bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice.
Authors: Tivol E A , Boyd S D , McKeon S , Borriello F , Nickerson P , Strom T B , Sharpe A H 
Published: December 2022

Abstract
Mice lacking CTLA-4 develop a fatal spontaneous lymphoproliferative disease with massive lymphocytic infiltrates and tissue destruction in many organs. CTLA-4-deficient (-/-) splenocytes and lymph node cells proliferate without added stimuli in vitro. We report here that CTLA4Ig treatment of CTLA-4 -/- mice prevents lymphoproliferation and fatal multiorgan tissue damage in vivo and proliferation of CTLA-4 -/- splenocytes and lymph node cells in vitro. Therefore, stimulation via CD28-B7 interactions appears necessary for CTLA-4 -/- T cell proliferation and the production of lymphoproliferative disease in vivo. When CTLA4Ig treatment is terminated, CTLA-4 -/- T cells become activated and lymphoproliferative disease develops. The lack of long term protective effects of CTLA4Ig treatment suggests that CTLA-4 is needed for the induction and or maintenance of tolerance.
Allelic variation in the mouse Tap-1 and Tap-2 transporter genes.
Authors: Marusina K , Iyer M , Monaco J J 
Published: December 2022

Abstract
The TAP1 and TAP2 proteins form a heterodimer that transports short peptides from the cytosol into the endoplasmic reticulum lumen. Extensive allelic polymorphism of the rat TAP transporter has been shown to affect the repertoire of peptides presented by MHC class I molecules. Structural polymorphism in the human TAP genes is much more limited and has not been observed to have functional consequences. We have examined the polymorphism in mouse TAP1 and TAP2 in inbred mice. While the number of polymorphic positions in these molecules is more similar to that in human than to that in the rat, all strains examined have a structurally unique TAP transporter, suggesting the possibility of functional polymorphism. Furthermore, allelic variations in the mouse transporter are predominantly located in or adjacent to membrane-spanning domains, although no significant bias in the ratio of nonsynonymous to synonymous substitutions is observed. We also report that mouse TAP1 begins 172 amino acids upstream of the previously published start site and report the genomic organization of mouse Tap-1 and Tap-2.
Sequential development of structural and functional alterations in T cells from tumor-bearing mice.
Authors: Correa M R , Ochoa A C , Ghosh P , Mizoguchi H , Harvey L , Longo D L 
Published: December 2022

Abstract
The TCR alpha beta or -gamma delta chains bind the peptide ligand, whereas the associated CD3 delta epsilon gamma and TCR zeta subunits couple the TCR to intracellular signal transduction components. Recently, several groups have described marked alterations in signal transduction elements in T cells from cancer patients or in mice bearing tumor for a few weeks (&gt;26 days). The sequence in which these alterations develop is unknown. The aim of this study was to explore the kinetics of the development of alterations in signal transduction molecules (TCR zeta chain, NF kappaB family proteins, and tyrosine kinase p56(lck)) in mice bearing MC38 colon adenocarcinoma. The results demonstrate that alterations in NF kappaB family proteins, specifically the failure of p65 translocation to the nucleus, occur earlier and more frequently than the decrease in zeta-chain. These defects are paralleled by an impaired ability to produce Th1 cytokines (IL-2 and IFN-gamma). These initial changes are followed by the eventual loss of TCR zeta chain and p56(lck) and a marked decrease in cytotoxic function. An increased rate of lysosomal degradation is one of the mechanisms responsible for the loss of zeta-chain.
Listeria monocytogenes infection of cultured endothelial cells stimulates neutrophil adhesion and adhesion molecule expression.
Authors: Drevets D A 
Published: December 2022

