bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heat Shock Protein 70 Is Able to Prevent Heat Shock-Induced Resistance of Target Cells to CTL
Authors: Dressel Ralf , Elsner Leslie , Quentin Thomas , Walter Lutz , Günther Eberhard 
Published: April 2014

Abstract
Heat shock or transfection with heat shock protein 70 (Hsp70) genes has been shown to protect tumor cell lines against immune mechanisms of cytotoxicity. We have reported previously that heat shock confers resistance to CTL in the rat myeloma cell line Y3 that is Hsp70 defective. Evidence is now presented that Hsp70 is able to prevent the induction of the resistant phenotype. In Con A-stimulated lymphocytes and in lymphocyte × Y3 somatic cell hybrid clones a severe, non-Hsp70-inducing heat shock elicits resistance to CTL in contrast to a heat shock that results in Hsp70 expression. Thus, Hsp70 expression appears to be negatively associated with the development of resistance. Furthermore, loading of Y3 cells with recombinant Hsp70 protein before heat shock is able to prevent resistance. Because apoptosis induced in Y3 cells by heat shock is not affected, Hsp70 appears to interfere selectively with the CTL-induced lethal pathway that is found to be calcium but not caspase dependent. It is suggested that after heat shock Hsp70 enhances the CTL-induced apoptotic pathway by chaperoning certain proteins in the target cell that are involved in the execution of cell death. Thus, although shown to confer protection against many cytotoxic mechanisms, Hsp70 does not appear to be generally cytoprotective. This observation could also be of relevance when interpreting the effectiveness of tumor immunity.
CpG-DNA Activates In Vivo T Cell Epitope Presenting Dendritic Cells to Trigger Protective Antiviral Cytotoxic T Cell Responses
Authors: Vabulas Ramunas M. , Pircher Hanspeter , Lipford Grayson B. , Häcker Hans , Wagner Hermann 
Published: April 2014

AbstractMHC class I-restricted T cell epitopes lack immunogenicity unless aided by IFA or CFA. In an attempt to circumvent the known inflammatory side effects of IFA and CFA, we analyzed the ability of immunostimulatory CpG-DNA to act as an adjuvant for MHC class I-restricted peptide epitopes. Using the immunodominant CD8 T cell epitopes, SIINFEKL from OVA or KAVYNFATM (gp33) from lymphocytic choriomeningitis virus glycoprotein, we observed that CpG-DNA conveyed immunogenicity to these epitopes leading to primary induction of peptide-specific CTL. Furthermore, vaccination with the lymphocytic choriomeningitis virus gp33 peptide triggered not only CTL but also protective antiviral defense. We also showed that MHC class I-restricted peptides are constitutively presented by immature dendritic cells (DC) within the draining lymph nodes but failed to induce CTL responses. The use of CpG-DNA as an adjuvant, however, initiated peptide presenting immature DC progression to professional licensed APC. Activated DC induced cytolytic CD8 T cells in wild-type mice and also mice deficient of Th cells or CD40 ligand. CpG-DNA thus incites CTL responses toward MHC class I-restricted T cell epitopes in a Th cell-independent manner. Overall, these results provide new insights into CpG-DNA-mediated adjuvanticity and may influence future vaccination strategies for infectious and perhaps tumor diseases.
HLA-DR-Mediated Apoptosis Susceptibility Discriminates Differentiation Stages of Dendritic/Monocytic APC
Authors: Bertho Nicolas , Drénou Bernard , Laupeze Béatrice , Berre Claudine Le , Amiot Laurence , Grosset Jean-Marc , Fardel Olivier , Charron Dominique , Mooney Nuala , Fauchet Renée 
Published: April 2014

AbstractProfessional APC are characterized by their ability to present peptide via HLA class II in the presence of costimulatory molecules (CD40, CD80, and CD86). The efficiency of Ag presentation can be classed as follows: mature dendritic cells (DC) are most efficient, immature DC and macrophages are intermediate, and monocytes are considered poor APC. There is a large body of evidence demonstrating that HLA-DR transmits signals in the APC. In this study, we have addressed the question of the outcome of HLA-DR signals on APC of the monocyte/DC lineages throughout their differentiation from immature to mature APC. DC were generated from both monocytes and CD34+ cells of the same individual, macrophages were differentiated from monocytes. Immunophenotypical analysis clearly distinguished these populations. HLA-DR-mediated signals led to marked apoptosis in mature DC of either CD34 or monocytic origin. Significantly less apoptosis was observed in immature DC of either origin. Nonetheless, even immature DC were more susceptible to HLA-DR-mediated apoptosis than macrophages, whereas monocytes were resistant to HLA-DR-mediated apoptosis. The mechanism of HLA-DR-mediated apoptosis was independent of caspase activation. Taken together, these data lead to the notion that signals generated via HLA-DR lead to the demise of mature professional APC, thereby providing a means of limiting the immune response.
NK1.1+ T Cells in the Liver Arise in the Thymus and Are Selected by Interactions with Class I Molecules on CD4+CD8+ Cells
Authors: Coles Mark C. , Raulet David H. 
Published: April 2014

