bluuebunny/crossref_metadata_2025_split huggingface dataset:
EAE TCR Motifs and Antigen Recognition in Myelin Basic Protein-Induced Anterior Uveitis in Lewis Rats
Authors: Buenafe Abigail C. , Offner Halina , Machnicki Michael , Elerding Heather , Adlard Kirsten , Jacobs Ray , Vandenbark Arthur A. , Adamus Grazyna 
Published: December 2022

AbstractT cells infiltrating the iris/ciliary body of Lewis rats with anterior uveitis (AU) that had been induced by myelin basic protein (MBP) immunization were previously found to share surface markers common to the T cells that cause experimental autoimmune encephalomyelitis (EAE). To determine whether these AU-associated T cells are in fact the same as those that infiltrate the central nervous system to cause EAE, we examined TCR V gene expression in T cells infiltrating the anterior chamber in rats with AU. As with EAE, we found a biased expression of Vβ8.2 and Vα2 in the iris/ciliary body and, although one would expect an influx of nonspecific inflammatory T cells, these biases were still evident at the peak of AU. An analysis of the TCR Vβ8.2 and Vα2 sequences derived from the iris/ciliary body demonstrated the presence of the same complementarity determining region 3 motifs found in MBP-specific T cells that are pathogenic for EAE and found in T cells derived from the central nervous system of rats with EAE. Finally, T cells isolated from the iris/ciliary body of rats with AU were found to proliferate in a specific fashion to MBP Ags. Thus, it appears that MBP-specific T cells are pathogenic for AU as well as EAE in the Lewis rat. In addition, the long-term presence of this highly restricted MBP response in the iris/ciliary body indicates that distinct immunoregulatory mechanisms exist in the environment of the eye. This provides an interesting model with which to address questions pertaining to the nature of T cells infiltrating the eye and their regulation during EAE and other systemic diseases.
Constitutive IL-10 Production Accounts for the High NK Sensitivity, Low MHC Class I Expression, and Poor Transporter Associated with Antigen Processing (TAP)-1/2 Function in the Prototype NK Target YAC-1
Authors: Petersson Max , Charo Jehad , Salazar-Onfray Flavio , Noffz Gabriele , Mohaupt Mariette , Qin Zhihai , Klein George , Blankenstein Thomas , Kiessling Rolf 
Published: December 2022

AbstractTumor cells that are treated with rIL-10 or transfected with the IL-10 gene show phenotypic changes. These include low but peptide-inducible expression of MHC class I, low sensitivity to specific CTL-mediated lysis, and increased NK sensitivity. In vitro-established mouse tumor lines were screened for IL-10 expression and production, and a large proportion of plasmocytomas or T cell lymphomas were found to produce IL-10. Since one of these lines was the prototype NK target cell YAC-1, we investigated whether the high IL-10 production of this cell line was related to its high NK sensitivity and its defects in MHC class I expression. The decrease in H-2 expression following the in vitro culture of in vivo-passaged YAC-1 cells was accompanied by a gradual increase in IL-10 production, whereas the reverse was found when passing in vitro-grown YAC-1 in vivo as an ascites tumor in syngenic mice. In addition, differences in YAC-1 MHC class I expression correlated with alterations in the functional activity of TAP-1/2 proteins. YAC-1 cells that were transduced with a retroviral IL-10 antisense construct (Y-IL-10 AS) only produced about half of the IL-10 that was produced by YAC-1 transduced with the control construct (Y-IL-10 Mock). Relative to Y-IL-10 Mock cells, the expression of H-2 on Y-IL-10 AS cells was markedly increased, and NK sensitivity was decreased. These data argue for a mechanism wherein IL-10 production is causally related to the low H-2 expression, decreased TAP function, and high NK sensitivity of YAC-1 cells.
Switch of CD4+ T Cell Differentiation from Th2 to Th1 by Treatment with Cathepsin B Inhibitor in Experimental Leishmaniasis
Authors: Maekawa Yoichi , Himeno Kunisuke , Ishikawa Hiroyuki , Hisaeda Hajime , Sakai Tohru , Dainichi Teruki , Asao Tetsuji , Good Robert A , Katunuma Nobuhiko 
Published: December 2022

