bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenovirus-Induced Liver Pathology Is Mediated Through TNF Receptors I and II but Is Independent of TNF or Lymphotoxin
Authors: Hayder Hikmat , Blanden Robert V. , Körner Heinrich , Riminton D. Sean , Sedgwick Jonathon D. , Müllbacher Arno 
Published: December 2022

Abstract
Mice infected with an adenovirus mutant in which the E3 region is deleted, including TNF-resistance genes, develop fatal liver pathology within 3–4 days after infection. At least 10-fold more wild-type virus was needed to cause comparable pathology. These results indicate that the E3 region is critically involved in modulating the pathogenesis of adenovirus infection and that TNF may play a role in liver damage. To explore the latter possibility, the course of disease was examined in infected mice lacking TNFR-I and/or TNFRII, TNF only, or both TNF and lymphotoxin-α. Only mice lacking both TNFRI and TNFRII were protected from the lethal affects of the mutant adenovirus. Mice deficient in TNF or TNF and lymphotoxin-α displayed the fatal pathology. This outcome is consistent with the existence of another related ligand that binds TNFRI/II to mediate liver damage during infection with this mutant.
Evidence That β Cell Death in the Nonobese Diabetic Mouse Is Fas Independent
Authors: Thomas Helen E. , Darwiche Rima , Corbett John A. , Kay Thomas W. H. 
Published: December 2022

AbstractRecent studies suggest that Fas expression on pancreatic β cells may be important in the development of autoimmune diabetes in the nonobese diabetic (NOD) mouse. To address this, pancreatic islets from NOD mice were analyzed by flow cytometry to directly identify which cells express Fas and Fas ligand (FasL) ex vivo and after in vitro culture with cytokines. Fas expression was not detected on β cells isolated from young (35 days) NOD mice. In vitro, incubation of NOD mouse islets with both IL-1 and IFN-γ was required to achieve sufficient Fas expression and sensitivity for islets to be susceptible to lysis by soluble FasL. In islets isolated from older (≥125 days) NOD mice, Fas expression was detected on a limited number of β cells (1–5%). FasL was not detected on β cells from either NOD or Fas-deficient MRLlpr/lpr islets. Also, both NOD and MRLlpr/lpr islets were equally susceptible to cytokine-induced cell death. This eliminates the possibility that cytokine-treated murine islet cells commit “suicide” due to simultaneous expression of Fas and FasL. Last, we show that NO is not required for cytokine-induced Fas expression and Fas-mediated apoptosis of islet cells. These findings indicate that β cells can be killed by Fas-dependent cytotoxicity; however, our results raise further doubts about the clinical significance of Fas-mediated β cell destruction because few Fas-positive cells were isolated immediately before the development of diabetes.
Involvement of Distinct Cellular Compartments in the Abnormal Lymphoid Organogenesis in Lymphotoxin-α-Deficient Mice and Alymphoplasia (aly) Mice Defined by the Chimeric Analysis
Authors: Matsumoto Mitsuru , Iwamasa Kikue , Rennert Paul D. , Yamada Takuji , Suzuki Rika , Matsushima Akemi , Okabe Masaru , Fujita Shigeru , Yokoyama Minesuke 
Published: December 2022

AbstractBoth lymphotoxin-α (LTα)-deficient mice and alymphoplasia (aly) mice, a natural mutant strain, manifest a quite similar phenotype: lack of lymph nodes (LN) and Peyer’s patches (PP), with disturbed spleen architecture. The mechanisms underlying the defective lymphoid organogenesis in these mice were investigated by generating aggregation chimeras; ex vivo fused morulae were implanted into pseudo-pregnant host females and allowed to develop to term. Chimeric mice between LTα-deficient mice and wild-type mice restored LN and PP almost completely, suggesting that LTα expressed by circulating bone marrow-derived cells is essential for lymphoid organogenesis as well as for organization of spleen architecture. By contrast, chimeric mice between aly mice and wild-type mice showed only limited restoration of LN and PP. This suggests that the putative aly gene product does not act as a circulating ligand for lymphoid organogenesis, like LTα. Rather, abnormal development of lymphoid organs in aly mice seems most likely due to the defective development of the incipient stromal cells of the LN and PP. Supporting this hypothesis, up-regulation of VCAM-1 on aly mouse embryonic fibroblasts by signals through LTβR, which is exclusively expressed by nonlymphoid cells, was disturbed. These studies demonstrate that LTα and the putative aly gene product together control lymphoid organogenesis with a close mechanistic relationship in their biochemical pathways through governing the distinct cellular compartments, the former acting as a circulating ligand and the latter as a LTβR-signaling molecule expressed by the stroma of the lymphoid organs.
Lymphocyte Adhesion to Epithelia and Endothelia Mediated by the Lymphocyte Endothelial-Epithelial Cell Adhesion Molecule Glycoprotein
Authors: Shieh Chi-Chang , Sadasivan Bhanu K. , Russell Gary J. , Schön Michael P. , Parker Christina M. , Brenner Michael B. 
Published: December 2022

