bluuebunny/crossref_metadata_2025_split huggingface dataset:
Major differences in transporter associated with antigen presentation (TAP)-dependent translocation of MHC class I-presentable peptides and the effect of flanking sequences.
Authors: Neisig A , Roelse J , Sijts A J , Ossendorp F , Feltkamp M C , Kast W M , Melief C J , Neefjes J J 
Published: December 2022

Abstract
The MHC-encoded transporter associated with Ag presentation (TAP) translocates peptides from the cytosol to the ER lumen, where association with MHC class I molecules occurs. The MHC class I/peptide complex is subsequently transported to the cell surface for presentation to CD8+T cells. We studied TAP-dependent translocation of defined MHC class I presentable murine peptides by competition for translocation of a radiolabeled model peptide, to address whether efficient peptide presentation by MHC class I molecules is preceded by equal efficient peptide translocation by TAP. Surprisingly, we observed that four immunodominant viral peptides of 16 peptides tested were very inefficiently transported by TAP. Inefficient translocation could be overcome by substitution of a proline residue present at position 3 in the peptides. Furthermore, addition of natural flanking amino acids directly surrounding a poorly transported peptide could considerably improve translocation by TAP. Our data suggest that some peptides are efficiently transported by TAP in their optimal size for MHC class I binding, whereas other peptides are transported as larger peptide fragments that need further trimming in the ER for MHC class I binding.
Dexamethasone or cyclosporin A suppress mast cell-leukocyte cytokine cascades. Multiple mechanisms of inhibition of IgE- and mast cell-dependent cutaneous inflammation in the mouse.
Authors: Wershil B K , Furuta G T , Lavigne J A , Choudhury A R , Wang Z S , Galli S J 
Published: December 2022

Abstract
In allergic diseases, exposure of sensitized subjects to allergen induces the activation of tissue mast cells that results in an immediate-type hypersensitivity response and, in some individuals, a a late phase response. We previously have reported that the neutrophil infiltration associated with IgE-dependent cutaneous inflammation in mice is mast cell-dependent and that TNF-alpha contributes significantly to this response. We report here that either dexamethasone or cyclosporin A can inhibit mouse mast cell TNF-alpha production in vitro, and that these agents also can significantly suppress the tissue swelling and leukocyte infiltration associated with two forms of TNF-alpha-associated inflammation in vivo: the entirely IgE- and mast cell-dependent inflammation at sites of passive cutaneous anaphylaxis reactions and the entirely TNF-alpha-dependent inflammation that is elicited by the direct intradermal injection of recombinant mouse TNF-alpha. Taken together, our in vitro and in vivo findings in mice indicate that dexamethasone or cyclosporin A can have at least three actions that interfere with the pathogenesis of IgE, mast cell, and cytokine-dependent inflammatory reactions:suppression of the IgE-dependent increase in TNF-alpha mRNA by mast cells, inhibition of the IgE-dependent production of TNF-alpha protein by mast cells, and diminution of the responsiveness of target cells to TNF-alpha. Our findings in mice raise the possibility that similar actions of these agents in humans may account for some of the clinical efficacy of corticosteroids and cyclosporin A in allergic diseases.
Balance of IL-1 receptor antagonist/IL-1 beta in rheumatoid synovium and its regulation by IL-4 and IL-10.
Authors: Chomarat P , Vannier E , Dechanet J , Rissoan M C , Banchereau J , Dinarello C A , Miossec P 
Published: December 2022

Abstract
The spontaneous production of IL-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) by rheumatoid arthritis (RA) synovium, and the regulation of their production by IL-4 and IL-10, were studied. Supernatants from cultured synovium pieces from 19 RA patients were assayed for IL-1 beta and IL-1Ra production using ELISA and RIA, respectively. After 10 days of culture, spontaneous production of IL-1Ra was 1.42 +/- 0.43 ng/ml/100 mg of synovium whereas spontaneous production of IL-1 beta was 4.03 +/- 0.90 ng/ml/100 mg of synovium (n = 19). The addition of IL-4 reduced IL-1 beta production by 2.3-fold (p = 0.001) and increased that of IL-1Ra by 2.8-fold (p = 0.003). IL-10 had no significant effect on IL-1Ra production and suppressed IL-1 beta production (primarily in samples producing high levels of IL-1 beta). However, IL-10 was less potent than IL-4 in suppressing IL-1 beta production. IL-1Ra was mainly produced by rheumatoid synovial monocytes/macrophages. IL-4 was more potent than IL-10 in inducing IL-1Ra production by monocytes/macrophages purified from RA synovium, as well as from RA blood. Thus, RA synovium is characterized by an imbalance between IL-1Ra and IL-1 beta production, in favor of the latter. IL-4, and to a lesser extent IL-10, shift this balance in favor of an anti-inflammatory situation.
Activation of human thymocytes after infection by EBV.
Authors: Paterson R L , Kelleher C A , Streib J E , Amankonah T D , Xu J W , Jones J F , Gelfand E W 
Published: December 2022