Abstract
When activated, CD4+ T helper cells differentiate functionally into one of two subsets, Th1 or Th2. Before the Th differentiation, Ags must be processed into peptide epitopes and presented to CD4+ T cells in association with MHC class II molecules. However, the proteases responsible for this Ag processing have not been well defined. When BALB/c mice susceptible to infection with Leishmania major were treated with a specific inhibitor (CA074) of cathepsin B, a lysosomal cysteine protease that digests exogenous antigenic proteins, those mice acquired resistance against infection with L. major and showed the shift of immune responses from Th2 to Th1; that is, they produced specific IgG2a Ab and generated IFN-γ in contrast to untreated and infected mice that produced IgG1 and IgE and generated IL-4. CA074 interfered with the digestion of L. major Ags with lysosomal enzymes in vivo as well as in vitro. However, this inhibitor did not show any direct influence on the growth of L. major and the functions of T cells stimulated with anti-CD3 Ab. These findings indicate that cathepsin B inhibitor could switch CD4+ T cell differentiation from Th2 to Th1, suggesting that the alteration in Ag processing modulates the polarity of Th differentiation.
Autoimmunity Without Diabetes in Transgenic Mice Expressing β Cell-Specific CD86, But Not CD80: Parameters that Trigger Progression to Diabetes
Authors: Guerder Sylvie , Eynon Elizabeth E. , Flavell Richard A. 
Published: December 2022

AbstractTo define more clearly the roles of CD80 (RIP-CD80) and CD86 (RIP-CD86) in the activation of autoreactive T cells in vivo, we generated transgenic mice expressing either or both costimulatory molecules on the β cells of the pancreas. While RIP-CD80 mice do not show any sign of autoimmunity, at the age of 7 mo RIP-CD86 transgenic mice develop a lymphoid infiltrate with both IFN-γ- and IL-4-positive cells in the vicinity of the islets; these mice, however, never progress to diabetes. This fundamental difference in the ability of CD80 and CD86 to activate self-reactive T cells in vivo is, however, obliterated when the level of TCR signaling is increased by either TNF-α or transgenic MHC class II expression. These results support the suggestion that CD80 and CD86 mainly differ at the level of the intensity of the signals they deliver.
Natural Killer Cell Lysis of Cytomegalovirus (CMV)-Infected Cells Correlates with Virally Induced Changes in Cell Surface Lymphocyte Function-Associated Antigen-3 (LFA-3) Expression and Not with the CMV-Induced Down-Regulation of Cell Surface Class I HLA
Authors: Fletcher Jean M. , Prentice H. Grant , Grundy Jane E. 
Published: December 2022

AbstractCMV and other viruses down-regulate the cell surface expression of class I HLA, and while this allows them to evade CTL, it may make infected cells more susceptible to lysis by NK cells, due to the failure to engage class I inhibitory receptors on the NK cell. We studied CMV infection and found that fibroblasts infected with virus strains Towne, Toledo, Davis, and C1FE were refractory to NK lysis, while those infected with strains AD169, C1F, or R7 were susceptible. All viral strains down-regulated class I HLA to a similar extent, and we concluded that there was no evidence for any correlation between the latter and susceptibility to NK lysis. In contrast, there was a strong correlation between NK killing of CMV-infected cells and cell surface levels of lymphocyte function-associated antigen-3 (LFA-3). Fibroblasts infected with the Towne, Toledo, Davis, and C1FE strains of CMV down-regulated LFA-3 expression and were refractory to lysis, while strains AD169, C1F, and R7 up-regulated LFA-3 and were susceptible to NK killing. U373 MG (malignant glioma) cells expressed constitutively high levels of LFA-3 and were sensitive to NK lysis when infected with any of the above-listed CMV strains. We estimated that a minimum of between 29,000 and 71,000 LFA-3 molecules per target cell were needed for NK susceptibility. The effects on LFA-3 expression were due to immediate early/early viral gene products. We also demonstrated that fibroblasts infected with the strains Towne, Toledo, Davis, and C1FE expressed a ganciclovir-sensitive late CMV gene product, which delivered an inhibitory signal to NK cells.
The Roles of L-Selectin, β7 Integrins, and P-Selectin in Leukocyte Rolling and Adhesion in High Endothelial Venules of Peyer’s Patches
Authors: Kunkel Eric J. , Ramos Carroll L. , Steeber Douglas A. , Müller Werner , Wagner Norbert , Tedder Thomas F. , Ley Klaus 
Published: December 2022