AbstractNK1.1+ T cells represent a specialized T cell subset specific for CD1d, a nonclassical MHC class I-restricting element. They are believed to function as regulatory T cells. NK1.1+ T cell development depends on interactions with CD1d molecules presented by hematopoietic cells rather than thymic epithelial cells. NK1.1+ T cells are found in the thymus as well as in peripheral organs such as the liver, spleen, and bone marrow. The site of development of peripheral NK1.1+ T cells is controversial, as is the nature of the CD1d-expressing cell that selects them. With the use of nude mice, thymectomized mice reconstituted with fetal liver cells, and thymus-grafted mice, we provide direct evidence that NK1.1+ T cells in the liver are thymus dependent and can arise in the thymus from fetal liver precursor cells. We show that the class I+ (CD1d+) cell type necessary to select NK1.1+ T cells can originate from TCRα−/− precursors but not from TCRβ−/− precursors, indicating that the selecting cell is a CD4+CD8+ thymocyte. 5-Bromo-2′-deoxyuridine-labeling experiments suggest that the thymic NK1.1+ T cell population arises from proliferating precursor cells, but is a mostly sessile population that turns over very slowly. Since liver NK1.1+ T cells incorporate 5-bromo-2′-deoxyuridine more rapidly than thymic NK1.1+ T cells, it appears that liver NK1.1+ T cells either represent a subset of thymic NK1.1+ T cells or are induced to proliferate after having left the thymus. The results indicate that NK1.1+ T cells, like conventional T cells, arise in the thymus where they are selected by interactions with restricting molecules.
NOD/LtSz-Rag1nullMice: An Immunodeficient and Radioresistant Model for Engraftment of Human Hematolymphoid Cells, HIV Infection, and Adoptive Transfer of NOD Mouse Diabetogenic T Cells
Authors: Shultz Leonard D. , Lang Pamela A. , Christianson Sherri W. , Gott Bruce , Lyons Bonnie , Umeda Syuji , Leiter Edward , Hesselton RuthAnn , Wagar Eric J. , Leif Jean H. , Kollet Órit , Lapidot Tsvee , Greiner Dale L. 
Published: April 2014

AbstractDevelopment of a small animal model for the in vivo study of human immunity and infectious disease remains an important goal, particularly for investigations of HIV vaccine development. NOD/Lt mice homozygous for the severe combined immunodeficiency (Prkdcscid) mutation readily support engraftment with high levels of human hematolymphoid cells. However, NOD/LtSz-scid mice are highly radiosensitive, have short life spans, and a small number develop functional lymphocytes with age. To overcome these limitations, we have backcrossed the null allele of the recombination-activating gene (Rag1) for 10 generations onto the NOD/LtSz strain background. Mice deficient in RAG1 activity are unable to initiate V(D)J recombination in Ig and TCR genes and lack functional T and B lymphocytes. NOD/LtSz-Rag1null mice have an increased mean life span compared with NOD/LtSz-scid mice due to a later onset of lymphoma development, are radioresistant, and lack serum Ig throughout life. NOD/LtSz-Rag1null mice were devoid of mature T or B cells. Cytotoxic assays demonstrated low NK cell activity. NOD/LtSz-Rag1null mice supported high levels of engraftment with human lymphoid cells and human hemopoietic stem cells. The engrafted human T cells were readily infected with HIV. Finally, NOD/LtSz-Rag1null recipients of adoptively transferred spleen cells from diabetic NOD/Lt+/+ mice rapidly developed diabetes. These data demonstrate the advantages of NOD/LtSz-Rag1null mice as a radiation and lymphoma-resistant model for long-term analyses of engrafted human hematolymphoid cells or diabetogenic NOD lymphoid cells.
Lymphotoxin-α-Dependent Spleen Microenvironment Supports the Generation of Memory B Cells and Is Required for Their Subsequent Antigen-Induced Activation
Authors: Fu Yang-Xin , Huang Guangming , Wang Yang , Chaplin David D. 
Published: April 2014