Abstract
The discovery of EBV in certain T cell malignancies and the expression of the EBV receptor, CR2/CD21, on a population of immature thymocytes, T lymphoblastoid cell lines, and childhood acute T lymphoblastic leukemia cells suggested that EBV-receptor interactions on T cells may be of importance. We have shown that, within the thymus, a population of large, immature cells expresses CD21. EBV altered the activation responses of immature thymocytes in vitro. Triggering through CD2 is mitogenic for mature, but not immature, T cells. However, during infection by EBV, ligation of CD2 caused thymocytes to proliferate in the absence of exogenous cytokines. This function was a result of the interaction of EBV with its receptor, CD21, but was caused by infection rather than surface signaling, because neither specific mAb nor the P3HR-1 strain of virus mimicked the effect of B95-8. Immature thymocytes were infected by EBV, as determined by the internalization of the viral genome and its transcriptional activity. Consistent with the activity of B95-8, EBNA-2 transcripts were identified within infected thymocyte populations. In addition, components of the viral replicative pathway were expressed during infection of thymocytes. These components included transcription of BZLF-1, an early gene that characterizes EBV-infected B cells after disruption of latency. A second transcript was identified as encoding the recently characterized RAZ, which also is associated with replicative infection. The consequences of EBV infection of T cells at an early stage of differentiation may lead to failure of normal T cell repertoire development, autoimmunity, or malignancy.
Direct cellular communications between CD45R0 and CD45RA T cell subsets via CD27/CD70.
Authors: Agematsu K , Kobata T , Sugita K , Hirose T , Schlossman S F , Morimoto C 
Published: December 2022

Abstract
The engagement of CD27 with its ligand CD70 is considered to play an important role in T cell costimulation. In the present study, we investigated both the kinetics of CD70 expression and the contribution of its interaction with CD27 in T cell immune responses. CD70 was found to be expressed almost equally on both activated CD4 and CD8 T cells. On subsets of CD4 T cells, however, CD70 expression was induced preferentially on the CD45R0 T cell population after activation, whereas its expression was not noted on CD45RA T cells for almost 2 wk following activation. In long-term culture with media containing T cell growth factor (TCGF) and rIL-2, the expression of CD70 was increased markedly on CD45R0 T cells and minimally expressed on CD45RA T cells. In addition, strong surface expression of CD70 was observed on T cell clones originally derived from CD45R0+ CD4 T cells, whereas T cell clones originally derived from CD45RA+ CD4 T cells showed lower levels of expression. The addition of irradiated, activated CD45R0 T cells to CD45RA T cells caused a down-regulation of CD27 expression and an up-regulation of CD25 expression. These changes were blocked by addition of the anti-CD70 mAb, suggesting that direct contact between CD45R0 T cells and CD45RA T cells via CD27/CD70 occurred, leading to the activation of CD45RA T cells as measured by CD25 expression. These observations strongly support the notion that the engagement of CD27 plays an important regulatory role in the communication of subsets of CD45R0 and CD45RA T cells.
Daudi lymphoma killing triggers the programmed death of cytotoxic V gamma 9/V delta 2 T lymphocytes.
Authors: Ferrarini M , Heltai S , Toninelli E , Sabbadini M G , Pellicciari C , Manfredi A A 
Published: December 2022

Abstract
A common feature of human V gamma 9/V delta 2 gamma delta T lymphocytes is their ability to kill Daudi lymphoma cells. We show here that during this killing a substantial fraction of cytotoxic gamma delta T cells dies as well. Their death has morphologic, cytometric, and biochemical features of apoptosis and depends on TCR triggering. We suggest that interaction with the target physiologically induces the programmed death of the cytotoxic gamma delta effector. The death of activated gamma delta T cells upon challenge with the relevant Ag may represent a negative feedback mechanism and contribute to explain the limited time span of gamma delta T cell expansions during infectious diseases, even when pathogens are not eliminated and persist in the host.
Characterization of the autoreactive T cell repertoire in cyclosporin-induced syngeneic graft-versus-host disease. A highly conserved repertoire mediates autoaggression.
Authors: Fischer A C , Ruvolo P P , Burt R , Horwitz L R , Bright E C , Hess J M , Beschorner W E , Hess A D 
Published: December 2022