AbstractUpon encountering the relevant vascular bed, lymphocytes attach to endothelial adhesion molecules, transmigrate out of circulation, and localize within tissues. Lymphocytes may then be retained at microanatomic sites, as in tissues, or they may continue to migrate to the lymphatics and recirculate in the blood. Lymphocytes also interact transiently, but with high avidity, with target cells or APC that are infected with microbes or have taken up exogenous foreign Ags. This array of adhesive capabilities is mediated by the selective expression of lymphocyte adhesion molecules. Here, we developed the 6F10 mAb, which recognizes a cell surface glycoprotein designated lymphocyte endothelial-epithelial cell adhesion molecule (LEEP-CAM), that is distinct in biochemical characteristics and distribution of expression from other molecules known to play a role in lymphocyte adhesion. LEEP-CAM is expressed on particular epithelia, including the suprabasal region of the epidermis, the basal layer of bronchial and breast epithelia, and throughout the tonsillar and vaginal epithelia. Yet, it is absent from intestinal and renal epithelia. Interestingly, it is expressed also on vascular endothelium, especially high endothelial venules (HEV) in lymphoid organs, such as tonsil and appendix. The anti-LEEP-CAM mAb specifically blocked T and B lymphocyte adhesion to monolayers of epithelial cells and to vascular endothelial cells in static cell-to-cell binding assays by ∼40–60% when compared with control mAbs. These data suggest a role for this newly identified molecule in lymphocyte binding to endothelium, as well as adhesive interactions within selected epithelia.
A Novel Human CC Chemokine, Eotaxin-3, Which Is Expressed in IL-4-Stimulated Vascular Endothelial Cells, Exhibits Potent Activity Toward Eosinophils
Authors: Shinkai Akeo , Yoshisue Hajime , Koike Masamichi , Shoji Emi , Nakagawa Satoshi , Saito Akiko , Takeda Tsuyoshi , Imabeppu Susumu , Kato Yuzuru , Hanai Nobuo , Anazawa Hideharu , Kuga Tetsuro , Nishi Tatsunari 
Published: December 2022

AbstractIL-4 has been shown to be involved in the accumulation of leukocytes, especially eosinophils, at sites of inflammation by acting on vascular endothelial cells. To identify novel molecules involved in the IL-4-dependent eosinophil extravasation, cDNA prepared from HUVEC stimulated with IL-4 was subjected to differential display analysis, which revealed a novel CC chemokine designated as eotaxin-3. The human eotaxin-3 gene has been localized to chromosome 7q11.2, unlike most other CC chemokine genes. The predicted mature protein of 71 aa showed 27–42% identity to other human CC chemokines. The recombinant protein induced a transient increase in the cytosolic Ca2+ concentration and in vitro chemotaxis on eosinophils. Furthermore, in cynomolgus monkeys, the accumulation of eosinophils was observed at the sites where the protein was injected. Eotaxin-3 inhibited the binding of 125I-eotaxin, but not 125I-macrophage inflammatory protein-1α, to eosinophils and acted on cell lines transfected with CCR-3, suggesting that eotaxin-3 recognized CCR-3. IL-13 as well as IL-4 up-regulated eotaxin-3 mRNA in HUVEC, whereas neither TNF-α, IL-1β, IFN-γ, nor TNF-α plus IFN-γ did. The expression profile of eotaxin-3 is different from those of eotaxin, RANTES, and monocyte chemoattractant protein-4, which are potent eosinophil-selective chemoattractants and are induced by either TNF-α or TNF-α plus IFN-γ. These results suggest that eotaxin-3 may contribute to the eosinophil accumulation in atopic diseases.
CD28 Costimulation Accelerates IL-4 Receptor Sensitivity and IL-4-Mediated Th2 Differentiation
Authors: Kubo Masato , Yamashita Masakatsu , Abe Ryo , Tada Tomio , Okumura Ko , Ransom John T. , Nakayama Toshinori 
Published: December 2022

