bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Endothelial Cells Augment Early CD40 Ligand Expression in Activated CD4+ T Cells Through LFA-3-Mediated Stabilization of mRNA
Authors: Murakami Kenji , Ma Weilie , Fuleihan Ramsay , Pober Jordan S. 
Published: December 2022

AbstractHuman endothelial cells (EC) augment CD40 ligand (CD40L) expression on PHA-activated CD4+ T cells at early times (e.g., 4–6 h). Fixed EC, devoid of mRNA, are comparable to living EC in their capacity to augment early CD40L expression on CD4+ T cells. Fixed EC increase T cell mRNA expression of both IL-2 and CD40L compared with PHA alone at 6 h. EC are unable to increase the rate of transcription of CD40L compared with PHA alone as measured with a promoter-reporter gene, although they do increase transcription of an IL-2 promoter-reporter gene. Fixed EC prolong the half-life of CD40L mRNA &gt;2-fold. Inclusion of anti-human LFA-3 (CD58) mAb or pretreatment of EC with an LFA-3 antisense oligonucleotide blocks EC-induced increases in CD40L expression, whereas mAb to ICAM-1 or pretreatment with ICAM-1 antisense oligonucleotide does not. Moreover, mAb to LFA-3 reverses the capacity of EC to prolong the half-life of CD40L mRNA, whereas mAb to ICAM-1, even in combination with mAb to ICAM-2, does not. We conclude that EC use LFA-3 to increase early CD40L protein expression on newly activated CD4+ T cells by stabilizing CD40L mRNA.
Attenuation of MHC Class II Expression in Macrophages Infected withMycobacterium bovisBacillus Calmette-Guerin Involves Class II Transactivator and Depends on theNramp1Gene
Authors: Wojciechowski Wojciech , DeSanctis Juan , Skamene Emil , Radzioch Danuta 
Published: December 2022

AbstractThe natural resistance associated macrophage protein 1 (Nramp1) gene determines the ability of murine macrophages to control infection with a group of intracellular pathogens, including Salmonella typhimurium, Leishmania donovani, and Mycobacterium bovis bacillus Calmette-Guérin (BCG). The expression of the resistant allele of the Nramp1 gene in murine macrophages is associated with a more efficient expression of several macrophage activation-associated genes, including class II MHC loci. In this study, we investigated the molecular mechanisms involved in IFN-γ-induced MHC class II expression in three types of macrophages: those expressing a wild-type allele of the Nramp1 gene (B10R and 129/Mφ), those carrying a susceptible form of the Nramp1 gene (B10S), and those derived from 129-Nramp1-knockout mice (129/Nramp1-KO). Previously, we published results showing that Ia protein expression is significantly higher in the IFN-γ-induced B10R macrophages, compared with its susceptible counterpart. In this paper, we also show that the higher expression of Ia protein in B10R cells is associated with higher I-Aβ mRNA expression, which correlates with a higher level of IFN-γ-induced phosphorylation of the STAT1-α protein and subsequently with elevated expression of class II transactivator (CIITA) mRNA, compared with B10S. Furthermore, we demonstrate that the infection of macrophages with M. bovis BCG results in a down-regulation of CIITA mRNA expression and, consequently, in the inhibition of Ia induction. Therefore, our data explain, at least in part, the molecular mechanism involved in the inhibition of I-Aβ gene expression in M. bovis BCG-infected macrophages activated with IFN-γ.
Role of Complement Component C1q in the IgG-Independent Opsonophagocytosis of Group BStreptococcus
Authors: Butko Peter , Nicholson-Weller Anne , Wessels Michael R. 
Published: December 2022