Abstract
Syngeneic graft-vs-host disease (SGVHD) is a MHC class II-restricted T cell-mediated autoimmune syndrome that occurs following syngeneic bone marrow transplantation and the administration of cyclosporin (CsA). The present studies evaluated the V beta repertoire of T lymphocytes that mediate SGVHD. To facilitate analysis, SGVHD effector cells were adoptively transferred into thymectomized syngeneic recipients reconstituted with T cell-depleted bone marrow to provide an environment that allows for the selective clonal expansion of autoreactive T cells. Analysis of target tissues and PBL by reverse transcriptase PCR using oligonucleotide V beta-specific primers revealed a predominance of V beta 8.5+ T cells and a minor population expressing V beta 10. The majority of infiltrating lymphocytes in target tissues was confirmed to be V beta 8.5+ by in situ hybridization and by immunoperoxidase staining. A small population of V beta 10+ cells could also be detected. Furthermore, SGVHD effector T splenocytes depleted of lymphocytes expressing either the TCR-alpha beta or the V beta 8.5 determinant could not adoptively transfer SGVHD. Depletion of T cells expressing the V beta 10 determinant delayed the onset of this autoaggression syndrome. Subset analysis of the autoreactive T cell compartment revealed that the V beta 8.5 determinant was expressed on both CD4+ and CD8+ lymphocytes whereas the V beta 10 determinant was principally expressed on a minor population of CD4+ autoreactive T cells. These data were confirmed by limiting dilution analysis. Additional studies examining the effect of CsA on thymic differentiation revealed that although V beta 8.5 is not normally clonally deleted, there was a pronounced shift in the expression of this determinant between CD4 and CD8 single positive thymocytes, suggesting that CsA may inhibit normal positive selection processes for MHC class I and class II reactive T cells.
Expression of the Fas ligand in cells of T cell lineage.
Authors: Suda T , Okazaki T , Naito Y , Yokota T , Arai N , Ozaki S , Nakao K , Nagata S 
Published: December 2022

Abstract
Fas ligand (FasL) is a membrane-type cytokine belonging to the TNF family, and induces apoptosis through its cell-surface receptor, Fas. To determine the cell types that express FasL, various mouse tissues and cell lines were examined by Northern hybridization using a mouse FasL cDNA as a probe. Among tissues, lymphoid organs (thymus, lymph node, spleen), lung, and small intestine express low levels of FasL mRNA, suggesting the role of FasL in the general immune system and mucosal immunity. The testis expressed FasL mRNA most abundantly; however, the size of FasL mRNA in the testis was slightly shorter than those in other tissues. Distribution of FasL mRNA in a panel of cell lines indicated that the FasL expression is rather restricted to the cells of T cell lineage. Activation of the splenocytes with the T cell activators such as PMA and ionomycin, Con A, anti-CD3, or even IL-2 alone induced the expression of the FasL. CD8+ splenocytes expressed the FasL more abundantly than did the CD4+ splenocytes upon activation by Con A and IL-2. Among CD4+ CTL cell lines, the FasL was expressed in all Th1 and Th0, and some Th2 clones.
Compared TCR and CD3 epsilon expression on alpha beta and gamma delta T cells. Evidence for the association of two TCR heterodimers with three CD3 epsilon chains in the TCR/CD3 complex.
Authors: Thibault G , Bardos P 
Published: December 2022

