bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-α and IL-7
Authors: Audigé Annette , Schlaepfer Erika , Joller Helen , Speck Roberto F. 
Published: April 2014

AbstractCytokine-based therapies have been examined for purging viral reservoirs and immunomodulation in HIV infection. However, single cytokines did not result in either HIV eradication or an efficient HIV-specific immune response. We hypothesize that cytokines with distinct biologic effects need to be combined for immunotherapy of HIV infection. In this study, we investigated the anti-HIV activity and immune-enhancing effects of the combination of IFN-α and IL-7. In human lymphocyte aggregate cultures infected ex vivo with the X4 HIV strain NL4-3, IFN-α/IL-7 potently inhibited HIV replication and preserved CD4+ T cells, probably by up-regulating Bcl-2. IFN-α/IL-7 also strongly inhibited R5 HIV replication. Furthermore, in allogeneic MLRs, IFN-α/IL-7 increased T cell proliferation and IFN-γ production. IFN-α alone also had strong anti-HIV activity, but neither preserved CD4+ T cells nor increased T cell responses in MLRs. IL-7 alone maintained T cells and enhanced T cell activation in MLRs, but only moderately inhibited or increased HIV replication. Thus, coadministration of IFN-α/IL-7 combines the potent anti-HIV activity of IFN-α with the beneficial effects of IL-7 on T cell survival and function. We speculate that IFN-α will block viral replication, activate APCs, and up-regulate MHC molecules, thus allowing IL-7 to display its effects for generating an efficient immune response. In this scenario, the known reactivation of latent HIV by IL-7 may be advantageous.
Are Extensive T Cell Epitope Polymorphisms in the Plasmodium falciparum Circumsporozoite Antigen, a Leading Sporozoite Vaccine Candidate, Selected by Immune Pressure?
Authors: Kumkhaek Chutima , Phra-ek Kooruethai , Rénia Laurent , Singhasivanon Pratap , Looareesuwan Sornchai , Hirunpetcharat Chakrit , White Nicholas J. , Brockman Alan , Grüner Anne Charlotte , Lebrun Nicolas , Alloueche Ali , Nosten François , Khusmith Srisin , Snounou Georges 
Published: April 2014

Abstract
Protective cellular immune responses depend on MHC presentation of pathogen-derived Ag fragments. MHC diversity renders this process sensitive to point mutations coding for altered amino acid sequence of the short target Ag-derived peptides epitopes. Thus, in a given host, a pathogen with an altered epitope sequence will be more likely to escape detection and elimination by the immune system. At a population level, selection by immune pressure will increase the likelihood of polymorphism in important pathogen antigenic epitopes. This mechanism of immune evasion is found in viruses and other pathogens. The detection of polymorphic hot spots in an Ag is often taken as a strong indication of its role in protective immunity. We provide evidence that polymorphisms in the T cell epitopes of a malaria vaccine candidate are unlikely to have been selected by immune pressure in the human host.
Influence of CD14 on Ligand Interactions between Lipopolysaccharide and Its Receptor Complex
Authors: Gangloff Sophie C. , Zähringer Ulrich , Blondin Catherine , Guenounou Moncef , Silver Jack , Goyert Sanna M. 
Published: April 2014

Abstract
The interaction of LPS (endotoxin) with the CD14-TLR4 receptor complex modulates the host innate immune response. Several studies using partial structures of LPS have suggested that TLR4 determines the ligand specificity of this complex, and that CD14 indiscriminately serves to deliver the ligand to TLR4. This conclusion has been made despite observations that the response of TLR4+/+,CD14−/− macrophages to LPS is very weak. To determine whether CD14 itself plays a role in specific ligand recognition, the influences of various partial structures of LPS on induction of the proinflammatory cytokine, TNF, by CD14+/+ and CD14−/− macrophages were compared. These studies show that the ligand specificities of CD14+/+ and CD14−/− macrophages are very different. When CD14 is present, the receptor complex shows exquisite specificity for smooth LPS, the major form expressed by Gram-negative bacteria; however, as increasing amounts of carbohydrate are removed from smooth LPS, the sensitivity of CD14+/+ macrophages decreases as much as 500-fold. In contrast, CD14−/− macrophages are unable to distinguish between smooth LPS and its various partial structures. Furthermore, CD14−/− macrophages are 150,000-fold less sensitive than CD14+/+ macrophages to smooth LPS. A similar ability to distinguish the differing LPS structures of various bacteria such as Bacteroides fragilis and Salmonella abortus are observed for CD14+/+, but not CD14−/−, macrophages. Thus, CD14+/+, but not CD14−/−, macrophages are highly sensitive to stimulation by natural forms of LPS and show the ability to distinguish between various LPS ligands, consistent with CD14 being a highly specific receptor.
Treatment of Passive Experimental Autoimmune Encephalomyelitis in SJL Mice with a Recombinant TCR Ligand Induces IL-13 and Prevents Axonal Injury
Authors: Offner Halina , Subramanian Sandhya , Wang Chunhe , Afentoulis Michael , Vandenbark Arthur A. , Huan Jianya , Burrows Gregory G. 
Published: April 2014