Abstract
Microbial infection of the endothelium with the resultant up-regulation of adhesion molecule expression and stimulated leukocyte adhesion to endothelial cells can promote an inflammatory response. Previous work demonstrated that Listeria monocytogenes can replicate within cultured endothelial cells; thus, we tested whether L. monocytogenes infection of HUVEC stimulated an inflammatory phenotype on these cells. Infection with 10(4) CFU of bacteria increased neutrophil adhesion to HUVEC 40-fold and up-regulated E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression. Approximately 80% of neutrophil adhesion to infected HUVEC was blocked by anti-E-selectin mAb, 35% was blocked by anti-CD18 mAb, and anti-vascular cell adhesion molecule-1 mAb was without effect. Microscopy of infected HUVEC monolayers showed that neutrophils bound to infected and uninfected cells and that infected and uninfected HUVEC expressed E-selectin. Interestingly, uninfected HUVEC that bound neutrophils or expressed E-selectin typically were adjacent to infected cells. However, infected monolayers did not produce soluble factors that stimulated E-selectin expression on uninfected cells. Nuclear translocation of the p65 subunit of the transcription factor NF-kappaB accompanied the HUVEC response, and hemolysin secretion appeared critical for stimulating HUVEC. These studies show that L. monocytogenes infection stimulates up-regulation of adhesion molecule expression on endothelial cells, resulting in neutrophil adhesion to them. This response includes induction of an inflammatory phenotype on uninfected cells and may be triggered by listeriolysin O-mediated activation of host response mechanisms. Additionally, cell-to-cell spread of L. monocytogenes throughout the monolayer, without stimulating secondarily infected endothelial cells for neutrophil adhesion, is a possible means of immune avoidance.
Cytolytically active memory CTL present in lymphocytic choriomeningitis virus-immune mice after clearance of virus infection.
Authors: Selin L K , Welsh R M 
Published: December 2022

Abstract
Generally, it has been assumed that memory T cells are dormant and inactive cells in the absence of their specific Ag. Recent work has challenged this assumption by showing that a portion of the CD8+ memory T cell pool is in cycle. In this study, we demonstrate that a significant number of blast-size memory CD8+ T cells in mice, long after lymphocytic choriomeningitis virus (LCMV) infection, mediate cytolysis against highly sensitive targets without any in vivo or in vitro restimulation and expansion with Ag. Peptide-coated RMA-S targets were sufficiently sensitive to detect low but significant cytolytic activity in bulk 51Cr release assays in nonstimulated LCMV-specific splenic memory CTL populations. Most of the directly cytotoxic activity was against the GP33 epitope, and this persisted throughout the lifetime of the mouse following infection. The cytotoxic activity was not inhibited by cyclosporin A, indicating that these cells were already in an active state and not dependent on further stimulation in vitro. It was formally shown that the cytotoxic activity was mediated by the CD8+ CTL by sorting for the blast-size CD8+ population and by blocking target cell lysis with anti-CD8 Ab. Thus, at any time after the original infection some portion of the memory CD8+ T cell pool is cycling, and it remains cytolytically active long after resolution of the original infection. These CTL may provide a rapidly acting defense mechanism against reinfection.
Role of a sialyl Lewis(x)-like epitope selectively expressed on vascular endothelial cells in local skin inflammation of the rat.
Authors: Akahori T , Yuzawa Y , Nishikawa K , Tamatani T , Kannagi R , Miyasaka M , Okada H , Hotta N , Matsuo S 
Published: December 2022

Abstract
The role of the inducible L-selectin ligand was studied in complement-dependent acute dermatitis in rats. Although mAbs against typical sialyl Lewis(x) (CSLEX-1 and SNH-3) did not react with skin venules, a sialyl Lewis(x)-like epitope defined by mAb 2H5 (2H5-Ag) was de novo expressed on the endothelial cells of skin venules in the area of inflammation. Expression of 2H5-Ag increased concomitantly with the progression of inflammation. 2H5-Ag was identified at the 75-, 150-, and 180-kDa bands when inflammatory skin tissue was analyzed by Western blotting. In contrast, P- and E-selectins were not detectable. The role of 2H5-Ag in this model was studied in in vitro and in vivo methods. First, 2H5 was i.v. injected 15 min before induction of dermatitis. 2H5 bound to skin venules and significantly reduced the neutrophil infiltration and plasma protein leakage. In contrast, CSLEX-1, mAb ARP2-4 (P-selectin blocker), or mAb ARE-5 (E-selectin blocker) had no effects. Second, adhesion of isolated rat neutrophils to the inflammatory skin section was inhibited significantly when the sections, but not neutrophils, were preincubated with 2H5. Third, fluorescein-labeled normal rat neutrophils were injected into a rat 10 h after induction of dermatitis. The number of labeled neutrophils infiltrated into the inflammatory site was reduced significantly when they were preincubated with HRL-3 (blocking mAb against rat L-selectin), but not with 2H5 or HRL-4 (nonblocking mAb against rat L-selectin). These data show that de novo expressed 2H5-Ag/L-selectin adhesion pathway contributes to the development of acute complement-dependent inflammation in the skin.
Tyrosine kinase-dependent regulation of L-selectin expression through the Leu-13 signal transduction molecule: evidence for a protein kinase C-independent mechanism of L-selectin shedding.
Authors: Frey M , Appenheimer M M , Evans S S 
Published: December 2022