AbstractThe development of Th1 and Th2 cells is determined by the type of antigenic stimulation involved in the initial cell activation step. Evidence indicates that costimulatory signals, such as those delivered by CD28, play an important role in Th2 development, but little is known about how CD28 costimulation contributes to Th2 development. In this study, TCR cross-linking was insufficient for Th2 development, while the addition of CD28 costimulation drastically increased Th2 generation through the IL-4-mediated pathway. Th2 generation following CD28 costimulation was not simply explained by the enhancement of IL-4 production in naive T cells. To generate Th2 cells after TCR cross-linking only, it was necessary to add a 20- to 200-fold excess of IL-4 generated after TCR and CD28 stimulation. TCR cross-linking increased the expression level and binding property of the IL-4R, but enhanced the sensitivity to IL-4 only slightly. In contrast, as evidenced by the enhanced phosphorylation of Jak3, the IL-4Rα-chain, and STAT6 following IL-4 stimulation, CD28 costimulation increased IL-4R sensitivity without affecting its expression and binding property. This evidence of the enhancement of IL-4R sensitivity increases our understanding of how CD28 costimulation accelerates Th2 development.
Induction of Allograft Tolerance in the Absence of Fas-Mediated Apoptosis
Authors: Li Xian Chang , Li Yongsheng , Dodge Ingrid , Wells Andrew D. , Zheng Xin Xiao , Turka Laurence A. , Strom Terry B. 
Published: December 2022

Abstract
Using certain immunosuppressive regimens, IL-2 knockout (KO) mice, in contrast to wild-type (wt) controls, are resistant to the induction of allograft tolerance. The mechanism by which IL-2 regulates allograft tolerance is uncertain. As IL-2 KO mice have a profound defect in Fas-mediated apoptosis, we hypothesized that Fas-mediated apoptosis of alloreactive T cells may be critical in the acquisition of allograft tolerance. To definitively study the role of Fas in the induction of transplantation tolerance, we used Fas mutant B6.MRL-lpr mice as allograft recipients of islet and vascularized cardiac transplants. Alloantigen-stimulated proliferation and apoptosis of Fas-deficient cells were also studied in vivo. Fas mutant B6.MRL-lpr (H-2b) mice rapidly rejected fully MHC-mismatched DBA/2 (H-2d) islet allografts and vascularized cardiac allografts with a tempo that is comparable to wt control mice. Both wt and B6.MRL-lpr mice transplanted with fully MHC-mismatched islet allografts or cardiac allografts can be readily tolerized by either rapamycin or combined costimulation blockade (CTLA-4Ig plus anti-CD40L mAb). Despite the profound defect of Fas-mediated apoptosis, Fas-deficient T cells can still undergo apoptotic cell death in vivo in response to alloantigen stimulation. Our study suggests that: 1) Fas is not necessarily essential for allograft tolerance, and 2) Fas-mediated apoptosis is not central to the IL-2-dependent mechanism governing the acquisition of allograft tolerance.
Autocrine IL-12 Is Involved in Dendritic Cell Modulation Via CD40 Ligation
Authors: Bianchi Roberta , Grohmann Ursula , Vacca Carmine , Belladonna Maria L. , Fioretti Maria C. , Puccetti Paolo 
Published: December 2022

Abstract
Ligation of CD40 on dendritic cells (DC) triggers production of IL-12. Using an adoptive transfer model we have previously shown that rIL-12 acts directly on DC to enhance presentation of an otherwise poorly immunogenic tumor peptide. Using the same experimental model, we now describe a similar adjuvanticity of CD40 ligation on peptide presentation by DC. We also explore the possibility that the IL-12 resulting from CD40 ligation directly affects the APC function of DC, mediating or contributing to the adjuvant effect of CD40 ligation. CD40 engagement in vitro and rIL-12 at concentrations in the range induced by CD40 ligation were equally effective in priming DC for presentation of the tumor peptide in vivo. Remarkably, the copresence in vitro of neutralizing Ab to IL-12, but not to TNF-α, IL-1β, or IFN-γ, ablated the enhancing effect of CD40 engagement on the APC function of DC. These data suggest a major role for autocrine IL-12 in DC modulation via CD40 ligation.
Differential Responses of Invariant Vα24JαQ T Cells and MHC Class II-Restricted CD4+ T Cells to Dexamethasone
Authors: Milner Joshua D. , Kent Sally C. , Ashley Timothy A. , Wilson S. Brian , Strominger Jack L. , Hafler David A. 
Published: December 2022

