bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cutting Edge: Lymphocyte Inhibitor of TRAIL (TNF-Related Apoptosis-Inducing Ligand): A New Receptor Protecting Lymphocytes from the Death Ligand TRAIL
Authors: Mongkolsapaya Juthathip , Cowper Alison E. , Xu Xiao-Ning , Morris Gwilym , McMichael Andrew J. , Bell John I. , Screaton Gavin R. 
Published: January 2023

Abstract
Apoptosis can be triggered by the engagement of cell surface receptors by their ligands. A growing number of receptors belonging to the TNF receptor family have been identified that contain a conserved cytoplasmic death domain. These include Fas, TNF-R1, lymphocyte-associated receptor of death (LARD), DR4, and TNF-related apoptosis-inducing ligand receptor inducer of cell killing-2 (TRICK2). The latter two are receptors for the cytotoxic ligand TNF-related apoptosis-inducing ligand (TRAIL), and one of the paradoxes raised by the cloning of these molecules was why do most cells not die upon contact with the widely expressed TRAIL molecule? This is a particular problem for lymphocytes that express DR4 and TRICK2 and are in constant circulation through TRAIL-expressing tissues. We have cloned LIT (lymphocyte inhibitor of TRAIL), which lacks a death domain. LIT is expressed predominantly on PBL, where it can competitively inhibit TRAIL-induced apoptosis through DR4/TRICK2, and may function to modulate lymphocyte sensitivity to TRAIL.
Septic Arthritis Following Staphylococcus aureus Infection in Mice Lacking Inducible Nitric Oxide Synthase
Authors: McInnes Iain B. , Leung Bernard , Wei Xiao-Qing , Gemmell Curtis C. , Liew Foo Y. 
Published: January 2023

Abstract
Nitric oxide (NO), produced in large amounts by inducible NO synthase (iNOS), has emerged recently as an important microbicidal and immunomodulatory mediator. We have investigated its role in bacterial septic arthritis caused by Staphylococcus aureus infection using iNOS-deficient mice. The incidence, rate of development, and severity of arthritis were greater in iNOS-deficient than in heterozygous or wild-type control mice. Similarly, the incidence and severity of septicemia and mortality were significantly higher in iNOS-deficient mice compared with controls. Increased TNF-α synthesis in vivo and in vitro and enhanced IFN-γ compared with IL-4 production in vitro in iNOS-mutant mice demonstrated exaggerated Th1 polarization of the host response. These data indicate that high output NO production is not a prerequisite for severe articular destruction and imply that NO is of importance in synovial defense against staphylococcal infection.
Legionella pneumophila Infection in Intratracheally Inoculated T Cell-Depleted or -Nondepleted A/J Mice
Authors: Susa Milorad , Ticac Brigita , Rukavina Tomislav , Doric Miljenko , Marre Reinhard 
Published: January 2023

Abstract
The inflammatory response and influence of T cell depletion on the pathogenesis of an experimental Legionella infection were studied. A/J mice were infected with 106 CFU of Legionella pneumophila intratracheally. With this dose all infected animals survived the infection and bacteria were cleared from lung, spleen, liver, and kidney within 10 to 11 days, leaving no residual changes in the affected organs. Inflammatory cells were recruited into the lung on the second day of infection, reaching a maximum on the third day and filling out predominantly the interstitial areas. During the first 3 days after inoculation, mainly macrophages, B cells, NK cells, and large mononuclear cells of an unknown phenotype were attracted into the lung interstitium, whereas T lymphocytes infiltrated subsequently. During the early phase of infection, serum concentrations of IFN-γ, TNF-α, IL-1β, IL-4, and IL-6 but not IL-2 increased dramatically. The cytokine secretion decreased on the third day after infection although bacteria were still present in the lung or even disseminated in different organs. Successful clearance of bacteria from the lung was not observed before recruitment of T cells into the lung. In mice depleted of both CD4+ and CD8+ T cells, control of infection was impaired and lethality of infection increased. Depletion of either subset left residual antibacterial mechanisms, which, however, were not sufficient to clear the Legionella as rapidly as in undepleted mice.
Macrophages Kill T9 Glioma Tumor Cells Bearing the Membrane Isoform of Macrophage Colony Stimulating Factor Through a Phagocytosis-Dependent Pathway
Authors: Jadus Martin R. , Williams Christopher C. , Avina Maria D. , Ly Mann , Kim Suzanna , Liu Ying , Narasaki Ryan , Lowell Clifford A. , Wepsic H. Terry 
Published: January 2023

