bluuebunny/crossref_metadata_2025_split huggingface dataset:
Susceptibility to Pneumocystis carinii in Mice Is Dependent on Simultaneous Deletion of IFN-γ and Type 1 and 2 TNF Receptor Genes
Authors: Rudmann Daniel G. , Preston Angela M. , Moore Mark W. , Beck James M. 
Published: January 2023

Abstract
Pneumocystis carinii pneumonia is an important cause of morbidity and mortality in immunosuppressed patients, particularly HIV-infected individuals. An improved understanding of pulmonary host response, including the cytokines required for defense, could suggest novel immunotherapeutic approaches to this infection. The cytokines IFN-γ and TNF have contributory roles in host defense against P. carinii, but their combined and interactive importance is unclear. To test the roles of these cytokines in defense against P. carinii directly, organisms were inoculated intratracheally into wild-type mice and into three groups of gene-deleted mice: those lacking genes for IFN-γ (IFN-γ−/−), for TNF receptors 1 and 2 (TNFR−/−), and for both IFN-γ and TNFR (TNFR-IFN-γ−/−). Four weeks after P. carinii inoculation, lungs of the wild-type, IFN-γ−/−, and TNFR−/− mice demonstrated clearance of P. carinii and only mild inflammation. However, TNFR-IFN-γ−/− mice demonstrated severe P. carinii infection and lung inflammation. Our findings demonstrate conclusively that deletion of either IFN-γ or TNF activity alone does not block clearance of P. carinii. However, simultaneous deletion of IFN-γ and TNF receptor genes results in susceptibility to P. carinii. Rather than focusing exclusively on individual cytokines, our data suggest that immunotherapy targeted at maximizing both the IFN-γ and TNF responses to P. carinii may be required to augment host defense against this important opportunistic pathogen.
Differential Expression and Function of L-Selectin on CD56bright and CD56dim Natural Killer Cell Subsets
Authors: Frey Margaret , Packianathan Nalini B. , Fehniger Todd A. , Ross Mary E. , Wang Wan-Chao , Stewart Carleton C. , Caligiuri Michael A. , Evans Sharon S. 
Published: January 2023

AbstractNK cells are the first line of defense against foreign cells, virally infected cells, and tumors. The mechanisms whereby NK cells accumulate in extralymphoid sites in response to pathogenic stimuli are not well understood. The L-selectin adhesion molecule (CD62L) plays a primary role in mediating the initial interaction of leukocytes with vascular endothelium, a crucial step in the extravasation of immune effector cells into tissues. In this report, we show L-selectin to be uniquely expressed on a subset of resting human NK cells (CD56bright). Notably, CD56bright NK cells expressed L-selectin at a higher density than all other peripheral blood leukocytes. NK activation by PMA, IL-2, IL-15, or TGF-β down-regulated L-selectin on the CD56bright subset, while increased L-selectin levels were observed in both the CD56bright and CD56dim NK subsets in response to IL-12, IL-10, or IFN-α. Moreover, CD56bright NK cells bound with high efficiency to physiologic L-selectin ligands on peripheral lymph node high endothelial venules (HEV). In sharp contrast, CD56dim NK cells adhered poorly to HEV and were predominantly L-selectin− or expressed L-selectin only at low density. In CD56bright cells and a subpopulation of CD56dim cells, L-selectin ligation by mAb cross-linking activated lymphocyte function-associated Ag 1 (LFA-1), a second adhesion molecule required for leukocyte extravasation. LFA-1 was expressed on both NK subsets, although its density was constitutively higher on CD56dim cells. Taken together, evidence of differential expression of L-selectin and LFA-1 on CD56bright and CD56dim NK subsets strongly suggests unique migratory properties and functions of these cells during the early immune response to foreign pathogens.
Oral Administration of the Bacterial Superantigen Staphylococcal Enterotoxin B Induces Activation and Cytokine Production by T Cells in Murine Gut-Associated Lymphoid Tissue
Authors: Spiekermann Gerburg M. , Nagler-Anderson Cathryn 
Published: January 2023