Abstract
Current models for TCR/CD3 complex stoichiometry involve one or alternatively two TCR heterodimer(s) associated with two CD3 epsilon per complex. They mainly constructed on the basis of biochemical studies involving disruption of membrane complexes. The present study was undertaken to quantify the relative proportions of CD3 epsilon and TCR chains on alpha beta and gamma delta lymphocytes in nondenaturing conditions. Quantitative flow cytometry revealed that alpha beta and gamma delta PBL express on an average 1.56 and 1.52 more CD3 epsilon-chain than beta- and delta-chains, respectively. Accordingly, CD3 epsilon to TCR-alpha, TCR-beta, TCR-gamma, and TCR-delta ratios found on three polyclonal cell lines and on Jurkat cells were all very close to 1.50. These results clearly demonstrate that alpha beta as well as gamma delta T cells express approximately 1.50 more CD3 epsilon-chain than each of the TCR chains. They strongly suggest that alpha beta and gamma delta TCR/CD3 complexes involve two TCR heterodimers associated with three CD3 epsilon-chains (or a multiple of this combination). In addition, our results showed that gamma delta PBL expressed about 1.90 more TCR (-delta vs -beta) and CD3 epsilon-chains than alpha beta PBL. Furthermore, TCR-beta expression and CD3 epsilon expression were higher on CD4+ alpha beta PBL than on CD8+ alpha beta PBL, whereas TCR-delta expression and CD3 epsilon expression were both identical on CD8+ gamma delta PBL and on CD8- gamma delta PBL. These results demonstrate that CD8+ or CD8- gamma delta PBL, CD4+ alpha beta PBL and CD8+ alpha beta PBL express decreasing levels of the TCR/CD3 complex.
Representation of rearranged VH gene segments in the human adult antibody repertoire.
Authors: Suzuki I , Pfister L , Glas A , Nottenburg C , Milner E C 
Published: December 2022

Abstract
The heavy chain variable region composition of the human adult Ab repertoire is poorly defined, but recent evidence suggests that peripheral blood B cells may express a nonstochastic assortment of VH genes. In this study, the contribution of individual VH gene segments to the human Ab repertoire has been assessed. As a measure of VH gene utilization, the frequency of occurrence of eight individual VH3 gene segments contained in rearrangements was assessed in the peripheral blood B cells of two adult subjects. In addition, the frequency of occurrence of rearrangements containing nine individual VH4 gene segments was analyzed in one of the subjects. More than 2500 independent rearrangements were analyzed. For controls, amplifications and subsequent identification of nonrearranged VH3 and VH4 genes from the same individuals were also performed. The results of this germ-line analysis indicated that approximately 25 VH3 gene segments and nine VH4 gene segments could be amplified quantitatively. However, usage of elements was not uniform; one VH3 element, V3-23, and one VH4 element, V4-34, were represented among rearrangements more frequently than were other members of their respective families. This pattern of VH utilization was apparent in B cells isolated from the same subject after an 8-mo interval, indicating the relative stability of the repertoire over time. These results indicate that the adult human Ab repertoire is dominated by a few VH genes demonstrating a pattern of nonrandom utilization that could involve preferential rearrangement and/or receptor-dependent selection.
Activation of serine/threonine protein kinases and early growth response 1 gene expression by tumor necrosis factor in human myeloid leukemia cells.
Authors: Saleem A , Yuan Z M , Taneja N , Rubin E , Kufe D W , Kharbanda S M 
Published: December 2022

Abstract
The early growth response 1 (EGR-1) gene is induced by mitogenic and differentiating signals in diverse cell types. The present studies have examined the effects of TNF-alpha on the induction of EGR-1 expression in human myeloid leukemia cells and the potential cytoplasmic signaling cascades that transduce TNF-induced signals to the nucleus. The results demonstrate that treatment of HL-60 cells with TNF is associated with the transient induction of the EGR-1 gene. The results also demonstrate that TNF treatment is associated with activation of the serine/threonine kinase, pp90rsk, which acts upstream to EGR-1 gene induction. Partial purification of pp90rsk by affinity chromatography demonstrated an increase in S6 peptide phosphorylation in response to TNF treatment. Because TNF activates sphingomyelin hydrolysis, we also studied the effects of sphingomyelinase (SMase) on induction of EGR-1 and pp90rsk. The results demonstrate that SMase also activates pp90rsk and induces EGR-1 gene expression. Previous work has demonstrated that mitogen-activated protein (MAP) kinase activates pp90rsk. The present studies further show that treatment with TNF or SMase is associated with induction of both the pp42/44 MAP and the related Jun kinases. Induction of pp42/44 MAP kinase activity is temporally related to activation of pp90rsk and the EGR-1 gene. These findings support the involvement of an MAP kinase/pp90rsk/EGR-1 cascade in the response of myeloid leukemia cells to TNF.
Autoantibody germ-line gene segment encodes VH and VL regions of a human anti-streptococcal monoclonal antibody recognizing streptococcal M protein and human cardiac myosin epitopes.
Authors: Quinn A , Adderson E E , Shackelford P G , Carroll W L , Cunningham M W 
Published: December 2022