Abstract
Rat T9 glioma cells transfected with the gene for the membrane isoform of macrophage-CSF (mM-CSF) but not for the secreted isoform of M-CSF were directly killed by bone marrow-derived macrophages. Macrophage-mediated cytolysis of the mM-CSF-transfected clone was blocked by using chemical inhibitors of phagocytosis such as iodoacetate, 2-deoxyglucose, gadolinium chloride, and cytochalasin B. In contrast, macrophage-mediated killing of mM-CSF-expressing tumor cells was augmented by the microtubule inhibitor, colchicine. Use of nitric oxide and reactive oxygen intermediate inhibitors failed to alter the macrophage-mediated killing of the mM-CSF-transfected tumor cells. Photomicroscopy, using immunohistochemical staining with the anti-Hck Ab to distinguish macrophages from tumor cells, revealed that phagocytosis began within 2 h after addition of the mM-CSF-bearing tumor cells. Photocinematography confirmed that macrophages first phagocytosized and then lysed the internalized mM-CSF transfectant cells. Using annexin V and acridine orange staining techniques, macrophages phagocytosized living mM-CSF-transfected tumor cells.
ChronicListeriaInfection in SCID Mice: Requirements for the Carrier State and the Dual Role of T Cells in Transferring Protection or Suppression
Authors: Bhardwaj Vatsala , Kanagawa Osami , Swanson Paul E. , Unanue Emil R. 
Published: January 2023

AbstractListeriosis in mice with the SCID mutation results in a chronic infection. The chronic infection is characterized by abundant granulomas and neutrophil infiltrates. Both lesions were particularly noticeable in the liver. In the liver, about 95% are granulomas with 5% microabscesses involving intrahepatic infection. The majority of Listeria resided in membrane-bound vacuolar structures of the macrophages and not in the cytosol. Three manipulations resulted in alterations in the equilibrium between granulomas and liver microabscesses, with massive transfer of the infection to the hepatocyte and dissolution of the granulomas: depletion of neutrophils and neutralization of IFN-γ and TNF-α. We did not find a role for IL-12, IL-10, or nitric oxide. Adoptive transfer studies showed a decisive role for both CD4+ and CD8+ T cells for an effective immune response, i.e., clearance of bacteria, granuloma formation with lymphocytes, and disappearance of microabscess. Clearance of Listeria was induced by transfer of CD8+ T cells from mice with targeted disruption of the IFN-γ structural gene (IfgTM1KO), even in the presence of neutralizing mAb to IFN-γ. In marked contrast, transfer of CD4+ T cells from IfgTM1KO mice exacerbated the infection in the chronically infected SCID mice, resulting in increased mortality with dissolution of the granulomas and severe hepatic infection with neutrophil infiltration. Thus, these data indicate that both IFN-γ-dependent and -independent mechanisms are operative in the context of a chronic listerial infection.
Lymphoid Hyperplasia, Autoimmunity, and Compromised Intestinal Intraepithelial Lymphocyte Development in Colitis-Free Gnotobiotic IL-2-Deficient Mice
Authors: Contractor Nikhat V. , Bassiri Hamid , Reya Tannishtha , Park Audrey Y. , Baumgart Daniel C. , Wasik Mariusz A. , Emerson Stephen G. , Carding Simon R. 
Published: January 2023