Abstract
The toxicity of the staphylococcal enterotoxins (SEs) has been linked to the activation of large numbers of T cells in the peripheral lymphoid tissues. Because the primary manifestations of foodborne enterotoxic poisoning are associated with the gastrointestinal tract, we have compared the responses of T cells in the gut-associated lymphoid tissue and in the periphery to intragastric (i.g.) and i.p. administration of SEB. Intraperitoneal SEB results in an early expansion of peripheral Vβ8+ T cells and Th1 cytokine secretion followed by deletion at 7–10 days. We found that i.g. SEB rapidly (within 4 h) leads to the expansion and activation of Vβ8+ T cells in the Peyer’s patch and mesenteric lymph nodes. Analysis of cytokine mRNA in purified Vβ8+ T cells by competitive RT-PCR showed that, 4 h after i.g. SEB, the induction of mRNA for IL-2 and IFN-γ is about 10-fold greater in mucosal than in peripheral lymphoid tissue. Our results show that activated mucosal T cells expand and up-regulate cytokine mRNA in response to luminal exposure to SEB, suggesting a role for the gut-associated lymphoid tissue in the gastrointestinal manifestations of enterotoxic poisoning.
Astrocytes Express Elements of the Class II Endocytic Pathway and Process Central Nervous System Autoantigen for Presentation to Encephalitogenic T Cells
Authors: Soos Jeanne M. , Morrow Jennifer , Ashley Timothy A. , Szente Brian E. , Bikoff Elizabeth K. , Zamvil Scott S. 
Published: January 2023

AbstractAstrocytes are nonprofessional APCs that may participate in Ag presentation and activation of pathogenic CD4+ T cells involved in central nervous system (CNS) inflammatory diseases. Using immortalized pure astrocytes as a complement to the study of primary astrocytes, we investigated whether these astrocytes express elements involved in the class II endocytic pathway and if they are capable of processing native myelin basic protein (MBP), a step that could be necessary for initiating or perpetuating T cell recognition of this self-Ag in vivo. Upon IFN-γ-stimulation, primary and immortalized astrocytes up-regulate class II transactivator (CIITA), invariant chain (Ii) (p31 and p41), H-2Ma, and H-2Mb. Analysis of CIITA cDNA sequences demonstrated that CIITA transcription in astrocytes is directed by a promoter (type IV) that mediates IFN-γ-inducible CIITA expression and encodes a CIITA protein that differs in its N-terminal sequence from CIITA reported in professional APC. Comparing live and fixed APC for Ag presentation, we show that Ag processing by APC is required for presentation of native MBP to autopathogenic T cells specific for the major MBP epitope, Ac1-11. We have observed that primary astrocytes and some, but not all, astrocyte lines in the absence of contaminating microglia are capable of processing and presenting native MBP, suggesting that there may be heterogeneity. Our study provides definitive evidence that astrocytes are capable of processing CNS autoantigen, indicating that astrocytes have potential for processing and presentation of CNS autoantigen to proinflammatory T cells in CNS autoimmune disease.
External and Internal Calibration of the MHC Class I-Specific Receptor Ly49A on Murine Natural Killer Cells
Authors: Kåse Anna , Johansson Maria H. , Olsson-Alheim Mats Y. , Kärre Klas , Höglund Petter 
Published: January 2023

AbstractExpression of the H-2Dd-specific inhibitory receptor Ly49A on murine NK cells is subject to MHC class I-dependent modulation in vivo. As a result, NK cells in H-2Dd-transgenic mice express low cell surface levels of Ly49A, whereas NK cells from nontransgenic C57BL/6 (B6) mice express high levels. The purpose of this study was to assess the role of MHC class I molecules on the NK cell itself vs those on surrounding cells in this calibration and to test whether the Ly49A levels are subject to regulation in mature NK cells also. Analysis of transgenic mice with mosaic expression of an H-2Dd/Ld transgene showed that MHC class I molecules on surrounding cells (external ligands) and on the NK cell itself (internal ligands) played distinct roles in the determination of Ly49A levels. External ligands were involved in down-regulation of Ly49A levels in vivo, whereas internal ligands kept the down-regulated levels of Ly49A low upon NK cell activation in vitro. Furthermore, in an experimental system based on adoptive transfer of spleen cells, receptor down-regulation of Ly49A occurred as a rapid adaptation process in mature NK cells after interaction with the H-2Dd ligand in vivo. This suggests that Ly49 levels are not fixed but can be changed in mature NK cells when they are exposed to a changed MHC class I environment.
The IL-4 Rapidly Produced in BALB/c Mice After Infection with Leishmania major Down-Regulates IL-12 Receptor β2-Chain Expression on CD4+ T Cells Resulting in a State of Unresponsiveness to IL-12
Authors: Himmelrich Hayo , Parra-Lopez Carlos , Tacchini-Cottier Fabienne , Louis Jacques A. , Launois Pascal 
Published: January 2023