AbstractThe major goal of this study was to evaluate the efficacy and mechanism of a rTCR ligand (RTL) construct (I-As/proteolipid protein (PLP)-139–151 peptide = RTL401) for treatment of SJL/J mice developing passive experimental autoimmune encephalomyelitis (EAE) that did not involve coimmunization with the highly inflammatory CFA. Our results demonstrated clearly that RTL401 was highly effective in treating passive EAE, with kinetics of recovery from disease very similar to treatment of actively induced EAE. The potent RTL401 treatment effect was reflected by a partial reduction of infiltrating mononuclear cells into CNS, minimal inflammatory lesions in spinal cord, and preservation of axons injured in vehicle-treated mice during the progression of EAE. Interestingly, in the absence of CFA, RTL401 treatment strongly enhanced production of the Th2 cytokine, IL-13, in spleen, blood, and spinal cord tissue, with variable effects on other Th1 and Th2 cytokines, and no significant effect on the Th3 cytokine, TGF-β1, or on FoxP3 that is expressed by regulatory T cells. Moreover, pretreatment of PLP-139–151-specific T cells with RTL401 in vitro induced high levels of secreted IL-13, with lesser induction of other pro- and anti-inflammatory cytokines. Given the importance of IL-13 for protection against EAE, these data strongly implicate IL-13 as a dominant regulatory cytokine induced by RTL therapy. Pronounced IL-13 levels coupled with marked reduction in IL-6 levels secreted by PLP-specific T cells from blood after treatment of mice with RTL401 indicate that IL-13 and IL-6 may be useful markers for following effects of RTL therapy in future clinical trials in multiple sclerosis.
Cutting Edge: TLR2-Mediated Proinflammatory Cytokine and Chemokine Production by Microglial Cells in Response to Herpes Simplex Virus
Authors: Aravalli Rajagopal N. , Hu Shuxian , Rowen Timothy N. , Palmquist Joseph M. , Lokensgard James R. 
Published: April 2014

Abstract
Recent studies indicate that TLRs are critical in generating innate immune responses during infection with HSV-1. In this study, we investigated the role of TLR2 signaling in regulating the production of neuroimmune mediators by examining cytokine and chemokine expression using primary microglial cells obtained from TLR2−/− as well as wild-type mice. Data presented here demonstrate that TLR2 signaling is required for the production of proinflammatory cytokines and chemokines: TNF-α, IL-1β, IL-6, IL-12, CCL7, CCL8, CCL9, CXCL1, CXCL2, CXCL4, and CXCL5. CXCL9 and CXCL10 were also induced by HSV, but their production was not dependent upon TLR2 signaling. Because TLR2−/− mice display significantly reduced mortality and diminished neuroinflammation in response to brain infection with HSV, the TLR2-dependent cytokines identified here might function as key players influencing viral neuropathogenesis.
CIN85 Regulates the Ligand-Dependent Endocytosis of the IgE Receptor: A New Molecular Mechanism to Dampen Mast Cell Function
Authors: Molfetta Rosa , Belleudi Francesca , Peruzzi Giovanna , Morrone Stefania , Leone Laura , Dikic Ivan , Piccoli Mario , Frati Luigi , Torrisi Maria Rosaria , Santoni Angela , Paolini Rossella 
Published: April 2014