Abstract
Lymphocyte trafficking into Peyer’s patches requires β7 integrins and L-selectin. Here, we use intravital microscopy to examine leukocyte rolling and adhesion in Peyer’s patch high endothelial venules (HEV) of wild-type, L-selectin-deficient (L−/−), β7 integrin-deficient (β7−/−), and β7/L−/− mice. Although the leukocyte rolling flux fraction was reduced by 70%, Peyer’s patches in L−/− mice were of normal size and cellularity. In β7−/− mice, the rolling flux fraction was normal, but the number of adherent leukocytes in HEV was greatly reduced. The median leukocyte rolling velocity was reduced in L−/− mice and increased in β7−/− mice, suggesting that β7 integrins and L-selectin mediate rolling in Peyer’s patch HEV at different velocities. β7/L−/− exhibited both a low rolling flux fraction and low adhesion and had severely reduced Peyer’s patch size and cellularity. The residual rolling in these mice was completely blocked by a P-selectin mAb. A significant P-selectin component was also detected in the other genotypes. Twenty-six percent of B and T lymphocytes isolated from Peyer’s patches of wild-type mice expressed functional ligands for P-selectin, and this fraction was increased to 57% in β7/L−/− mice. Peyer’s patch HEV were found to express P-selectin under the conditions of intravital microscopy, but not in situ. Our data suggest a novel P-selectin dependent mechanism of lymphocyte homing to Peyer’s patches. In situ, β7 integrins and L-selectin account for all lymphocyte homing to Peyer’s patches, but P-selectin-dependent rolling, as induced by minimal trauma, may support trafficking of effector T lymphocytes to Peyer’s patches.
IL-2 Induces T Cell Adherence to Extracellular Matrix: Inhibition of Adherence and Migration by IL-2 Peptides Generated by Leukocyte Elastase
Authors: Ariel Amiram , Yavin Eran J. , Hershkoviz Rami , Avron Ann , Franitza Suzanne , Hardan Izhar , Cahalon Liora , Fridkin Mati , Lider Ofer 
Published: December 2022

AbstractMigration of inflammatory cells requires cell adhesion and their subsequent detachment from the extracellular matrix (ECM). Leukocyte activation and migration must be terminated to stop inflammation. Here, we report that IL-2 enhances human T cell adherence to laminin, collagen type IV, and fibronectin (FN). In contrast, neutrophil elastase, an enzyme activated during inflammation, degrades IL-2 to yield IL-2 fractions that inhibit IL-2-induced T cell adhesion to FN. The amino acid composition of two of these IL-2 fractions, which appear to block T cell adherence to FN, were analyzed, and three peptides were consequently synthesized. The three peptides IVL, RMLT, and EFLNRWIT, but not the corresponding inversely synthesized peptides, inhibited T cell adhesion to FN induced by a variety of activators: IL-2, IL-7, macrophage inflammatory protein (MIP)-1β, and PMA, as well as anti-CD3 and anti-β1 integrin-activating mAb. Moreover, these IL-2 peptides inhibited T cell chemotaxis via FN-coated membranes induced by IL-2 and MIP-1β. Inhibition of T cell adherence and migration apparently involves abrogation of the rearrangement of the T cell actin cytoskeleton. Thus, the migrating immune cells, the cytokines, and the ECM can create a functional relationship in which both inflammation-inducing signals and inhibitory molecules of immune responses can coexist; the enzymatic products of IL-2 may serve as natural feedback inhibitors of inflammation.
TNF-α Released by Comigrating Monocytes Promotes Transendothelial Migration of Activated Lymphocytes
Authors: Green David M. , Trial JoAnn , Birdsall Holly H. 
Published: December 2022