Abstract
Within 1 day of infection with Leishmania major, susceptible BALB/c mice produce a burst of IL-4 in their draining lymph nodes, resulting in a state of unresponsiveness to IL-12 in parasite-specific CD4+ T cells within 48 h. In this report we examined the molecular mechanism underlying this IL-12 unresponsiveness. Extinction of IL-12 signaling in BALB/c mice is due to a rapid down-regulation of IL-12R β2-chain mRNA expression in CD4+ T cells. In contrast, IL-12R β2-chain mRNA expression was maintained on CD4+ T cells from resistant C57BL/6 mice. The down-regulation of the IL-12R β2-chain mRNA expression in BALB/c CD4+ T cells is a consequence of the early IL-4 production. In this murine model of infection, a strict correlation is shown in vivo between expression of the IL-12R β2-chain in CD4+ T cells and the development of a Th1 response and down-regulation of the mRNA β2-chain expression and the maturation of a Th2 response. Treatment of BALB/c mice with IFN-γ, even when IL-4 has been produced for 48 h, resulted in maintenance of IL-12R β2-chain mRNA expression and IL-12 responsiveness. The data presented here support the hypothesis that the genetically determined susceptibility of BALB/c mice to infection with L. major is primarily based on an up-regulation of IL-4 production, which secondarily induces extinction of IL-12 signaling.
FLT3-Ligand Administration Inhibits Liver Metastases: Role of NK Cells
Authors: Péron Jean-Marie , Esche Clemens , Subbotin Vladimir M. , Maliszewski Charles , Lotze Michael T. , Shurin Michael R. 
Published: January 2023

Abstract
FLT3-ligand (FL) is a recently described cytokine that stimulates the proliferation and differentiation of hematopoietic progenitors both in vivo and in vitro and, when administered to mice, induces an accumulation of dendritic cells (DC) in different lymphoid and nonlymphoid organs and tissues, including the liver. We have studied the antitumor effect of FL administered alone or in combination with IL-12 in a day 3 murine liver metastasis model. FL significantly reduced the number of hepatic metastases (36.00 ± 11.00 vs 92.00 ± 10.19 in control group, p &lt; 0.05). Histologic evaluation of the livers revealed that FL induced a significant infiltration of the tumor border by lymphocytes and DC associated with increased number of apoptotic figures. Immunohistochemical analysis demonstrated that FL significantly enhanced the number of DC in the liver parenchyma and within the liver metastases, as well as the number of CD4+ and CD8+ T lymphocytes. These data support the suggestion that DC may be directly involved in the antitumor effect of FL. Interestingly, the antitumor effect of FL was greatly reduced by the NK depletion. Combination of FL and IL-12 resulted in greater antitumor efficacy than these cytokines alone. In summary, we have shown that FL has significant antitumor effect on preexisting murine C3 liver tumors that is mediated by NK cells. We have also demonstrated that the FL/IL-12 combination has an enhanced antitumor activity in the same murine tumor model.
Interaction of the Fungal PathogenCandida albicanswith Integrin CD11b/CD18: Recognition by the I Domain Is Modulated by the Lectin-Like Domain and the CD18 Subunit
Authors: Forsyth Christopher B. , Plow Edward F. , Zhang Li 
Published: January 2023

AbstractInteractions of microorganisms with integrins are central to the host defense mechanisms. The leukocyte integrin CD11b/CD18 is the principal adhesion receptor on leukocytes for Candida albicans, a major opportunistic pathogen. In this study we have investigated the roles of three regions within the receptor, the inserted (I) and lectin-like domains within the CD11b subunit, and the CD18 subunit, in CD11b/CD18-C. albicans interactions. We report four major findings. 1) A mutation in CD18 exerts a dominant negative effect on the function of the CD11b/CD18 complex. This interpretation is based on the observation that in the absence of CD18, the CD11b subunit alone binds C. albicans well, but a single point mutation at Ser138 of CD18 abolishes CD11b/CD18 binding of the fungus. 2) The lectin-like domain is not sufficient for CD11b/CD18-C. albicans interactions. Rather, the lectin-like domain appears to influence CD11b/CD18 binding activity by modulating the function of the I domain. 3) The I domain is the primary binding site for C. albicans in the receptor and is sufficient to support an efficient interaction. 4) We have identified specific amino acid sequences within the I domain that engage the microorganism. Compared with other ligands of CD11b/CD18, C. albicans has some unique as well as common contact sites within the I domain of the receptor. Such unique contact sites may underlie the ability of C. albicans to modulate CD11b/CD18 function and raise the possibility for selective interference of the microorganism-host leukocyte interactions.
Host Genetic Determinants of Vaccine-Induced Eosinophilia During Respiratory Syncytial Virus Infection
Authors: Hussell Tracy , Georgiou Andrew , Sparer Tim E. , Matthews Stephen , Pala Pietro , Openshaw Peter J. M. 
Published: January 2023