AbstractWe investigated the role of complement component C1q in the IgG-independent opsonophagocytosis of type III group B Streptococcus (GBS) by peripheral blood leukocytes. We report that C1q binds to type III GBS both in normal human serum deficient in IgG specific for type III capsular polysaccharide and in a low-ionic strength buffer. The dissociation constant Kd ranged from 2.0 to 5.5 nM, and the number of binding sites Bmax ranged from 630 to 1360 molecules of C1q per bacterium (CFU). An acapsular mutant strain of GBS bound C1q even better than the wild type, indicating that the polysaccharide capsule is not the receptor for C1q. In serum, binding of C1q to GBS was associated with activation of the classical complement pathway. However, normal human serum retained significant opsonic activity after complete depletion of C1q, suggesting that the serum contains a molecule that is able to replace C1q in opsonization and/or complement activation. Mannan-binding lectin, known to share some functions with C1q, appeared not to be involved, since its depletion from serum had little effect on opsonic activity. Excess soluble C1q or its collagen-like fragment inhibited phagocytosis mediated by normal human serum, suggesting that C1q may compete with other opsonins for binding to receptor(s) on phagocytes. We conclude that, although C1q binds directly to GBS, C1q binding is neither necessary nor sufficient for IgG-independent opsonophagocytosis. The results raise the possibility that additional unknown serum factor(s) may contribute to opsonization of GBS directly or via a novel mechanism of complement activation.
Mice with a Targeted Mutation in Lymphotoxin-α Exhibit Enhanced Tumor Growth and Metastasis: Impaired NK Cell Development and Recruitment
Authors: Ito Daisuke , Back Timothy C. , Shakhov Alexander N. , Wiltrout Robert H. , Nedospasov Sergei A. 
Published: December 2022

AbstractMice deficient in lymphotoxin (LT)-α lack peripheral lymph nodes and Peyer’s patches and have profound defects in development of follicular dendritic cell networks, germinal center formation, and T/B cell segregation in the spleen. Although LTα is known to be expressed by NK cells as well as T and B lymphocytes, the requirement of LTα for NK cell functions is largely unknown. To address this issue, we have assessed NK cell functions in LTα-deficient mice by evaluating tumor models with known requirements for NK cells to control their growth and metastasis. Syngeneic B16F10 melanoma cells inoculated s.c. grew more rapidly in LTα−/− mice than in the wild-type littermates, and the formation of experimental pulmonary metastases was significantly enhanced in LTα−/− mice. Although LTα−/− mice exhibited almost a normal total number of NK cells in spleen, they showed an impaired recruitment of NK cells to lung and liver. Additionally, lytic NK cells were not efficiently produced from LTα−/− bone marrow cells in vitro in the presence of IL-2 and IL-15. These data suggest that LTα signaling may be involved in the maturation and recruitment of NK cells and may play an important role in antitumor surveillance.
The Human B Cell Response to IL-13 Is Dependent on Cellular Phenotype as Well as Mode of Activation
Authors: Ford Dwayne , Sheehan Catherine , Girasole Christopher , Priester Rory , Kouttab Nicola , Tigges John , King Thomas C. , Luciani Andrea , Morgan John W. , Maizel Abby L. 
Published: December 2022

AbstractNormal mature quiescent human B lymphocytes, isolated as a function of buoyant density, require activation for up-regulation of IL-13R constituents. Cell activation through a combination of surface Ig and CD40 receptor ligation leads to the most substantial message production for IL-13Rα1. Functional consequences of this receptor variation, in initially quiescent cells, includes demonstrable effects on cellular proliferation in response to ligand exposure. Variations in the method of surface activation, with particular emphasis on the CD40 receptor, reveals that immobilized CD40 ligand may be sufficient, in and of itself, to up-regulate IL-13Rα1, which may bear significance for B-lymphocyte bystander proliferation. Regulation of the IL-13Rα1 protein and message also differs as a function of cellular phenotype. Although values are greater in memory than naive B cells, as they are initially isolated from extirpated tonsils, variations in the magnitude of message and protein, as a function of surface stimulation, are more substantial in the naive subset. The magnitude of variation in message production in naive cells is associated with a more vigorous proliferative response to IL-13 than seen in memory lymphocytes. The cellular response to IL-13, as a function of activation and phenotype, is the converse of that demonstrated for IL-2. Evaluation of proliferation, receptor message, ligand binding protein production, and the response to putatively synergistic cytokines reveals that IL-2 is the predominant lymphokine utilized by memory cells. This is in contradistinction to IL-13, which along with IL-4, are the predominant moieties for naive lymphocytes.
The Importance of the Light Chain for the Epitope Specificity of Human Anti-U1 Small Nuclear RNA Autoantibodies Present in Systemic Lupus Erythematosus Patients
Authors: Hoet René M. A. , Pieffers Martijn , Stassen Maurice H. W. , Raats Jos , de Wildt Ruud , Pruijn Ger J. M. , van den Hoogen Frank , van Venrooij Walther J. 
Published: December 2022