AbstractWe investigated mechanisms that increase motility and transendothelial trafficking of activated lymphocytes. Freshly isolated lymphocytes stimulated with immobilized anti-CD3 for 2 h migrate into polymerized collagen in 1.99 ± 0.25-fold greater numbers and across confluent endothelial monolayers in 4.8 ± 0.5-fold greater numbers compared with leukocytes incubated with nonspecific IgG. Activated lymphocytes form clusters with monocytes, and their increased motility was dependent on the presence of comigrating monocytes. Five lines of evidence support the idea that monocytes modulate lymphocyte motility through the release of TNF-α: 1) flow-cytometric analyses, using highly specific and avid mAbs to probe permeabilized whole blood leukocytes, showed that &gt;80% of circulating monocytes contain intracellular TNF-α, whereas &lt;5% contain IL-1 and none contain IL-6; 2) stimulation with immobilized anti-CD3 that was intended to activate lymphocytes also induced monocytes to release increased quantities of TNF-α; 3) rTNF-α, added in doses of 1 to 20 pg/ml to purified anti-CD3-stimulated lymphocytes, reproduced, in a dose-dependent manner, the motility-enhancing effect of adding monocytes; 4) the transient increase in the expression of TNF R-I on CD3-activated T lymphocytes parallels their transiently increased motility; and 5) addition of anti-TNF-α, anti-TNF R-I, anti-TNF R-II, or soluble TNF R-I decreased the motility of stimulated lymphocytes. These results suggest that T lymphocyte stimulation via the CD3-TCR complex signals nearby monocytes to release TNF-α, which feeds back on the lymphocytes to increase their locomotor activity.
Lipopolysaccharide and Ceramide Use Divergent Signaling Pathways to Induce Cell Death in Murine Macrophages
Authors: Lakics Viktor , Vogel Stefanie N. 
Published: December 2022

AbstractCeramide is a well-known apoptotic agent that has been implicated in LPS signaling. Therefore, we examined whether LPS-induced macrophage cytotoxicity is mediated by mimicking ceramide. Both LPS and the cell-permeable ceramide analogue, C2 ceramide, induced significant cell death in IFN-γ-activated, thioglycollate-elicited peritoneal macrophages after 48 and 24 h, respectively. Ceramide-induced cell death was neither accompanied by DNA fragmentation nor phosphatidyl serine externalization, characteristics of apoptosis. In contrast, LPS induced a significant fraction of cells to undergo apoptosis, as demonstrated by DNA fragmentation and quantified by DNA analysis on FACS, yet the majority of the cells died in a necrotic fashion. C3H/HeJ Lpsd macrophages were resistant to LPS-induced cell death and less sensitive to C2 ceramide-evoked cytotoxicity, when compared with Lpsn macrophages. C2 ceramide plus IFN-γ failed to activate release of nitric oxide (NO·), whereas LPS-induced cell death, but not C2-induced cytotoxicity, was blocked by an inhibitor of inducible NO· synthase (iNOS), NG-monomethyl-l-arginine. Macrophages from IFN regulatory factor-1 (−/−) mice shown previously to respond marginally to LPS plus IFN-γ to express iNOS mRNA and NO·, were refractory to LPS plus IFN-γ-induced cytotoxicity and apoptosis. These data suggest that although LPS may mimic certain ceramide effects, signal transduction events that lead to cytotoxicity, as well as the downstream mediators, diverge.
Short-Term and Long-Term Cytokine Release by Mouse Bone Marrow Mast Cells and the Differentiated KU-812 Cell Line Are Inhibited by Brefeldin A
Authors: Zhu Fu-Gang , Gomi Kaede , Marshall Jean S. 
Published: December 2022