Abstract
IL-2-deficient (IL-2−/−) mice develop disorders of the hemopoietic and immune systems characterized by anemia, lymphocytic hyperplasia, and colitis. The mechanisms responsible for these abnormalities remain unclear. To investigate the underlying basis of autoimmunity, the particular role of commensal gut flora in the initiation of colitis, and the role of IL-2 in the development of intestinal intraepithelial lymphocytes (iIEL), we evaluated IL-2−/− mice reared and maintained under gnotobiotic (germfree) conditions. By 8 wk of age, 80% (20 of 25) of germfree IL-2−/− mice show signs of disease, including anemia, disturbances in bone marrow hemopoietic cells, lymphocytic hyperplasia, and generalized autoimmunity, similar to those seen in specific pathogen-free (SPF) IL-2−/− mice. In striking contrast to SPF IL-2−/− mice, germfree IL-2−/− mice do not develop colitis. However, the numbers of γδ+ and TCRαβ+CD8αα+ iIELs are reduced, and in lethally irradiated SPF IL-2+/+ mice, reconstituted with IL-2−/− bone marrow TCRγδ+ iIELs fail to develop, consistent with an important role of IL-2/IL-2R signaling in the development of γδ iIELs. Consequently, our findings demonstrate that the colitis seen in SPF IL-2−/− mice depends upon the presence of intestinal bacterial flora and that environmental Ags are not responsible for the anemia and extraintestinal lymphoid hyperplasia that occur in IL-2−/− mice. Thus, germfree IL-2−/− mice represent a unique system in which the role of IL-2 deficiency in hemopoietic and immune system disorders can be investigated in dissociation from complications that may arise due to colitis.
An Alternative Translational Reading Frame Encodes an Immunodominant Retroviral CTL Determinant Expressed by an Immunodeficiency-Causing Retrovirus
Authors: Mayrand Shawn-Marie , Schwarz David A. , Green William R. 
Published: January 2023

Abstract
Recognition of virus-infected or transformed cells by CD8+ CTL requires a trimolecular complex composed of MHC class I, β2-microglobulin, and a specific foreign peptide composed of 8 to 10 linear amino acids. The generation of such CTL epitopes has traditionally been thought to be from the primary open reading frame encoding the viral or tumor-associated proteins. In this report it is demonstrated that a viral CTL epitope can also be generated from an alternative reading frame. Using a combination of synthetic peptides and Sindbis or vaccinia expression systems, MHC class I Kd-restricted BALB/cByJ CTL directed against defective gag gene constructs of the LP-BM5 virus complex that causes murine AIDS were shown to have specificity for the antigenic peptide SYNTGRFPPL. This epitope is generated in a novel fashion from the second open reading frame (ORF2) of both the defective and ecotropic helper virus components of LP-BM5. Importantly, lysis of target cells expressing BM5 ecotropic helper, and/or defective viral gag, demonstrated that the SYNTGRFPPL epitope is generated during the course of a normal retroviral infection. Furthermore, MAIDS-resistant BALB/cByJ mice also generated secondary restimulated CTL specific for SYNTGRFPPL following in vivo priming with the LP-BM5 retroviral complex. These data suggest that retroviruses, and potentially other viruses and foreign genes, are capable of expressing T cell epitopes from alternative open reading frames. If one considers the influence of self peptides on T cell development, these “alternative reading frame-derived” peptides could provide an important additional influence on the functional T cell repertoire.
Human CD38 (ADP-Ribosyl Cyclase) Is a Counter-Receptor of CD31, an Ig Superfamily Member
Authors: Deaglio Silvia , Morra Massimo , Mallone Roberto , Ausiello Clara M. , Prager Elisabeth , Garbarino Giovanni , Dianzani Umberto , Stockinger Hannes , Malavasi Fabio 
Published: January 2023