Abstract
The L-selectin adhesion molecule mediates lymphocyte extravasation in peripheral lymph nodes, and has also been implicated in directing leukocyte recruitment to inflammatory tissues and metastasis of lymphoid malignancies. In this study, we demonstrate a novel level of regulation of L-selectin expression that involves the 16-kDa Leu-13 signal transduction molecule. Leu-13 is a member of a multimeric cell surface complex in lymphocytes that includes TAPA-1 (target of antiproliferative Ab-1, CD81) as well as lineage-specific proteins. In the present study, mAb-induced ligation of Leu-13 was shown to rapidly down-regulate L-selectin surface density on normal and malignant human lymphocytes, and to markedly inhibit L-selectin-mediated adhesion of lymphocytes to soluble carbohydrate ligands (i.e., PPME, phosphomonoester core polysaccharide) and to lymph node high endothelial venules. Through the use of genistein and staurosporine, potent inhibitors of tyrosine kinases (TK) and protein kinase C (PKC), respectively, Leu-13-induced L-selectin down-modulation was demonstrated to involve a TK-dependent, PKC-independent pathway, and was attributed to increased L-selectin shedding from surface membranes. Notably, direct L-selectin ligation, modeling cross-linking interactions with endothelial cell ligands, similarly down-regulates L-selectin surface expression through a TK-dependent, PKC-independent mechanism. In sharp contrast, PMA and anti-CD3 mAb down-regulate L-selectin via a staurosporine-sensitive, genistein-resistant pathway that is closely linked to lymphocyte proliferation. Taken together, these results demonstrate a novel role for Leu-13- and L-selectin-induced TK activity in control of L-selectin expression, thus providing insight into the complex molecular mechanisms that potentially regulate L-selectin-dependent lymphocyte homing in vivo.
Human alveolar macrophages synthesize endothelins by thrombin.
Authors: Kobayashi Y , Sakamoto Y , Shibasaki M , Kimura I , Matsuo H 
Published: December 2022

Abstract
Alveolar macrophages (AM) play pivotal roles in the defense mechanism and the regulation of inflammatory processes in the airways. Macrophages express receptors for thrombin on their surfaces, and thrombin induces the chemotaxis and the proliferation of macrophages. Thrombin acts on vascular endothelial cells to synthesize endothelin (ET)-1. AM have been known to express prepro ET-1 mRNA. Thus, we hypothesized that thrombin stimulates AM so as to synthesize ET. Surgically resected human lungs were irrigated by saline to remove intravascular blood, then saline was instilled into the bronchus, and the fluids were recovered. AM were separated by Percoll density centrifugation (density, 1.060 g/ml). AM were resuspended in culture medium without FCS in the presence or absence of thrombin. ET was synthesized by thrombin in a concentration-dependent manner, and the amounts of ET synthesized by thrombin (10 U/ml) were equivalent to those by LPS (10 microg/ml). Dexamethasone (10(-6)-10(-10) M), IL-4 (100 U/ml), and TGF-beta (10 ng/ml) significantly suppressed the ET synthesis by thrombin (p &lt; 0.05). In contrast, 1,25-dihydroxyvitamin D3 (10(-8)-10(-10) M) enhanced the ET synthesis up to approximately 300%. The analysis using high pressure liquid chromatography revealed that AM-derived ET consists of ET-1, ET-2, and ET-3. Major constituents were ET-2 and ET-1, and the ratio of ET-2/ET-1 was 1.7 +/- 0.4 (mean +/- SE). These results indicate that thrombin is a potent agonist for AM to synthesize ET.
IFN-gamma is essential for the development of autoimmune glomerulonephritis in MRL/Ipr mice.
Authors: Haas C , Ryffel B , Le Hir M 
Published: December 2022

Abstract
MRL/lpr mice develop lymphoproliferation and accelerated autoimmune glomerulonephritis from which they ultimately die. To investigate the role of IFN-gamma in the manifestation of the disease, we generated MRL/lpr mice lacking the IFN-gamma receptor (MRL/lpr gammaR -/-). The absence of IFN-gamma signaling had no effect on generalized lymphoproliferation, expansion of CD4- CD8- double-negative T cells, or hypergammaglobulinemia. By contrast, glomerulonephritis as detected by proteinuria and histology was absent in MRL/lpr gammaR -/- mice. While serum IgG1 anti-dsDNA Abs were increased in all three strains of MRL/lpr mice (gammaR +/+, +/-, -/-), those of the IgG2a and IgG3 isotypes were low in MRL/lpr gammaR -/- mice. Immune complexes and C3 deposition were dramatically reduced in the glomerular capillaries of MRL/lpr gammaR -/- mice compared with MRL/lpr gammaR +/+ and +/- mice. Therefore, IFN-gamma plays a key regulatory role in the development of nephritis in MRL/lpr mice. Low levels of IFN-gamma-dependent IgG2a and IgG3 autoantibodies in MRL/lpr gammaR -/- mice might protect them from the pathogenic features of IgG3 cryoglobulins and complement-activating IgG2a and IgG3.
Mice lacking reduced nicotinamide adenine dinucleotide phosphate oxidase activity show increased susceptibility to early infection with Listeria monocytogenes.
Authors: Dinauer M C , Deck M B , Unanue E R 
Published: December 2022