Abstract
Ligation of the high-affinity receptor for IgE (FcεRI), constitutively expressed on mast cells and basophils, promotes cell activation and immediate release of allergic mediators. Furthermore, FcεRI up-regulation on APC from atopic donors is involved in the pathophysiology of allergic diseases. In consideration of the clinical relevance of the IgE receptor, the down-modulation of FcεRI expression in mast cells may represent a potential target for handling atopic diseases. In an effort to identify new molecular mechanisms involved in attenuating FcεRI expression and signaling, we focused our attention on CIN85, a scaffold molecule that regulates, in concert with the ubiquitin ligase Cbl, the clathrin-mediated endocytosis of several receptor tyrosine kinases. In the present study, we show that endogenous CIN85 is recruited in Cbl-containing complexes after engagement of the FcεRI on a mast cell line and drives ligand-induced receptor internalization. By confocal microscopic analysis, we provide evidence that CIN85 directs a more rapid receptor sorting in early endosomes and delivery to a lysosomal compartment. Furthermore, biochemical studies indicate that CIN85 plays a role in reducing the expression of receptor complex. Finally, we demonstrate that CIN85-overexpressing mast cells are dramatically impaired in their ability to degranulate following Ag stimulation, suggesting that the accelerated internalization of activated receptors by perturbing the propagation of FcεRI signaling may contribute to dampen the functional response. This role of CIN85 could be extended to include other multimeric immune receptors, such as the T and B cell receptors, providing a more general molecular mechanism for attenuating immune responses.
Absence of Caprin-1 Results in Defects in Cellular Proliferation
Authors: Wang Bin , David Muriel D. , Schrader John W. 
Published: April 2014

Abstract
Cytoplasmic activation/proliferation-associated protein-1 (Caprin-1) is a cytoplasmic phosphoprotein that is the prototype of a novel family of highly conserved proteins. Its levels, except in the brain, are tightly correlated with cellular proliferation. We disrupted caprin-1 alleles in the chicken B lymphocyte line DT40 using homologous recombination. We readily obtained clones with one disrupted allele (31% of transfectants), but upon transfection of heterozygous cells we obtained a 10-fold lower frequency of clones with disruption of the remaining allele. Clones of caprin-1-null DT40 cells exhibited marked reductions in their proliferation rate. To obviate the problem that we had selected for caprin-1-null clones with characteristics that partially compensated for the lack of Caprin-1, we generated clones of DT40 cells heterozygous for the caprin-1 gene in which, during disruption of the remaining wild-type allele of the chicken caprin-1 gene, the absence of endogenous Caprin-1 would be complemented by conditional expression of human Caprin-1. Suppression of expression of human Caprin-1 resulted in slowing of the proliferation rate, due to prolongation of the G1 phase of the cell cycle, formally demonstrating that Caprin-1 was essential for normal cellular proliferation.
Diabetes Is Predicted by the β Cell Level of Autoantigen
Authors: Byersdorfer Craig A. , Schweitzer George G. , Unanue Emil R. 
Published: April 2014

Abstract
Two novel transgenic (Tg) strains were created expressing hen egg-white lysozyme (HEL) in a pancreas-specific fashion. RmHP.111 mice had levels of HEL per cell similar to that of the established ILK-3 strain, while RmHP.117 mice had 10-fold lower levels (50,000 molecules per cell). When bred to 3A9 TCR Tg mice, negative selection occurred equally in all three double-Tg combinations, yet only ILK-3 × 3A9 and RmHP.111 × 3A9 mice became diabetic. Additionally, activated 3A9 cells readily transferred diabetes into ILK-3 or RmHP.111 mice, but only marginally into the RmHP.117 strain. In the peripancreatic lymph node, division of naive 3A9 cells was similar between RmHP.111 and RmHP.117 strains, but pancreatic APCs from RmHP.111 × 3A9 mice stimulated HEL-reactive cells to a much greater degree than those from RmHP.117 × 3A9 mice. In this model, diabetes was dependent upon both initial priming in the peripancreatic lymph node and subsequent presentation in the pancreas, with disease incidence predicted by the β cell level of autoantigen.
Signal 3 Tolerant CD8 T Cells Degranulate in Response to Antigen but Lack Granzyme B to Mediate Cytolysis
Authors: Curtsinger Julie M. , Lins Debra C. , Johnson Christopher M. , Mescher Matthew F. 
Published: April 2014