Abstract
Lymphotoxin α-deficient (LTα−/−) mice show dramatically reduced IgG responses after either primary or secondary immunizations with sheep red blood cells (SRBC). When splenocytes from SRBC-primed wild-type donor mice were infused into irradiated naive wild-type recipient mice, they generated a robust memory IgG response, but not when infused into LTα−/− recipients, indicating that the microenvironment that develops in LTα−/− mice is incompetent to support the activation of this memory response. When irradiated wild-type mice were reconstituted with splenocytes from primed LTα−/− donors and then challenged with the same immunizing Ag, no memory response was observed, indicating further that memory cells could not be generated in the LTα−/− environment. To address which lymphocyte subsets were impaired in the LTα−/− mice, we performed reconstitution experiments using a hapten/carrier system and T cells and B cells from different primed donors. There was no detectable defect in either the generation or expression of memory T cells from LTα−/− donors. In contrast, B cells were not primed for memory in the microenvironment of LTα−/− mice. Additionally, primed wild-type memory B cells could not express a memory IgG response in the LTα−/− microenvironment. Thus, splenic white pulp structure, which depends on the expression of LTα for its development and maintenance, is needed to support the generation of memory B cells and to permit existing memory B cells to express an isotype switched memory Ig response following antigenic challenge.
IL-12-Independent Th1-Type Immune Responses to Respiratory Viral Infection: Requirement of IL-18 for IFN-γ Release in the Lung But Not for the Differentiation of Viral-Reactive Th1-Type Lymphocytes
Authors: Xing Zhou , Zganiacz Anna , Wang Jun , Divangahi Maziar , Nawaz Fauzia 
Published: April 2014

Abstract
We demonstrated that IL-12 was induced during primary or secondary pulmonary adenoviral infection in wild-type (wt) mice. However, cellular responses were not compromised in the lungs of IL-12−/− mice. The level of IFN-γ in the lung was similar in wt and IL-12−/− mice during pulmonary viral infection. Upon Ag stimulation in vitro, lymphocytes from draining lymph nodes or spleen of infected IL-12−/− mice released large amounts of IFN-γ, but not IL-4, which were comparable to those released by wt lymphocytes. Furthermore, a predominantly IgG2a response to adenoviral infection was unimpaired in IL-12−/− mice. These significant anti-adenoviral Th1-type responses in IL-12−/− mice led to an efficient clearance of virus-infected cells in the lung. Whether IL-18 was involved in IL-12-independent anti-adenoviral immune responses was investigated. Abrogation of endogenous IL-18 by an Ab resulted in diminished IFN-γ release and lymphocytic infiltrate in the lung during adenoviral infection. Nevertheless, the development of lymphocytes of the Th1 phenotype was unimpaired in the absence of both IL-12 and IL-18. In contrast to their intact ability to mount Th1-type responses to viral infection, IL-12−/− mice suffered impaired Th1-type immune responses to pulmonary mycobacterial infection. Our findings suggest that IL-12, although induced, is not required for Th1-type responses to respiratory viral infection, in contrast to mycobacterial infection. IL-18 is required for the optimal release of IFN-γ in the lung during viral infection, but is not required for the generation of virus-reactive Th1-type lymphocytes. Th1 differentiation during respiratory adenoviral infection may involve molecules different from IL-12 or IL-18.
Schistosome Infection of Transgenic Mice Defines Distinct and Contrasting Pathogenic Roles for IL-4 and IL-13: IL-13 Is a Profibrotic Agent
Authors: Fallon Padraic G. , Richardson Emma J. , McKenzie Grahame J. , McKenzie Andrew N. J. 
Published: April 2014