Abstract
In BALB/c mice, sensitization with the attachment protein (G) of respiratory syncytial virus (RSV) leads to CD4+ T cell-mediated lung eosinophilia during subsequent challenge with RSV. To determine the host genetic influences on this model of lung eosinophilia, we tested 15 different inbred mouse strains. Eosinophilia developed in all H-2d (BALB/c, DBA/2n, and B10.D2), but not in H-2k (CBA/Ca, CBA/J, C3H, BALB.K, or B10.BR) mouse strains. Among H-2b mice, 129 and BALB.B developed eosinophilia, whereas C57BL/6 and C57BL/10 did not. Testing first generation crosses between sensitive and resistant strains showed that eosinophilia developed in all H-2dxk (n = 5), irrespective of background genes, but not in H-2dxb (n = 2) mice. In vivo depletion of CD8+ T cells or IFN-γ rendered C57BL/6, but not BALB.K mice, susceptible to eosinophilia. Analysis of B10 recombinant mice showed that the Dd allele (in B10.A(5R) mice) prevented CD8+ T cell accumulation in the lung, resulting in intense lung eosinophilia. However, the Db allele (in B10.A(2R) and B10.A(4R) mice) supported CD8+ T cell expansion and prevented eosinophilia. Intracellular cytokine staining showed that lung eosinophilia correlated with reduced IFN-γ and increased IL-10 expression in lung T cells. These results are compatible with the unifying model that Th2 cells mediate the disease but can be inhibited by CD8+ T cells secreting IFN-γ. Our findings have important implications for the development of protective, nonpathogenic vaccines for RSV disease.
α(1,3)-Fucosyltransferase VII-Dependent Synthesis of P- and E-Selectin Ligands on Cultured T Lymphoblasts
Authors: Knibbs Randall N. , Craig Ronald A. , Mály Petr , Smith Peter L. , Wolber Frances M. , Faulkner Neil E. , Lowe John B. , Stoolman Lloyd M. 
Published: January 2023

Abstract
T lymphocytes up-regulate the synthesis of ligands for E- and P-selectin during proliferative responses in vivo and in vitro. Previous studies from our laboratories indicated that the α(1,3)-fucosyltransferase FucT-VII regulates the synthesis of E-selectin ligands and sialylated Lewisx-related epitopes (sLex-related epitopes) in human T lymphoblasts. The current report shows that production of both P- and E-selectin ligands is FucT-VII dependent, but peak synthesis of each occurs at different levels of fucosyltransferase activity in intact cells. In brief, FucT-VII mRNA levels were higher in cultured T lymphoblasts expressing sLex-related epitopes and both selectin ligands than in cells expressing P-selectin ligands alone. However, synthesis of the epitopes and both selectin ligands required the FucT-VII enzyme in transfected Molt-4 cells. In contrast, neither constitutive nor transfection-enhanced levels of the FucT-IV enzyme generated active P-selectin ligands in these lines. In addition, targeted deletion of the FucT-VII gene in mice markedly inhibited the synthesis of both P- and E-selectin ligands during blast transformation in vitro. Finally, the optimal synthesis of active P-selectin ligands occurred at lower level of FucT-VII activity than required for synthesis of equally active E-selectin ligands in both cultured T lymphoblasts and FucT-VII transfectants. Consequently, the FucT-VII enzyme is essential for the synthesis of both P- and E-selectin ligands by T lymphoblasts, and its activity determines whether P-selectin ligands are expressed alone or in conjunction with E-selectin ligands and sLex-related epitopes on human T cells.
The Selective Inhibition of β1 and β7 Integrin-Mediated Lymphocyte Adhesion by Bacitracin
Authors: Mou Yanglong , Ni Heyu , Wilkins John A. 
Published: January 2023