AbstractMast cells and basophils produce a wide range of cytokines, including large amounts of both IL-6 and granulocyte-macrophage CSF (GM-CSF). However, the route by which cytokines are secreted is poorly understood. In the current study, we used two inhibitors of vesicular transport, brefeldin A and monensin, to examine the routes of secretion of IL-6 and GM-CSF in the differentiated KU812 human cell line and cultured mouse bone marrow mast cells (mBMMC). Studies of cytokine production over 6 to 24 h demonstrated that IL-6 and GM-CSF release from both cell types were inhibited by brefeldin A (BFA) following activation with calcium ionophore, A23187. Monensin had similar inhibitory effects to that of BFA on the initial and ongoing IL-6 release from KU812 cells. In contrast, the amount of each cytokine remaining within the cells was significantly enhanced. Similar results were obtained following IgE-mediated activation of mBMMC. BFA significantly inhibited both the constitutive secretion of IL-6 and the immediate ionophore-induced increase in IL-6 release from KU812 cells at 20 min postactivation. However, treatment with these agents did not alter the release of histamine and β-hexaminidase from either mBMMC or KU812 cells. These studies suggest that both the initial 20-min release of IL-6 and secretion of IL-6 and GM-CSF over up to 24 h by mBMMC and differentiated KU-812 cells occur predominately through a vesicular transport-dependent mechanism, and that little, if any, IL-6 and GM-CSF is released through degranulation.
Macrophage-Inflammatory Protein-3β/EBI1-Ligand Chemokine/CKβ-11, a CC Chemokine, Is a Chemoattractant with a Specificity for Macrophage Progenitors Among Myeloid Progenitor Cells
Authors: Kim Chang H. , Pelus Louis M. , White John R. , Broxmeyer Hal E. 
Published: December 2022

AbstractChemoattractants are potential factors influencing cell migration. Stromal cell-derived factor-1, a CXC chemokine, is the only chemokine reported to have chemotactic activity for hemopoietic progenitor cells (HPC). We report in this work another chemokine of the CC subfamily, which is chemotactic for HPC. Macrophage-inflammatory protein (MIP)-3β/EBI1-ligand chemokine/CKβ-11 attracted bone marrow and cord blood CD34+ cells. In contrast to stromal cell-derived factor-1, which attracts multiple types of HPC, MIP-3β attracted mainly CFU granulocyte macrophage, but not other HPC such as burst-forming unit erythrocyte or CFU granulocyte, erythrocyte, macrophage, and megakaryocyte. Chemoattracted CD34+ cells formed CFU granulocyte macrophage-like colonies, which were morphologically determined as large macrophages. These progenitors were selectively responsive to stimulation by macrophage CSF, demonstrating that MIP-3β attracts macrophage progenitors. Expression of CCR7, the receptor for MIP-3β, was detected at a mRNA level in the attracted CD34+ cells as well as input CD34+HPC. Expression of MIP-3β mRNA was not constitutive, but was inducible in bone marrow stromal cells by inflammatory agents such as bacterial LPS, IFN-γ, and TNF-α. Taken together, our findings suggest that MIP-3β is expressed in the bone marrow environment after induction with certain inflammatory cytokines and LPS, and may play a role in trafficking of macrophage progenitors in and out of the bone marrow in inflammatory conditions.
Ex Vivo Anti-CD3 Antibody-Activated Donor T Cells Have a Reduced Ability to Cause Lethal Murine Graft-Versus-Host Disease but Retain Their Ability to Facilitate Alloengraftment
Authors: Drobyski William R. , Majewski David , Ozker Kutlan , Hanson Gerald 
Published: December 2022