AbstractNK T cells are a T cell subset in the human that express an invariant α-chain (Vα24invt T cells). Because of the well-described immunomodulation by glucocorticoids on activation-induced cell death (AICD), the effects of dexamethasone and anti-CD3 stimulation on Vα24invt T cell clones and CD4+ T cell clones were investigated. Dexamethasone significantly enhanced anti-CD3-mediated proliferation of Vα24invt T cells, whereas CD4+ T cells were inhibited. Addition of neutralizing IL-2 Ab partially abrogated dexamethasone-induced potentiation of Vα24invt T cell proliferation, indicating a role for autocrine IL-2 production in corticosteroid-mediated proliferative augmentation. Dexamethasone treatment of anti-CD3-stimulated Vα24invt T cells did not synergize with anti-Fas blockade in enhancing proliferation or preventing AICD. The Vα24invt T cell response to dexamethasone was dependent on the TCR signal strength. In the presence of dexamethasone, lower doses of anti-CD3 inhibited proliferation of Vα24invt T cells and CD4+ T cells; at higher doses of anti-CD3, which caused inhibition of CD4+ T cells, the Vα24invt T cell clones proliferated and were rescued from AICD. These results demonstrate significant differences in TCR signal strength required between Vα24invt T cells and CD4+ cells, and suggest important immunomodulatory consequences for endogenous and exogenous corticosteroids in immune responses.
Inhibition of Kit Expression by IL-4 and IL-10 in Murine Mast Cells: Role of STAT6 and Phosphatidylinositol 3′-Kinase
Authors: Mirmonsef Paria , Shelburne Christopher P. , Fitzhugh Yeatman C. , Chong Hey Jin , Ryan John J. 
Published: December 2022

AbstractThe c-kit protooncogene encodes a receptor tyrosine kinase that is known to play a critical role in hemopoiesis and is essential for mast cell growth, differentiation, and cytokine production. Studies have shown that the Th2 cytokine IL-4 can down-regulate Kit expression on human and murine mast cells, but the mechanism of this down-regulation has remained unresolved. Using mouse bone marrow-derived mast cells, we demonstrate that IL-4-mediated Kit down-regulation requires STAT6 expression and phosphotidylinositide-3′-kinase activation. We also find that the Th2 cytokine IL-10 potently down-regulates Kit expression. IL-4 enhances IL-10-mediated inhibition in a manner that is STAT6 independent and phosphotidylinositide-3′-kinase dependent. Both IL-4- and IL-10-mediated Kit down-regulation were coupled with little or no change in c-kit mRNA levels, no significant change in Kit protein stability, but decreased total Kit protein expression. Inhibition of Kit expression by IL-4 and IL-10 resulted in a loss of Kit-mediated signaling, as evidenced by reduced IL-13 and TNF-α mRNA induction after stem cell factor stimulation. These data offer a role for STAT6 and phosphotidylinositide-3′-kinase in IL-4-mediated Kit down-regulation, coupled with the novel observation that IL-10 is a potent inhibitor of Kit expression and function. Regulating Kit expression and signaling may be essential to controlling mast cell-mediated inflammatory responses.
Requirement for Shc in TCR-Mediated Activation of a T Cell Hybridoma
Authors: Pratt Joanne C. , van den Brink Marcel R. M. , Igras Vivien E. , Walk Scott F. , Ravichandran Kodimangalam S. , Burakoff Steven J. 
Published: December 2022

Abstract
Engagement of the TCR determines the fate of T cells to activate their functional programs, proliferate, or undergo apoptosis. The intracellular signal transduction pathways that dictate the specific outcome of receptor engagement have only been partially elucidated. The adapter protein, Shc, is involved in cytokine production, mitogenesis, transformation, and apoptosis in different cell systems. We found that Shc becomes phosphorylated on tyrosine residues upon stimulation of the TCR in DO11.10 hybridoma T cells; therefore, we investigated the role of Shc in activation-induced cell death in these cells by creating a series of stably transfected cell lines. Expression of Shc-SH2 (the SH2 domain of Shc) or Shc-Y239/240F (full-length Shc in which tyrosines 239 and 240 have been mutated to phenylalanine) resulted in the inhibition of activation-induced cell death and Fas ligand up-regulation after TCR cross-linking. Expression of wild-type Shc or Shc-Y317F had no significant effect. In addition, we found that Shc-SH2 and Shc-Y239/240F, but not Shc-Y317F, inhibited phosphorylation of extracellular signal-regulated protein kinase and production of IL-2 after TCR cross-linking. These results indicate an important role for Shc in the early signaling events that lead to activation-induced cell death and IL-2 production after TCR activation.
Levels of Ly-49 Receptor Expression Are Determined by the Frequency of Interactions with MHC Ligands: Evidence Against Receptor Calibration to a “Useful” Level
Authors: Manilay Jennifer O. , Waneck Gerald L. , Sykes Megan 
Published: December 2022