AbstractHuman CD38 is a cell surface molecule involved in the regulation of lymphocyte adhesion to endothelial cells. This suggests that HUVEC bear a ligand(s) for CD38 on the cell surface. By means of the mAb Moon-1, which specifically inhibits CD38-mediated cell adhesion, we have identified a trans-membrane 130-kDa molecule acting as a ligand for CD38. Here, we report that the molecule recognized by the Moon-1 mAb is CD31, a member of the Ig superfamily. This conclusion is based on 1) cross-inhibition assays between Moon-1 and reference anti-CD31 mAbs; 2) sequential immunoprecipitation experiments using Moon-1 and known anti-CD31 mAbs, and 3) reactivity of the Moon-1 mAb with CD31 transfectants. Further, CD31 and CD38 cognate interactions were found to modulate heterotypic adhesion as well as to implement cytoplasmic calcium fluxes identical to those obtained by means of agonistic anti-CD38 mAbs. Other effects tested included the synthesis of messages for a panel of cytokines, markedly increased upon receptor-ligand interactions. These results suggest that the interplay between CD38 and its ligand CD31 is an important step in the regulation of cell life and of the migration of leukocytes (and CD38+ cancer cells) through the endothelial cell wall.
Regulated Production of Type I Collagen and Inflammatory Cytokines by Peripheral Blood Fibrocytes
Authors: Chesney Jason , Metz Christine , Stavitsky Abram B. , Bacher Michael , Bucala Richard 
Published: January 2023

Abstract
We recently described a novel population of blood-borne cells, termed fibrocytes, that display a distinct cell surface phenotype (collagen+/CD13+/CD34+/CD45+), rapidly enter sites of tissue injury, and contribute to scar formation. To further characterize the role of these cells in vivo, we examined the expression of type I collagen and cytokine mRNAs by cells isolated from wound chambers implanted into mice. Five days after chamber implantation, CD34+ fibrocytes but not CD14+ monocytes or CD90+ T cells expressed mRNA for type I collagen. Fibrocytes purified from wound chambers also were found to express mRNA for IL-1β, IL-10, TNF-α, JE/MCP, MIP-1α, MIP-1β, MIP-2, PDGF-A, TGF-β1, and M-CSF. The addition of IL-1β (1–100 ng/ml), a critical mediator in wound healing, to fibrocytes isolated from human peripheral blood induced the secretion of chemokines (MIP-1α, MIP-1β, MCP-1, IL-8, and GROα), hemopoietic growth factors (IL-6, IL-10, and macrophage-CSF), and the fibrogenic cytokine TNF-α. By contrast, IL-1β decreased the constitutive secretion of type I collagen as measured by ELISA. Additional evidence for a role for fibrocytes in collagen production in vivo was obtained in studies of livers obtained from Schistosoma japonicum-infected mice. Mouse fibrocytes localized to areas of granuloma formation and connective matrix deposition. We conclude that fibrocytes are an important source of cytokines and type I collagen during both the inflammatory and the repair phase of the wound healing response. Furthermore, IL-1β may act on fibrocytes to effect a phenotypic transition between a repair/remodeling and a proinflammatory mode.
A Model of Peptide-Induced Lupus Autoimmune B Cell Epitope Spreading Is Strain Specific and Is Not H-2 Restricted in Mice
Authors: James Judith A. , Harley John B. 
Published: January 2023

Abstract
Anti-Sm is a common and specific autoantibody found in systemic lupus erythematosus. The peptide PPPGMRPP from Sm B/B′ is an early target of the autoimmune response in some anti-Sm-positive human patients. After immunization with this peptide on a MAP backbone, rabbits develop anti-Sm autoantibodies with B cell epitope spreading of the autoimmune response as well as other features of lupus autoimmunity. Various strains of inbred mice have been immunized with peptide PPPGMRPP or PSQQVMTP (nonantigenic region of Sm B/B′) in Freund’s adjuvant or with no peptide. All peptide-immunized mouse strains eventually develop high titers of specific anti-peptide of immunization Abs. Mice immunized with Freund’s adjuvant alone have no measurable Ab binding to the PPPGMRPP peptide. With time, nearly half the mouse strains tested develop Abs that react with additional regions of Sm B/B′ and Sm D. All the regions bound by mouse serum are major epitopes of the human systemic lupus erythematosus anti-Sm response. These same strains also develop significant anti-Sm and anti-nuclear ribonucleoprotein titers. In addition, some of these strains demonstrate positive anti-nuclear Abs and anti-dsDNA Abs. Experiments with congenic H-2 mice demonstrate that the H-2 region does not play a role in spreading the immune response from the peptide of immunization to other epitopes of the spliceosome. These results present a new murine model of B cell epitope spreading and lupus autoimmunity induced by peptide immunization that is strain specific and not apparently dependent upon the loci at H-2.
Cutting Edge: Immature Dendritic Cells Generated from Monocytes in the Presence of TGF-β1 Express Functional C-C Chemokine Receptor 6
Authors: Yang De , Howard O. M. Zack , Chen Qian , Oppenheim Joost J. 
Published: January 2023