AbstractNaive CD8 T cells that respond in vivo to Ag and costimulation in the absence of a third signal, such as IL-12, fail to develop cytolytic function and become tolerized. We show in this study that CD8 T cells purified from TCR transgenic mice and stimulated in vitro in the presence or absence of IL-12 form conjugates with specific target cells, increase intracellular Ca2+, and undergo degranulation to comparable extents. Perforin is also expressed at comparable levels in the absence or presence of a third signal, but expression of granzyme B depends upon IL-12. Levels of granzyme B also correlate strongly with the cytolytic activity of cells responding in vivo. In contrast, an increase in CD107a (lysosomal-associated membrane protein 1) expression resulting from degranulation cannot distinguish in vivo generated lytic effector cells from tolerized, noncytolytic cells. Thus, it appears that cells rendered tolerant as a result of stimulation in the absence of a third signal fail to lyse target cells because they are “shooting blanks.”
Lipopolysaccharide-Induced Heme Oxygenase-1 Expression in Human Monocytic Cells Is Mediated via Nrf2 and Protein Kinase C
Authors: Rushworth Stuart A. , Chen Xi-Lin , Mackman Nigel , Ogborne Richard M. , O’Connell Maria A. 
Published: April 2014

Abstract
Monocytes play a key role in mobilization of the immune response during sepsis. In response to LPS, monocytes produce both proinflammatory mediators and regulatory proteins that counteract the inflammation and oxidative stress. In murine macrophages, LPS stimulates expression of heme oxygenase 1 (HO-1), a cytoprotective enzyme that catalyzes the degradation of heme. The HO-1 5′-untranslated region, similarly to other cytoprotective genes, contains antioxidant-response elements (AREs) that can bind the transcription factor NF-E2-related factor 2 (Nrf2). At present, the role of Nrf2 in LPS-induced HO-1 expression in monocytic cells has not been investigated. In this study, LPS induced HO-1 mRNA and protein expression in human monocytes and THP-1 cells. Nrf2 translocated from the cytosol to the nucleus in response to LPS and bound to the ARE site in the human HO-1 promoter. In addition, a dominant negative Nrf2 mutant inhibited LPS-induced HO-1 mRNA expression but not TNF-α mRNA expression in THP-1 cells. Ro-31-8220, a pan-protein kinase C (PKC) inhibitor, and Go6976, a classical PKC inhibitor, blunted LPS-induced HO-1 mRNA expression in monocytes and THP-1 cells. Both PKC inhibitors also blocked LPS-induced Nrf2 binding to the ARE. These results indicate that LPS-induced HO-1 expression in human monocytic cells requires Nrf2 and PKC.
Analyzing Expression of Perforin, Runx3, and Thpok Genes during Positive Selection Reveals Activation of CD8-Differentiation Programs by MHC II-Signaled Thymocytes
Authors: Liu Xiaolong , Taylor Barbara J. , Sun Guangping , Bosselut Rémy 
Published: April 2014

Abstract
Intrathymic positive selection matches CD4-CD8 lineage differentiation to MHC specificity. However, it is unclear whether MHC signals induce lineage choice or simply select thymocytes of the appropriate lineage. To investigate this issue, we assessed thymocytes undergoing positive selection for expression of the CD8 lineage markers perforin and Runx3. Using both population-based and single-cell RT-PCR analyses, we found large subsets of MHC class II (MHC-II)-signaled thymocytes expressing these genes within the CD4+8+ and CD4+8int, but not the CD4+8− populations of signaling competent mice. This indicates that MHC-II signals normally fail to impose CD4 differentiation and further implies that the number of mature CD8 single-positive (SP) thymocytes greatly underestimates CD8 lineage choice. We next examined whether MHC-II-restricted CD4+8− thymocytes remain competent to initiate CD8 lineage gene expression. In mice in which expression of the tyrosine kinase Zap70 and thereby TCR signaling were impaired selectively in SP thymocytes, MHC-II-signaled CD4+8− thymocytes expressed perforin and Runx3 and failed to up-regulate the CD4 marker Thpok. This indicated that impairing TCR signals at the CD4 SP stage switched gene expression patterns from CD4- to CD8-lineage specific. We conclude from these findings that MHC-II-signaled thymocytes remain competent to initiate CD8-specific gene expression even after CD8 down-regulation and that CD4 lineage differentiation is not fixed before the CD4 SP stage.
Id3 Induces Growth Arrest and Caspase-2-Dependent Apoptosis in B Lymphocyte Progenitors
Authors: Kee Barbara L. 
Published: April 2014