AbstractLy-49 receptor expression was studied in NK cells that developed in fully MHC-mismatched mixed bone marrow chimeras, in which host and donor MHC ligands were expressed solely on various proportions of hemopoietic cells or on both hemopoietic and nonhemopoietic cells. When hemopoietic cells were the only source of MHC ligand, a strong correlation between the level of down-regulation of Ly-49A, Ly-49C, and Ly-49G2 and the number of hemopoietic cells expressing their MHC ligands was observed on both donor and host NK cells. In some animals with low levels of donor hemopoietic chimerism, NK cells of donor origin expressed Ly-49 receptors at higher levels than was observed in normal mice of the same strain. This unexpected observation is inconsistent with the receptor calibration theory, which states that expression of Ly-49 inhibitory receptors is calibrated to an optimal level to maintain an NK cell repertoire that is sensitive to perturbations in normal class I ligand expression. Our data suggest a model in which Ly-49 receptors down-modulate in accordance with the frequency of their interactions with ligand-bearing cells, rather than a model in which these receptors calibrate to a specific “useful” level in response to ligands present in their environment.
Lipopolysaccharide Induces in Macrophages the Synthesis of the Suppressor of Cytokine Signaling 3 and Suppresses Signal Transduction in Response to the Activating Factor IFN-γ
Authors: Stoiber Dagmar , Kovarik Pavel , Cohney Solomon , Johnston James A. , Steinlein Peter , Decker Thomas 
Published: December 2022

AbstractThe goal of this study was to investigate how bacterial LPS affects macrophage responsiveness to the activating factor IFN-γ. Pretreatment of macrophages with LPS for &lt;2 h increased the transcriptional response to IFN-γ. In contrast, simultaneous stimulation with IFN-γ and LPS, or pretreatment with LPS for &gt;4 h, suppressed Stat1 tyrosine 701 phosphorylation, dimerization, and transcriptional activity in response to IFN-γ. Consistently, the induction of MHCII protein by IFN-γ was antagonized by LPS pretreatment. Neutralizing Abs to IL-10 were without effect on LPS-mediated suppression of Stat1 activation. Decreased IFN-γ signal transduction after LPS treatment corresponded to a direct induction of suppressor of cytokine signaling3 (SOCS3) mRNA and protein. Under the same conditions socs1, socs2, and cis genes were not transcribed. In transfection assays, SOCS3 was found to suppress the transcriptional response of macrophages to IFN-γ. A causal link of decreased IFN-γ signaling to SOCS3 induction was also suggested by the LPS-dependent reduction of IFN-γ-mediated Janus kinase 1 (JAK1) activation. Further consistent with inhibitory activity of SOCS3, LPS also inhibited the JAK2-dependent activation of Stat5 by GM-CSF. Our results thus link the deactivating effect of chronic LPS exposure on macrophages with its ability to induce SOCS3.
Differentiation of NK1.1+, Ly49+ NK Cells from flt3+ Multipotent Marrow Progenitor Cells
Authors: Williams Noelle Sevilir , Klem Jennifer , Puzanov Igor J. , Sivakumar P. V. , Bennett Michael , Kumar Vinay 
Published: December 2022

AbstractTo delineate factors involved in NK cell development, we established an in vitro system in which lineage marker (Lin)−, c-kit+, Sca2+ bone marrow cells differentiate into lytic NK1.1+ but Ly49− cells upon culture in IL-7, stem cell factor (SCF), and flt3 ligand (flt3L), followed by IL-15 alone. A comparison of the ability of IL-7, SCF, and flt3L to generate IL-15-responsive precursors suggested that NK progenitors express the receptor for flt3L. In support of this, when Lin−, c-kit+, flt3+ or Lin−, c-kit+, flt3− progenitors were utilized, 3-fold more NK cells arose from the flt3+ than from the flt3− progenitors. Furthermore, NK cells that arose from flt3− progenitors showed an immature NK1.1dim, CD2−, c-kit+ phenotype as compared with the more mature NK1.1bright, CD2+/−, c-kit− phenotype displayed by NK cells derived from flt3+ progenitors. Both progenitors, however, gave rise to NK cells that were Ly49 negative. To test the hypothesis that additional marrow-derived signals are necessary for Ly49 expression on developing NK cells, flt3+ progenitors were grown in IL-7, SCF, and flt3L followed by culture with IL-15 and a marrow-derived stromal cell line. Expression of Ly49 molecules, including those of which the MHC class I ligands were expressed on the stromal or progenitor cells, as well as others of which the known ligands were absent, was induced within 6–13 days. Thus, we have established an in vitro system in which Ly49 expression on developing NK cells can be analyzed and possibly experimentally manipulated.