AbstractThe purpose of this study was to determine whether ex vivo anti-CD3 Ab-activated T cells behaved in a biologically similar manner as naive T cells with respect to causing graft-vs-host disease (GVHD) and facilitating engraftment after allogeneic marrow transplantation. This question was addressed using two well-defined MHC-incompatible murine models of GVHD (C57BL/6 (H-2b)→B10.BR (H-2k)) and engraftment (C57BL/6 (H-2b)→AKR/J (H-2k)). Transplantation with anti-CD3-activated T cells significantly reduced GVHD compared with that in animals transplanted with equivalent numbers of naive T cells. Protection from GVHD was not T cell subset dependent, as highly enriched populations of either activated CD4+ or CD8+ T cells caused less lethal GVHD than comparable numbers of purified naive CD4+ or CD8+ T cells. Transplantation with activated T cells also resulted in protection from LPS-mediated GVH lethality in unirradiated F1 recipients. Analysis of immune recovery indicated that animals transplanted with activated T cells had thymic and splenic B cell reconstitution that compared favorably to that in non-GVHD control mice. When engraftment was analyzed, equivalent degrees of donor cell engraftment were observed when animals were transplanted with limiting numbers (5 × 105) of naive vs activated B6 T cells. Further studies indicated that activated CD8+ T cells were exclusively responsible for enhancing engraftment and that facilitation of engraftment was dependent upon the direct recognition of host MHC alloantigens. Collectively, these data demonstrate that transplantation with anti-CD3 Ab-activated T cells results in a reduction in GVHD, but these cells retain their ability to facilitate alloengraftment. The use of this approach in allogeneic marrow transplantation may represent an alternative strategy to mitigate GVHD without compromising engraftment.
Maternal B Lymphocytes Specific for Paternal Histocompatibility Antigens Are Partially Deleted During Pregnancy
Authors: Aït-Azzouzene Djemel , Gendron Marie-Claude , Houdayer Monique , Langkopf Anja , Bürki Kurt , Nemazee David , Kanellopoulos-Langevin Colette 
Published: December 2022

AbstractAlthough genetically different from its mother, a mammalian fetus bearing paternal alloantigens is normally not rejected. To investigate one of the many possible mechanisms involved in this important biologic phenomenon, we analyzed the consequences of fetal alloantigen recognition on maternal B lymphocytes. We used transgenic mice expressing a unique B cell receptor with a relatively high affinity for the MHC class I molecule H-2Kk on most B lymphocytes. We provide the first evidence for an alloantigen-specific B cell deletion in the spleens and bone marrow of transgenic mothers bearing H-2Kk-positive fetuses. This highly reproducible deletion affects ≤80% of Id-bearing B cells, starts at midpregnancy, and is only observed until term. Such a specific maternal B cell deletion could contribute to the success of the fetal allograft.
Sam68 Association with p120GAP in CD4+ T Cells Is Dependent on CD4 Molecule Expression
Authors: Jabado Nada , Jauliac Sébastien , Pallier Annaïck , Bernard Frédéric , Fischer Alain , Hivroz Claire 
Published: December 2022

Abstract
p120 GTPase-activating protein (p120GAP) is a major negative regulator of p21ras activity in several cell types including T cells. Catalytic activity of this enzyme is regulated in part by its interaction with several associated tyrosine-phosphorylated proteins. Sam68 was initially described as associated with p120GAP. It has been further established that Sam68 is a substrate of src kinases in mitosis and that it is not associated with p120GAP in transformed fibroblasts. We describe herein that Sam68 associates with p120GAP and PLCγ1 in human mature T cells and in a T cell line expressing the CD4 molecule HUT78 CD4+. This association is present in nonactivated cells and increases after anti-CD3 activation. It is dependent on CD4 expression and, in part, on the association of CD4 with p56lck, as shown by the strongly decreased association of Sam68 with p120GAP in the CD4− mutants, HUT78 CD4−, and by the reduced association of Sam68 with both p120GAP and p56lck in the HUT78 T cell line expressing a CD4 mutant unable to interact with p56lck, HUT78 C420/22. We propose that recruitment of Sam68, via CD4/p56lck, to the inner face of the plasma membrane may permit, via its docking properties, the correct association of key signaling molecules including PLCγ1 and p120GAP. This formation of transduction modules will enable the activation of different signaling cascades including the p21ras pathway and an array of downstream events, ultimately leading to T cell activation.