AbstractAbs to U1 RNA are frequently found in patients suffering from systemic lupus erythematosus overlap syndromes and Ab titers correlate with disease activity. We describe the isolation of the first human anti-U1 RNA autoantibodies from a combinatorial IgG library made from the bone marrow of a systemic lupus erythematosus patient. With the use of phage display technology, two anti-U1 RNA single-chain variable fragment (scFv) Abs were selected. Both high affinity anti-U1 RNA Ab fragments (Kd ∼ 1 nM) recognize stem II of U1 RNA and were derived from the same heavy chain gene (VH3–11) and the same λ (3r) light chain gene although somatic mutations, predominantly present in the complementarity-determining regions, are different. Experiments, in which the heavy chain genes of both anti-U1 RNA scFvs were reshuffled with the original light chain repertoire of the patient resulted, after selection on stem loop II, in a large number of RNA-binding Ab fragments. All these stem loop II-specific RNA binding clones used a similar, but not identical, 3r λ light chain. When scFvs were selected from the reshuffled libraries by stem loop IV, representing the other autoantigenic site of U1 RNA, most selected Ab clones did react with stem loop IV, but no longer with stem loop II. The stem loop IV-reactive Ab clones contained different, not 3r-related, light chains. These results point to a major role for the light chain in determining the sequence specificity of these disease-related anti-U1 RNA Abs. The possibility that secondary light chain rearrangements are involved in this autoimmune response is discussed.
A Monoclonal Antibody Directed Against the Murine Macrophage Surface Molecule F4/80 Modulates Natural Immune Response toListeria monocytogenes
Authors: Warschkau Holger , Kiderlen Albrecht F. 
Published: December 2022

AbstractWhole spleen cell cultures from SCID mice release high levels of IFN-γ when exposed to heat-killed Listeria monocytogenes (HKL). This microbe-induced and T cell-independent response depends on both macrophages (MΦ) and NK cells: HKL-stimulated MΦ release TNF-α and IL-12, which together activate NK cells for IFN-γ release. We show here that this cytokine-mediated activation cascade can be modulated by a mAb against the MΦ surface glycoprotein F4/80. HKL-induced IL-12, TNF-α, and IFN-γ in SCID whole spleen cell cultures was inhibited by coincubation with anti-F4/80 mAb whereas IL-1 and IL-10 were enhanced. Both effects were apparent at mRNA and protein release levels. Whereas inhibitory activities were F4/80 Ag specific, stimulatory effects were Fc dependent and nonspecific. Furthermore, cytokine inhibition by anti-F4/80 was only apparent when MΦ and NK cells were present simultaneously and in close vicinity, indicating that direct cell-to-cell contact is a prerequisite. These data suggest a novel pathway for microbe-induced MΦ/NK cell interaction involving direct cell-to-cell signaling and give the first evidence for a functional role of the MΦ surface glycoprotein F4/80.
Oral Administration of Lipopolysaccharide Exacerbates Collagen-Induced Arthritis in Mice
Authors: Yoshino Shin , Sasatomi Eizaburo , Mori Yoki , Sagai Masaru 
Published: December 2022

AbstractWe investigated whether oral administration of LPS exacerbated collagen-induced arthritis (CIA) in mice, which was an experimental model of autoimmune disease. CIA was induced by s.c. injection of type II collagen emulsified with CFA into the base of the tail (day 0) followed by a booster injection on day 21. To examine the ability of LPS to exacerbate CIA, varying doses of LPS were orally administered on day 50. The results showed that administration of LPS was followed by reactivation of CIA in a dose-related fashion. Histologically, on day 55 there were marked edema of synovium proliferated by day 50, new formation of fibrin, and intense infiltration of neutrophils accompanied with a large number of mononuclear cells. Severe destruction of cartilage and subchondral bone was also observed on day 70. The reactivation of CIA by oral administration of LPS was associated with increase in anti-type II collagen IgG and IgG2a Abs as well as varying kinds of cytokines including IL-12, IFN-γ, IL-1β, and TNF-α. Polymyxin B sulfate given either orally or i.v. suppressed the recurrence of CIA. Increased amounts of LPS were found in sera of mice given the endotoxin orally. LPS from Salmonella enteritidis, Salmonella typhimurium, and Klebsiella pneumoniae and its component, lipid A from Escherichia coli, also reactivated the disease. These findings suggest that LPS from intestinal bacteria may play a role in the exacerbation of autoimmune joint inflammation.
A Common TCR V-D-J Sequence in Vβ13.1 T Cells Recognizing an Immunodominant Peptide of Myelin Basic Protein in Multiple Sclerosis
Authors: Hong Jian , Zang Ying C. Q. , Tejada-Simon Maria V. , Kozovska Milena , Li Sufang , Singh Rana A. K. , Yang Deye , Rivera Victor M. , Killian James K. , Zhang Jingwu Z. 
Published: December 2022