Abstract
Mice lacking the gp91 protein of reduced nicotinamide adenine dinucleotide phosphate oxidase showed heightened susceptibility to Listeria infection. The enhanced susceptibility was noted 2 days after infection, the usual peak time of the neutrophil-dependent lesion in the liver. Infected gp91phox -/- mice had an increase of approximately 30-fold in Listeria in the liver and an increase in the number of microabscesses. The study of the gp91phox mice underscores the early role of the neutrophil and of an oxidative burst in this infection with an intracellular pathogen. These results contrast with others showing that the late macrophage-dependent stage of the infection is dependent on nitric oxide.
Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression.
Authors: Groux H , Sornasse T , Cottrez F , de Vries J E , Coffman R L , Roncarolo M G , Yssel H 
Published: December 2022

Abstract
Differential expression of cytokine receptors accounts for an important regulatory mechanism in differentiation of Th1/Th2 subsets. Here, we report that human Th0 and Th2 clones constitutively express transcripts for the IFN-gammaR beta-chain, whereas mRNA for this signaling component of the IFN-gamma receptor is absent in Th1 clones. Activation of T cell clones, however, resulted in a transient induction or enhancement of IFN-gammaR beta-chain mRNA expression in Th1 clones and Th0/Th2 clones, respectively. IL-12-mediated Th1 cell differentiation of naive CD4+, CD45RA+ cord blood T cells, which constitutively express IFN-gammaR beta-chain mRNA, resulted in a loss of expression of this cytokine receptor chain after 6 to 12 days of culture. In contrast, Th2 populations, differentiated from CD4+, CD45RA+ cord blood T cells in the presence of IL-4, continued to express high levels of IFN-gammaR beta-chain transcripts. The loss of IFN-gammaR beta-chain expression in Th1 populations was accompanied by a failure of IFN-gamma to induce the expression of the IFN-gamma-inducible gene, IFN response factor-1, whereas IFN-gamma was effective in inducing IFN response factor-1 mRNA expression in Th0 and Th2 cells. These results indicate that down-regulation of the IFN-gammaR beta-chain correlates with impaired IFN-gamma-induced signaling in Th1 cells. Finally, Th2 populations, generated in the presence of both IL-4 and IFN-gamma, expressed levels of IFN-gammaR beta-chain transcripts similar to those produced by cells differentiated in the presence of IL-4 only, demonstrating that IFN-gamma does not modulate the expression of its receptor. Together, these data indicate that human Th0/Th2 and Th1 subsets, respectively, can be distinguished based on the expression of the IFN-gammaR beta-chain.
Differential target cell sensitivity to CTL-activated death pathways in hepatitis B virus transgenic mice.
Authors: Nakamoto Y , Guidotti L G , Pasquetto V , Schreiber R D , Chisari F V 
Published: December 2022

Abstract
The current study was designed to explore the relative contribution of Fas ligand (FasL), perforin, IFN-gamma, and TNF-alpha-induced death pathways in the pathogenesis of CTL-induced liver disease. Hepatitis B virus-specific CTL that are genetically unable to produce either FasL, perforin, or IFN-gamma were injected into Fas-competent and Fas-deficient hepatitis B virus transgenic mice that are either sensitive or resistant to the cytopathic effects of IFN-gamma based on the extent to which their hepatocytes retain hepatitis B surface Ag (HBsAg). The results of these experiments indicate that FasL- and perforin-dependent signals are primarily responsible for the induction of liver disease in the absence of HBsAg retention, but both signaling pathways must be activated simultaneously by the CTL in order to kill the hepatocyte in vivo. In contrast, neither FasL nor perforin are required to kill hepatocytes that retain HBsAg as long as the CTL secrete IFN-gamma on antigen recognition. Finally the results indicate that, irrespective of their HBsAg content, hepatocytes are much less sensitive to destruction by TNF-alpha than by the other death pathways. While all of these death pathways appear to be operative during a normal CTL response, the current experiments suggest that the target cell determines which pathway is dominant and selects its mode of execution.
Association of the common gamma-chain with the human IL-7 receptor is modulated by T cell activation.
Authors: Page T H , Lali F V , Groome N , Foxwell B M 
Published: December 2022