Abstract
Integrins play an important role in lymphocyte adhesion to cellular and extracellular components of their microenvironment. The regulation of such adhesion often involves changes in the functional state of the integrins rather than alterations in their expression levels. Although the functional basis for such transitions is unknown, a possible role for disulfide exchange might be postulated based on the observations that integrin function can be activated by bifunctional reducing agents or by Abs that react with areas adjacent to predicted long-range disulfide bonds in integrins. Recently, it has been reported that enzymes that catalyze disulfide exchanges such as protein disulfide isomerase (PDI) are present on the surface of lymphoid cells, raising the possibility that such enzymes might be involved in the control of lymphocyte adhesion. A number of inhibitors of PDI function were examined for their effects on integrin-mediated adherence of T cells. The results did not support role for PDI in the regulation of integrin function, as the inhibitors somatostatin A, tocinoic acid, dithiobisnitrobenzoic acid, and anti-PDI mAb did not interfere with adherence. However, one of the PDI inhibitors, bacitracin, selectively interfered with the β1 integrin-mediated adherence of lymphoid cells to collagen, fibronectin, laminin, and VCAM-1, and with α4β7-dependent adherence to fibronectin and to VCAM-1. In contrast, αvβ3- and αLβ2-mediated adherence were not inhibited. Thus, it appears that bacitracin may be a selective inhibitor of β1 and β7 integrin functions by an as yet unknown mechanism.
Dengue Virus Infection of Human Endothelial Cells Leads to Chemokine Production, Complement Activation, and Apoptosis
Authors: Avirutnan Panisadee , Malasit Prida , Seliger Barbara , Bhakdi Sucharit , Husmann Matthias 
Published: January 2023

Abstract
Dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS) are severe complications of secondary dengue virus (DV) infection. Vascular leakage, hemorrhagic diathesis and complement activation are the hallmarks of the disease. The short-lived nature of the plasma leakage syndrome has led to the conclusion that altered permeability is most likely effected by a soluble mediator. In the present study, we show that infection of human endothelial cells with DV induces the transcriptional up-regulation and secretion of RANTES and IL-8 and, in the presence of anti-dengue Abs, the formation of nonlytic complement complexes. Extremely high levels of IL-8 were detected in plasma and pleural fluid samples from patients with DSS. Furthermore, DV infection of endothelial cells in vitro caused apoptosis. Complement activation, chemokine induction, and apoptotic cell death may act in concert to cause the fulminant but short-lived vascular leakage that is characteristic of DHF/DSS.
Macrophage Colony-Stimulating Factor Stimulates Synthesis and Secretion of a Mouse Homolog of a Human IgE-Dependent Histamine-Releasing Factor by Macrophages In Vitro and In Vivo
Authors: Teshima Shigetada , Rokutan Kazuhito , Nikawa Takeshi , Kishi Kyoichi 
Published: January 2023

AbstractTreatment of murine resident peritoneal macrophages with macrophage-CSF (M-CSF) up-regulated the synthesis of a discrete set of proteins, including a 26-kDa protein (p26). The sequence of 20 NH2-terminal amino acids of the purified p26 was identical with the mouse homolog of a human IgE-dependent histamine-releasing factor (HRF). Among macrophage activators tested (M-CSF, granulocyte-macrophage-CSF, IL-3, TNF-α, IFN-γ, and LPS), only M-CSF could up-regulate the p26 HRF synthesis by cultured macrophages. M-CSF not only increased the levels of p26 HRF mRNA and protein, but also stimulated the secretion of an N-glycosylated p26 HRF with a m.w. of 30 kDa. Repeated injections of M-CSF into mouse peritoneal cavity for 4 days elicited macrophages expressing abundant p26 HRF. A single i.p. injection of M-CSF failed to increase the p26 HRF level in peritoneal macrophages of thioglycollate-, LPS-, or adjuvant-treated mice, while M-CSF challenge to OVA-immunized mice caused macrophage infiltration and overproduction of p26 HRF, similarly as did OVA challenge. The Ag-specific priming for enhanced synthesis and secretion of p26 HRF by M-CSF was also demonstrated in cultured macrophages prepared from OVA-immunized mice. An i.p. injection of M-CSF or recombinant p26 HRF triggered eosinophil recruitment, even in the absence of the Ag, in the sensitized mice, but not in normal mice. Furthermore, recombinant p26 HRF could induce eosinophilia without marked macrophage and lymphocyte infiltrations. Our results suggest that p26 HRF secreted by M-CSF-stimulated macrophages may be an important mediator for the late phase allergic inflammation.