Abstract
Although CD34+ progenitor-derived immature dendritic cells (DCs) express CCR6, several recent studies reported that monocyte-derived immature DCs do not do so. We observed that DCs generated from monocytes in the presence of GM-CSF, IL-4, and TGF-β1 consistently responded to liver and activation-regulated chemokine (LARC, also known as macrophage inflammatory protein-3α). These immature DCs expressed one class of high-affinity binding sites for LARC, and expressed both CCR6 mRNA and protein. Therefore, LARC-CCR6 interaction presumably also contributes to the regulation of trafficking of monocyte-derived DCs, and utilization of TGF-β can potentially provide a ready source of CCR6+ monocyte-derived DCs for therapeutic purposes.
Cutting Edge: Association of Phospholipase C-γ2 Src Homology 2 Domains with BLNK Is Critical for B Cell Antigen Receptor Signaling
Authors: Ishiai Masamichi , Sugawara Hitoshi , Kurosaki Mari , Kurosaki Tomohiro 
Published: January 2023

Abstract
To explore the mechanism(s) by which phospholipase C (PLC)-γ2 participates in B cell Ag receptor (BCR) signaling, we have studied the function of PLC-γ2 mutants in B cells deficient in PLC-γ2. Mutation of the N-terminal Src homology 2 domain [SH2(N)] resulted in the complete loss of inositol 1,4,5-trisphosphate generation upon BCR engagement. A possible explanation for the SH2(N) requirement was provided by findings that this mutation abrogates the association of PLC-γ2 with an adaptor protein BLNK. Moreover, expression of a membrane-associated form (CD16/PLC-γ2) with SH2(N) mutation required coligation of BCR and CD16 for inositol 1,4,5-trisphosphate generation. Together, our results suggest a central role for the SH2(N) domain in directing PLC-γ2 into the close proximity of BCR signaling complex by its association with BLNK, whereby PLC-γ2 becomes tyrosine phosphorylated and thereby activated.
Cutting Edge: Dueling TCRs: Peptide Antagonism of CD4+ T Cells with Dual Antigen Specificities
Authors: Robertson Jennifer M. , Evavold Brian D. 
Published: January 2023

Abstract
T cells expressing two different TCRs were generated by interbreeding 3A9 and AND CD4+ TCR transgenic mice specific for the hen egg lysozyme (HEL) peptide 48–62:I-Ak and moth cytochrome c (MCC) peptide 88–103:I-Ek peptide:MHC ligands, respectively. Peripheral T cells in the offspring express two TCR Vβ-chains and respond to HEL and MCC. We observed minimal or no additive effects upon simultaneous suboptimal stimulation with both agonist peptides; however, an antagonist peptide for the 3A9 TCR was able to inhibit the response of the dual receptor T cells to MCC, the AND TCR agonist. This HEL antagonist peptide did not affect AND single transgenic T cells, indicating that the antagonism observed in the dual TCR cells is dependent on the presence of the HEL-specific 3A9 TCR. In contrast, anti-TCR Abs mediate receptor-specific antagonism. These results demonstrate that peptide antagonism exerts a dominant effect.
Strain Variation in Autoimmunity: Attempted Tolerization of DA Rats Results in the Induction of Experimental Autoimmune Encephalomyelitis
Authors: Lenz Derek C. , Wolf Norbert A. , Swanborg Robert H. 
Published: January 2023

