible. Supernatants from lymphocytes incubated on immobilized IgG contained 2.2 ± 0.8 ng/ml of IL-1β, while enriched monocyte preparations from the same donors incubated on immobilized IgG released only 0.1 ± 0.04 ng/ml of IL-1β (p = 0.05). Consistent with the identification of IL-1β as the lymphocyte factor, fibroblast or mesangial cell IL-8 release induced by the IgG-stimulated lymphocyte supernatants was inhibited by 1) the combination of IL-1R antagonist and soluble type II IL-1R, 2) an IL-1-converting enzyme inhibitor, or 3) anti-IL-1β but not preimmune Abs. These data suggest that targeted deposits of IgG can stimulate FcγRIII-bearing lymphocytes to produce IL-1β, which induces parenchymal cell IL-8 release.
Effect of Antigen-Processing Efficiency on In Vivo T Cell Response Magnitudes
Authors: Vijh Sujata , Pilip Ingrid M. , Pamer Eric G. 
Published: January 2023

AbstractT lymphocytes eradicate and provide long-term immunity to infections caused by intracellular pathogens. The mechanisms that determine in vivo T cell response sizes are poorly understood. Although it is speculated that the relative processing efficiency of different epitopes determines the hierarchy of T cell responses following immunization, this hypothesis has not been rigorously tested. We therefore mutagenized the secreted p60 Ag of Listeria monocytogenes to alter the efficiency of T cell epitope generation. Ag-processing efficiencies in cells infected with the different L. monocytogenes mutants ranged from one H2-Kd-associated p60 217–225 epitope generated per 15 intracellularly degraded p60 molecules (1/15) to one epitope per 350 degraded p60 molecules (1/350), i.e., a spectrum encompassing a 20-fold range of efficiencies. Mice infected with L. monocytogenes secreting inefficiently processed p60 (1/350) did not mount p60 217–225-specific T cell responses. However, increasing the efficiency of Ag processing by a factor of 5 to 1/70 restored the T cell response size to normal, while further increases in the efficiency of p60 217–225 generation to 1/50, 1/35, and 1/17 did not further augment specific T cell responses. Our studies demonstrate an Ag-processing threshold for in vivo T cell activation. Surprisingly, once this threshold is achieved, further enhancement of Ag-processing efficiency does not enhance the size of T cell responses.
Vascular Adhesion Protein-1 and ICAM-1 Support the Adhesion of Tumor-Infiltrating Lymphocytes to Tumor Endothelium in Human Hepatocellular Carcinoma
Authors: Yoong Khong F. , McNab Gillian , Hübscher Stefan G. , Adams David H. 
Published: January 2023

AbstractT cell-mediated mechanisms are important in the defense against solid organ tumors. Why some tumors are more heavily infiltrated by T cells than others is poorly understood but is likely to depend upon adhesive interactions between circulating lymphocytes and tumor endothelium. In support of this hypothesis, the present study shows that primary human hepatocellular carcinomas (HCC) are more heavily infiltrated with T cells than colorectal hepatic metastases (CHM), and that their tumor vessels express high levels of several adhesion molecules. In HCC, an intense T cell infiltrate is observed within the tumor associated with strong expression of ICAM-1 and vascular adhesion protein-1 (VAP-1) on tumor endothelium. In contrast, fewer T cells infiltrated CHM and these tumors have little ICAM-1 and no detectable VAP-1 or VCAM-1 on tumor endothelium. T cells infiltrating both tumors are LFA-1 and very late Ag (VLA)-4 high. In vitro tissue-binding studies demonstrated that T cells bound readily to tumor endothelium in HCC, and Abs to ICAM-1, VAP-1, and to a lesser extent VCAM-1 could inhibit this binding. VAP-1 supported sialic acid-dependent adhesion under shear stress, suggesting that VAP-1 and ICAM-1 mediate, respectively, tethering and firm adhesion. In contrast, very few T cells bound to tumor vessels in CHM. Thus our data suggest that the VAP-1/VAP-1 receptor and ICAM-1/LFA-1 pathways are important in the recruitment of T cells to HCC. The strong expression of VAP-1 on tumor endothelium distinguishes HCC from CHM and supports our previous hypothesis that VAP-1 is an important hepatic endothelial adhesion molecule.