AbstractExperimental Schistosoma mansoni infections of mice lead to a dynamic type 2 cytokine-mediated pathological process. We have used IL-4-deficient, IL-13-deficient, and IL-4/13-deficient mice to dissect the role of these cytokines in the development of immune response and pathology following S. mansoni infection. We demonstrate that while both of these cytokines are necessary to develop a robust Th2 cell-driven, eosinophil-rich granuloma response, they also perform disparate functions that identify novel sites for therapeutic intervention. IL-13-deficient mice demonstrated significantly enhanced survival following infection, which correlated with reduced hepatic fibrosis. In contrast, increased mortality was manifest in IL-4-deficient and IL-4/13-deficient mice, and this correlated with hepatocyte damage and intestinal pathology. Therefore, we demonstrate that during a dynamic type 2 cytokine disease process IL-13 is detrimental to survival following infection, whereas IL-4 is beneficial.
Lipopolysaccharide Inhibits HIV-1 Infection of Monocyte- Derived Macrophages Through Direct and Sustained Down-Regulation of CC Chemokine Receptor 5
Authors: Franchin Giovanni , Zybarth Gabriele , Dai Wei Wei , Dubrovsky Larisa , Reiling Norbert , Schmidtmayerova Helena , Bukrinsky Michael , Sherry Barbara 
Published: April 2014

Abstract
It is now well established that HIV-1 requires interactions with both CD4 and a chemokine receptor on the host cell surface for efficient infection. The expression of the CCR5 chemokine receptor in human macrophages facilitates HIV-1 entry into these cells, which are considered important in HIV pathogenesis not only as viral reservoirs but also as modulators of altered inflammatory function in HIV disease and AIDS. LPS, a principal constituent of Gram-negative bacterial cell walls, is a potent stimulator of macrophages and has been shown to inhibit HIV infection in this population. We now present evidence that one mechanism by which LPS mediates its inhibitory effect on HIV-1 infection is through a direct and unusually sustained down-regulation of cell-surface CCR5 expression. This LPS-mediated down-regulation of CCR5 expression was independent of de novo protein synthesis and differed from the rapid turnover of these chemokine receptors observed in response to two natural ligands, macrophage-inflammatory protein-1α and -1β. LPS did not act by down-regulating CCR5 mRNA (mRNA levels actually increased slightly after LPS treatment) or by enhancing the degradation of internalized receptor. Rather, the observed failure of LPS-treated macrophages to rapidly restore CCR5 expression at the cell-surface appeared to result from altered recycling of chemokine receptors. Taken together, our results suggest a novel pathway of CCR5 recycling in LPS-stimulated human macrophages that might be targeted to control HIV-1 infection.
Decreased Resistance of B Cell-Deficient Mice to Infection with Toxoplasma gondii Despite Unimpaired Expression of IFN-γ, TNF-α, and Inducible Nitric Oxide Synthase
Authors: Kang Hoil , Remington Jack S. , Suzuki Yasuhiro 
Published: April 2014

Abstract
The role of B cells in resistance against Toxoplasma gondii was studied using B cell-deficient (μMT) mice. Following peroral infection with 10 cysts of the ME49 strain, all μMT mice survived the acute stage of the infection but died between 3 and 4 wk after infection. In contrast, all control mice were alive at 8 wk after infection. At the stage during which μMT animals succumbed to the infection, parasite replication and pathology were most evident in their brains; small numbers of tachyzoites were also detectable in their lungs. Significantly greater numbers of T. gondii cysts and areas of inflammation associated with tachyzoites were observed in brains of μMT than in control mice. Large areas of necrosis associated with numerous tachyzoites were observed only in brains of μMT mice. Anti-T. gondii IgG Abs were detected only in sera of control mice, whereas similar levels of IFN-γ were detected in sera of both strains of mice. Amounts of mRNA for IFN-γ, IL-10, and inducible NO synthase in the brain did not differ between infected μMT and control mice. Expression of mRNA for TNF-α was increased in brains of μMT mice. Administration of polyclonal rabbit anti-T. gondii IgG Ab prevented early mortality and pathology associated with tachyzoites in the brain in the infected μMT mice. These results indicate that B cells play an important role, most likely through their production of specific Abs, in resistance to persistent active (tachyzoite) infection with T. gondii in mice, especially in the brain and lung.
Th Cell-Deficient Mice Control Influenza Virus Infection More Effectively Than Th- and B Cell-Deficient Mice: Evidence for a Th-Independent Contribution by B Cells to Virus Clearance
Authors: Mozdzanowska Krystyna , Maiese Krista , Gerhard Walter 
Published: April 2014