Abstract
IL-7 acts on both resting and activated T cells. The functional IL-7R is reported to consist of two subunits, the ligand binding IL-7R and the common gamma-chain (gamma c chain), where IL-7R:gamma c chain association is driven solely by ligand binding. However, we now demonstrate that in primary T cells this event is also controlled by cellular activation. We show that IL-7R:gamma c chain complexes are detected in activated, but not in resting, T cells despite similar levels of gamma c chain expression, implying that the gamma c chain is not associated with the IL-7R in unstimulated T cells. Furthermore, IL-7R:gamma c chain association correlates with the expression of JAK-3 in T cells, but not in transfected COS-7 cells. The finding that IL-7R:gamma c chain assembly is controlled at a level beyond that of receptor expression has important implications for the control of cytokine function in T cells.
Stress and autoimmunity: the neuropeptides corticotropin-releasing factor and urocortin suppress encephalomyelitis via effects on both the hypothalamic-pituitary-adrenal axis and the immune system.
Authors: Poliak S , Mor F , Conlon P , Wong T , Ling N , Rivier J , Vale W , Steinman L 
Published: December 2022

Abstract
Corticotropin-releasing factor (CRF) exerts a major role in the stress response. Both CRF and urocortin, a newly discovered neuropeptide homologous to CRF, suppressed experimental autoimmune encephalomyelitis (EAE). Suppression of paralysis with CRF involved stimulation of the hypothalamic-pituitary-adrenal axis and inhibitory effects on an encephalitogenic T cell line. While CRF increased glucocorticoid production, which is known to block EAE, it also suppressed EAE in adrenalectomized rats, where glucocorticoid stimulation via CRF plays no role. Moreover, the encephalitogenicity of a T cell line exposed to CRF in vitro was reduced. Stress may influence autoimmune disease through the hypothalamic-pituitary-adrenal axis and directly via the immune system.
Phosphatidylinositol-based glycolipid-anchored proteins enhance proximal TCR signaling events.
Authors: Romagnoli P , Bron C 
Published: December 2022

Abstract
Previous reports suggested that T lymphocyte activation through phosphatidylinositol-based glycolipid (GPI)-anchored molecules is dependent on surface expression of the TCR. Here we show that stimulation of the TCR in five mutant cell lines with deficiencies in GPI biosynthesis fails to induce tyrosine phosphorylation of the TCR zeta-chain and ZAP-70, indicating that early events in TCR-mediated signal transduction are affected in these mutants. The Src kinases Fyn and Lck coprecipitating with activated TCR complexes are significantly less kinase active in the GPI-processing mutants than in wild-type cells. These data suggest that GPI-anchored proteins may play an important role in the initiation of TCR signal transduction by contributing to the accumulation of Src kinase activity in the TCR complex.
Aberrant TCR-mediated signaling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-zeta, and ZAP-70.
Authors: Stone J D , Conroy L A , Byth K F , Hederer R A , Howlett S , Takemoto Y , Holmes N , Alexander D R 
Published: December 2022

Abstract
CD45 is a transmembrane phosphotyrosine phosphatase expressed on all nucleated hemopoietic cells. Targeting of CD45 exon 9 has generated a mouse line completely lacking CD45 expression (CD45-null) in which there are severe abnormalities in T cell development. Defects in TCR-mediated signals underlying these abnormalities have now been investigated using CD45-null T cells. No T cell proliferation was detected in response to a CD3 mAb. In thymocytes the p56(lck) and p59(fyn) tyrosine kinases were hyperphosphorylated, and p56(lck) was in its inactive conformation. Both basal and TCR-stimulated tyrosine phosphorylation of TCR-zeta and CD3-epsilon were much reduced, and TCR stimulation induced an abnormal p18 phosphoisomer of TCR-zeta previously noted in T cells stimulated by altered peptide ligands. These defects were associated with the failure of ZAP-70 kinase recruitment to the TCR-zeta chain. TCR coupling to the tyrosine phosphorylation of several proteins, including HS1 and p120(cbl), was also much reduced. However, TCR-induced signaling was not ablated, and significant inositol phosphate and calcium signals were observed in CD45-null thymocytes. Our molecular analysis suggests that the threshold for TCR signal transduction is greatly increased in CD45-null T cells, thus explaining the profound defects in thymic development.