AbstractThis paper reports that DA rats develop experimental autoimmune encephalomyelitis (EAE) when immunized with encephalitogenic myelin basic protein (MBP) peptide (MBP63–81) in IFA. In contrast, most rodent strains are tolerized by this procedure. Doses as low as 5 μg peptide + IFA induced EAE in DA rats. Lewis (LEW) rats did not develop EAE, even after immunization with 100 μg encephalitogenic peptide (MBP68–86) + IFA, but were rendered tolerant to EAE. DA rat T cells proliferated to peptide, and proliferation was inhibited by CTLA4Ig, and by anti-B7.1 and anti-B7.2 mAbs. This indicates that the ease of induction of EAE in this strain does not reflect a decreased requirement for T cell costimulation through the B7/CD28 costimulatory pathway. The inhibitory effect of CTLA4Ig was abrogated in the presence of anti-TGF-β-neutralizing Ab. An encephalitogenic DA T cell line expressed mRNA for the Th1 cytokines IFN-γ and TNF-α, as well as IL-10, and secreted these cytokines. In contrast, a T cell line from peptide + IFA-immunized LEW rats (which did not develop EAE) failed to secrete these cytokines. Although this line did not express TNF-α or IL-10 mRNA, IFN-γ mRNA was detected, suggesting posttranscriptional regulation of IFN-γ expression. Attempts to induce unresponsiveness in DA rats with encephalitogenic peptide-coupled splenocytes were also unsuccessful.
NK Lytic-Associated Molecule: A Novel Gene Selectively Expressed in Cells with Cytolytic Function
Authors: Kozlowski Miroslaw , Schorey Jeff , Portis Toni , Grigoriev Vitalii , Kornbluth Jacki 
Published: January 2023

AbstractNK cells are most effective in killing a broad spectrum of primary tumor cells after stimulation with cytokines. We have cloned a novel gene, designated NKLAM (for NK lytic-associated molecule), whose expression is associated with this cytokine-enhanced process. NKLAM expression is up-regulated in NK cells by IL-2 and IFN-β. NKLAM is also selectively expressed by activated macrophages and CTL. Treatment of NK cells and CTL with NKLAM antisense oligonucleotides specifically decreases their cytolytic activity, while having no effect on cell growth. The NKLAM gene encodes a 62-kDa ring finger-containing protein that localizes to the cytoplasmic granules in NK cells. Further study of this gene may add to our understanding of cytotoxic processes common to NK cells, CTL, and activated macrophages.
Insulin in Oral Immune “Tolerance”: A One-Amino Acid Change in the B Chain Makes the Difference
Authors: Homann Dirk , Dyrberg Thomas , Petersen Jacob , Oldstone Michael B. A. , von Herrath Matthias G. 
Published: January 2023

Abstract
Oral administration of self-Ags can dampen or prevent autoimmune processes by induction of bystander suppression. Based on encouraging results from experiments in nonobese diabetic (NOD) mice, clinical trials have been initiated in type 1 diabetes using human insulin as an oral Ag. However, neither the precise antigenic requirements nor the mechanism of bystander suppression are currently understood in detail. Here we report that 1) a 1-aa difference in position 30 of the insulin B chain abrogated the ability of insulin to confer protection in both NOD as well as a virus-induced transgenic mouse model for type 1 diabetes. In the latter model transgenic mice express the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) under the control of the rat insulin promotor (RIP) in the pancreatic β cells and develop diabetes only following LCMV infection; and 2) protection could be transferred with insulin B chain-restimulated but not LCMV-restimulated splenocytes from RIP-NP transgenic mice, demonstrating that the mechanism of diabetes prevention in the RIP-NP model is mediated by insulin B chain-specific, IL-4-producing regulatory cells acting as bystander suppressors.