Abstract
Cross-reactivity of anti-streptococcal Abs with human cardiac myosin may result in sequelae following group A streptococcal infections. Molecular mimicry between group A streptococcal M protein and cardiac myosin may be the basis for the immunologic cross-reactivity. In this study, a cross-reactive human anti-streptococcal/anti-myosin mAb (10.2.3) was characterized, and the myosin epitopes were recognized by the Ab identified. mAb 10.2.3 reacted with four peptides from the light meromyosin (LMM) tail fragment of human cardiac myosin, including LMM-10 (1411-1428), LMM-23 (1580-1597), LMM-27 (1632-1649), and LMM-30 (1671-1687). Only LMM-30 inhibited binding of mAb 10.2.3 to streptococcal M protein and human cardiac myosin. Human mAb 10.2.3 labeled cytoskeletal structures within rat heart cells in indirect immunofluorescence, and reacted with group A streptococci expressing various M protein serotypes, PepM5, and recombinant M protein. The nucleotide sequence of gene segments encoding the Ig heavy and light chain V region of mAb 10.2.3 was determined. The light chain V segment was encoded by a V kappa 1 gene segment that was 98.5% identical with germ-line gene humig kappa Vi5. The V segment of the heavy chain was encoded by a VH3a gene segment that differed from the VH26 germ-line gene by a single base change. VH26 is expressed preferentially in early development and encodes autoantibodies with anti-DNA and rheumatoid factor specificities. Anti-streptococcal mAb 10.2.3 is an autoantibody encoded by VH and VL genes, with little or no somatic mutation.
Hyperinducibility of HLA class II expression of thyroid follicular cells from Graves' disease. A primary defect?
Authors: Sospedra M , Obiols G , Babi L F , Tolosa E , Vargas F , Roura-Mir C , Lucas-Martin A , Ercilla G , Pujol-Borrell R 
Published: December 2022

Abstract
Thyroid follicular cells (thyrocytes) from Graves' disease (GD) patients' thyroid glands express HLA class II molecules "ectopically." This phenomenon has been attributed to induction by locally produced cytokines and may be relevant to disease pathogenesis. We have compared IFN-gamma-mediated induction of HLA class II in thyrocytes from glands affected with GD and a nonautoimmune disease (MNG), to investigate a possible differential regulation of HLA expression between these two pathologies. HLA induction has been measured in primary thyrocyte cultures and control autologous macrophages stimulated or not stimulated with IFN-gamma. Comparison of flow cytometric data using an improved algorithm demonstrated that expression of HLA class II molecules is more readily induced in thyrocytes from GD than from MNG thyroid glands. This higher inducibility was parallel to a faster and stronger induction of HLA class II message in GD thyrocytes but did not correlate with the levels of HLA class II or class I originally expressed by thyrocytes in the tissue or with the degree of lymphocytic infiltration of the gland. There was no association with a particular HLA class II allele or with the presence of IFN-gamma and IL-2 in the tissue, as assessed by reverse transcription-PCR. No differences in the induction of class II were found in macrophages from each group of patients. These results suggest that an intrinsic feature of thyrocytes from GD patients is an up-regulation of HLA class II expression and that this is a characteristic that may facilitate the triggering of autoimmunity to "hyperinducible" thyroid glands.
CD40 signaling-mediated induction of Bcl-XL, Cdk4, and Cdk6. Implication of their cooperation in selective B cell growth.
Authors: Ishida T , Kobayashi N , Tojo T , Ishida S , Yamamoto T , Inoue J 
Published: December 2022

Abstract
Signals sent through CD40 play crucial roles in B cell differentiation, including blocking apoptosis of germinal center B cells. In this study, using a murine B cell WEHI-231 line that undergoes apoptosis by the cross-linking of surface Ag receptors (sIgM), we have demonstrated that CD40 signalings are linked to induction of the Bcl-xL, Cdk4, and Cdk6 proteins whose expression was significantly suppressed by the apoptotic signal through sIgM. Mutational analyses of CD40 revealed that the domain of human CD40 required for blocking apoptosis of WEHI-231 cells coincides with that required for Bcl-xL induction. Signals through sIgM arrest cells in the G1 phase of the cell cycle, which is followed by apoptosis. However, while constitutive expression of Bcl-XL leads to the inhibition of apoptosis. Nevertheless, Bcl-xL fails to induce S phase entry. By CD40 signalings, both Cdk4 and Cdk6 resume their normal expression levels, which are sufficient for passing the restriction point in G1 even in the presence of the apoptotic signals mediated by sIgM. These results suggest that cooperation of Bcl-xL, Cdk4, and Cdk6 induced by CD40 signaling plays a key role in CD40-mediated selective growth of B cells.