AbstractThe notion that MHC class I- restricted CD8+ T (Tc) cells are capable of resolving autonomously infections with influenza virus is based largely on studies testing virus strains of low pathogenicity in CD4+ T (Th) cell-deficient/depleted mice. To test whether this holds also for pathogenic strains and to exclude possible contributions by B cells, we analyzed PR8 infection in Th cell-depleted B cell-deficient (μMT) mice. These mice, termed μMT (−CD4), showed 80% mortality after infection with a small dose of PR8, which resulted in insignificant mortality in intact or Th cell-depleted BALB/c mice. Infection of μMT(−CD4) mice with a virus of low pathogenicity was resolved without mortality, but, compared with intact BALB/c mice, with delay of ∼5 and ∼20 days from lung and nose, respectively. The low mortality of Th cell-depleted BALB/c mice suggested that B cells contributed to recovery in a Th-independent manner. This was verified by showing that transfer of 8–10 million T cell-depleted naive spleen cells into μMT(−CD4) mice 1 day before infection reduced mortality to 0%. The mechanism by which B cells improved recovery was investigated. We found no evidence that they operated by improving the lung-associated Tc response. Treatment of infected μMT(−CD4) mice with normal mouse serum spiked with hemagglutinin-specific IgM did not reduce mortality. Taken together, the data show that 1) the Tc response is capable of resolving autonomously (in conjunction with innate defenses) influenza virus infections, although with substantial delay compared with intact mice, and 2) B cells can contribute to recovery by a Th-independent mechanism.
Neutralization of IL-18 Reduces Neutrophil Tissue Accumulation and Protects Mice Against Lethal Escherichia coli and Salmonella typhimurium Endotoxemia
Authors: Netea Mihai G. , Fantuzzi Giamila , Kullberg Bart Jan , Stuyt Rogier J. L. , Pulido Edward J. , McIntyre Robert C. , Joosten Leo A. B. , Van der Meer Jos W. M. , Dinarello Charles A. 
Published: April 2014

Abstract
In addition to stimulating IFN-γ synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1β and the chemokines IL-8 and macrophage inflammatory protein-1α. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1β converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1β, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1β−/− mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-γ but not IL-1β in ICE−/− mice is responsible for this resistance. However, IFN-γ-deficient mice were not resistant to S. typhimurium LPS, suggesting an IFN-γ-independent role for IL-18. Anti-IL-18 Abs protected mice against a lethal injection of either LPS. Anti-IL-18 treatment also reduced neutrophil accumulation in liver and lungs. The increased survival was accompanied by decreased levels of IFN-γ and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-γ and TNF concentrations were decreased in treated mice challenged with S. typhimurium. In conclusion, neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN-γ production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved.
Neutrophil Activation by Bacterial Lipoprotein Versus Lipopolysaccharide: Differential Requirements for Serum and CD14
Authors: Soler-Rodriguez Ana Maria , Zhang Hongwei , Lichenstein Henri S. , Qureshi Nilofer , Niesel David W. , Crowe Sheila E. , Peterson Johnny W. , Klimpel Gary R. 
Published: April 2014

AbstractNeutrophil activation plays an important role in the inflammatory response to Gram-negative bacterial infections. LPS has been shown to be a major mediator of neutrophil activation which is accompanied by an early down-regulation of L-selectin and up-regulation of CD1lb/CD18. In this study, we investigated whether lipoprotein (LP), the most abundant protein in the outer membrane of bacteria from the family Enterobacteriaceae, can activate neutrophils and whether this activation is mediated by mechanisms that differ from those used by LPS or Escherichia coli diphosphoryl lipid A (EcDPLA). Neutrophil activation was assessed by measuring down-regulation of L-selectin and up-regulation of CD11b/CD18. When comparing molar concentrations of LP vs EcDPLA, LP was more potent (four times) at activating neutrophils. In contrast to LPS/EcDPLA, LP activation of neutrophils was serum independent. However, LP activation of neutrophils was enhanced by the addition of soluble CD14 and/or LPS-binding protein. In the presence of serum, LP activation of neutrophils was inhibited by different mAbs to CD14. This inhibition was significantly reduced or absent when performed in the absence of serum. Diphosphoryl lipid A from Rhodobacter spheroides (RaDPLA) completely inhibited LPS/EcDPLA activation of neutrophils but only slightly inhibited LP activation of neutrophils. These results suggest that LP activation of human neutrophils can be mediated by a mechanism that is different from LPS activation and that LP is a potentially important component in the development of diseases caused by Gram-negative bacteria of the family Enterobacteriaceae.