Abstract
T cell responses to the immunodominant peptide (residues 83–99) of myelin basic protein are potentially associated with multiple sclerosis (MS). This study was undertaken to examine whether a common sequence motif(s) exists within the TCR complementarity-determining region (CDR)-3 of T cells recognizing the MBP83–99 peptide. Twenty MBP83–99-reactive T cell clones derived from patients with MS were analyzed for CDR3 sequences, which revealed several shared motifs. Some Vβ13.1 T cell clones derived from different patients with MS were found to contain an identical CDR3 motif, Vβ13.1-LGRAGLTY. Oligonucleotides complementary to the shared CDR3 motifs were used as specific probes to detect identical target CDR3 sequences in a large panel of T cell lines reactive to MBP83–99 and unprimed PBMC. The results revealed that, in contrast to other CDR3 motifs examined, the LGRAGLTY motif was common to T cells recognizing the MBP83–99 peptide, as evident by its expression in the majority of MBP83–99-reactive T cell lines (36/44) and PBMC specimens (15/48) obtained from randomly selected MS patients. The motif was also detected in lower expression in some PBMC specimens from healthy individuals, suggesting the presence of low precursor frequency of T cells expressing this motif in healthy individuals. This study provides new evidence indicating that the identified LGRAGLTY motif is preferentially expressed in MBP83–99-reactive T cells. The findings have important implications in monitoring and targeting MBP83–99-reactive T cells in MS.
IgG and Complement-Mediated Tissue Damage in the Absence of C2: Evidence of a Functionally Active C2-Bypass Pathway in a Guinea Pig Model
Authors: Wagner Eric , Platt Jeffrey L. , Howell David N. , Marsh Henry C. , Frank Michael M. 
Published: December 2022

AbstractIn vitro complement-mediated lysis of heavily sensitized sheep erythrocytes by C4-deficient (C4D) guinea pig and C2-deficient (C2D) human sera was demonstrated some years ago. It was postulated that these “complement-bypass” pathways resulted from activation of C1 and components of the alternative pathway. We used normal, C2D, and C4D guinea pigs in a Forssman shock model to test the in vivo relevance of the C2- and C4-bypass pathways of complement activation. High concentrations of both anti-Forssman Ab and C2D or C4D guinea pig serum induced efficient lysis of sheep erythrocytes in vitro. The most efficient lysis was observed when IgG Ab and C2D guinea pig serum were used. Blocking either the classical pathway (treatments with EGTA-Mg2+ or soluble recombinant complement receptor type 1 (sCR1)) or the alternative pathway (treatment with heating at 50°C, sCR1, or soluble recombinant CR1 lacking the first of the four long homologous repeat sequences (sCR1[desLHR-A])) inhibited lysis; both pathways were required for lysis of sheep erythrocytes by C2D and C4D guinea pig sera. i.v. injection of anti-Forssman Ab in normal guinea pigs resulted in rapid death from pulmonary shock, whereas C4D guinea pigs had no adverse effect. Surprisingly, C2D guinea pigs either died in a delayed fashion or had a sublethal reaction. sCR1 treatment prevented Forssman shock in both normal and C2D guinea pigs, whereas sCR1[desLHR-A] prevented Forssman shock only in C2D animals. Our results suggest that the C2-bypass pathway occurs in vivo to produce tissue damage. Activation of complement in the absence of C2 appears to be far more efficient than in the absence of C4.
Cutting Edge: TCRαβ+ CD8αα+ T Cells Are Found in Intestinal Intraepithelial Lymphocytes of Mice That Lack Classical MHC Class I Molecules
Authors: Gapin Laurent , Cheroutre Hilde , Kronenberg Mitchell 
Published: December 2022

Abstract
TCRαβ+ intestinal intraepithelial lymphocytes (IEL) can express either the typical CD8αβ heterodimer or an unusual CD8αα homodimer. Both types of CD8+ IEL require class I molecules for their differentiation, since they are absent in β2m−/− mice. To gain insight into the role of class I molecules in forming TCRαβ+ CD8+ IEL populations, we have analyzed the IEL in mice deficient for either TAP, β2m, CD1, or K and D. We find that K−/−D−/− mice have TCRαβ+ CD8αα+ IEL, although they are deficient for TCRαβ+ CD8αβ+ cells. This indicates that at least some TCRαβ+ CD8αα+ IEL require only nonclassical class I molecules for their development. Surprisingly, the TCRαβ+ CD8αα+ IEL are significantly increased in K−/−D−/− mice, suggesting a complex interaction between CD8+ IEL and class I molecules that might include direct or indirect negative regulation by K and D, as well as positive effects mediated by nonclassical class I molecules.
Cutting Edge: Differentiation of Antitumor CTL In Vivo Requires Host Expression of Stat1
Authors: Fallarino Francesca , Gajewski Thomas F. 
Published: December 2022

AbstractSeveral lines of evidence suggest that an IFN-γ-producing, Th1/Tc1 phenotype may be optimal for tumor rejection. Recent work has indicated that IFN signaling on tumor cells is important for protection against carcinogenesis. However, the potential involvement of IFN signaling among host immune cells has not been carefully examined. To this end, Stat1-deficient mice were employed as tumor recipients. In contrast to wild-type mice, Stat1−/− mice failed to reject immunogenic tumors and did not support regression of poorly immunogenic tumors when treated with an IL-12-based vaccine. T cells from immunized Stat1−/− mice produced 50% of the levels of IFN-γ and lacked cytolytic activity compared with wild-type mice, and NK lytic activity also was not observed. Lack of cytolytic function correlated with a failure to up-regulate serine esterase activity. Thus, IFN-mediated signaling on host cells is required for the development of antitumor lytic effector cells.
Deficiency of Transporter for Antigen Presentation (TAP) in Tumor Cells Allows Evasion of Immune Surveillance and Increases Tumorigenesis
Authors: Johnsen A. K. , Templeton D. J. , Sy M.-S. , Harding C. V. 
Published: December 2022

Abstract
Proteins involved in class I MHC (MHC-I) Ag processing, such as the TAP, are deficient in some human tumor cells. This suggests that antitumor responses by CD8 T cells provide selection pressure to favor outgrowth of cells with defective processing of tumor Ags. Nonetheless, this evidence is only correlative, and controlled in vivo experiments have been lacking to demonstrate that TAP deficiency promotes survival of tumor cells. To explore the role of Ag processing defects in tumor progression, matched panels of TAP1-positive and TAP1-negative tumor cell lines were generated from a parental transformed murine fibroblast line. Inoculation of C57BL/6 mice with TAP1-negative cells produced large and persistent tumors. In contrast, TAP1-positive cells did not generate lasting tumors, although small tumors were detected transiently and regressed spontaneously. Both TAP1-positive and TAP1-negative cells produced tumors in athymic mice, confirming that TAP-dependent differences in tumorigenicity were due to T cell-dependent immune responses. Inoculation of C57BL/6 mice with mixtures of TAP1-positive and TAP1-negative cells produced tumors composed exclusively of TAP1-negative cells, indicating in vivo selection for cells with TAP deficiency. Thus, loss of TAP function allows some tumor cells to avoid T cell-dependent elimination, resulting in selection for tumor cells with deficient Ag processing.
Naive and Memory T Lymphocytes Migrate in Comparable Numbers Through Normal Rat Liver: Activated T Cells Accumulate in the Periportal Field
Authors: Luettig Birgit , Pape Lars , Bode Ulrike , Bell Eric B. , Sparshott Sheila M. , Wagner Siegfried , Westermann Jürgen 
Published: December 2022

AbstractAlthough the liver is known to contain a significant number of lymphocytes, migration of these through the compartments of the liver, parenchyma and periportal field, has not been studied. The periportal field, in particular, is affected in several immunological disorders of the liver. Populations of labeled naive, activated, and memory T cells were injected into congenic rats. The recipient livers and draining lymph nodes were removed at various time points, and cryostat sections were analyzed for the presence of donor cells using quantitative immunohistology. Donor cell proliferation and apoptosis were examined in vivo by BrdU (5 μM 5-bromo-2-deoxyuridine) incorporation and the TUNEL technique, respectively. Early after injection (0.5–1 h), naive, activated, and memory T cells were localized to the parenchyma and periportal field in comparable numbers. With time, all T cell subsets left the parenchyma but remained or, in the case of activated T cells, significantly accumulated in the periportal field. Furthermore, 12% of activated donor T cells proliferated in vivo within the periportal field, and 0.5% showed evidence of apoptosis. Taken together, not only activated and memory, but also naive T cells continuously migrate through the liver, showing a preference for the periportal field, and activated T cells mainly proliferate there. This may explain why many immunological liver diseases predominantly affect the periportal field.