Abstract
The E-protein transcription factors E2A, HEB, and E2-2 play an essential role in the differentiation, proliferation, and survival of B lymphocyte progenitors (BLPs). In this study, we show that the E-protein antagonist Id3 induces apoptosis of both primary and transformed BLPs through a caspase-2-dependent mechanism that does not require p53 and is not inhibited by bcl-2. Id3 expressing B lineage cells show reduced expression of known E-protein target genes as well as multiple genes involved in cell proliferation. We hypothesize that Id3 induces activation of caspase-2 as a consequence of severe or “catastrophic” growth arrest. In support of this hypothesis, we show that chemical-induced growth arrest is sufficient to activate caspase-2 and induce apoptosis in BLPs. Our data suggest that E-proteins function in the control of differentiation and proliferation and that diminished E-protein activity results in apoptosis as a consequence of growth arrest.
IL-16 Is Critical for Tropheryma whipplei Replication in Whipple’s Disease
Authors: Desnues Benoît , Raoult Didier , Mege Jean-Louis 
Published: April 2014

Abstract
Whipple’s disease (WD) is a rare systemic disease caused by Tropheryma whipplei. We showed that T. whipplei was eliminated by human monocytes but replicated in monocyte-derived macrophages (Mφ) by inducing an original activation program. Two different host molecules were found to be key elements for this specific pattern. Thioredoxin, through its overexpression in infected monocytes, was involved in bacterial killing because adding thioredoxin to infected Mφ inhibited bacterial replication. IL-16, which was up-regulated in Mφ, enabled T. whipplei to replicate in monocytes and increased bacterial replication in Mφ. In addition, anti-IL-16 Abs abolished T. whipplei replication in Mφ. IL-16 down-modulated the expression of thioredoxin and up-regulated that of IL-16 and proapoptotic genes. In patients with WD, T. whipplei replication was higher than in healthy subjects and was related to high levels of circulating IL-16. Both events were corrected in patients who successfully responded to antibiotics treatment. This role of IL-16 was not reported previously and gives an insight into the understanding of WD pathophysiology.
Increased Susceptibility of Mice Lacking T-bet to Infection withMycobacterium tuberculosisCorrelates with Increased IL-10 and Decreased IFN-γ Production
Authors: Sullivan Brandon M. , Jobe Ousman , Lazarevic Vanja , Vasquez Kristine , Bronson Roderick , Glimcher Laurie H. , Kramnik Igor 
Published: April 2014

AbstractA sustained CD4+ Th1-dominated type 1 immune response is required to successfully control Mycobacterium tuberculosis infection. Considerable work has demonstrated that the transcription factor, T-bet, is required for IFN-γ expression and fundamental to the generation of type 1 immunity in multiple cell types. Mice lacking T-bet are susceptible to virulent M. tuberculosis infection. Susceptibility of T-bet-deficient mice is associated with increased systemic bacterial burden, diminished IFN-γ production, and the striking accumulation of eosinophilic macrophages and multinucleated giant cells in the lung. Interestingly, T-bet−/− mice did not develop a fully polarized Th2 response toward M. tuberculosis, but exhibited selective elevation of IL-10 production. These results indicate that T-bet plays a central role in controlling M. tuberculosis disease progression, in part through the regulation of both IFN-γ and IL-10.
A Novel Role of CD30/CD30 Ligand Signaling in the Generation of Long-Lived Memory CD8+ T Cells
Authors: Nishimura Hitoshi , Yajima Toshiki , Muta Hiromi , Podack Eckhard R. , Tani Kenzaburo , Yoshikai Yasunobu 
Published: April 2014

AbstractMemory CD8+ T cells can be divided into two subsets, central memory (TCM) and effector memory (TEM) CD8+ T cells. We found that CD30, a member of the TNFR-associated factor (TRAF)-linked TNFR superfamily, signaling is involved in differentiation of long-lived CD8+ TCM cells following Listeria monocytogenes infection. Although CD8+ TEM cells transiently accumulated in the nonlymphoid tissues of CD30 ligand (CD153−/−) mice after infection, long-lived memory CD8+ TCM cells were poorly generated in these mice. CCR7 mRNA expression was down-regulated in CD8+ T cells of the spleen of CD153−/− mice in vivo and the expression was up-regulated in CD8+ TEM cells by anti-CD30 mAb cross-linking in vitro. These results suggest that CD30/CD30 ligand signaling plays an important role in the generation of long-lived memory CD8+ T cells at least partly by triggering homing receptors for TCM cells.
A Dipalmitoylated Lipoprotein fromMycoplasma pneumoniaeActivates NF-κB through TLR1, TLR2, and TLR6
Authors: Shimizu Takashi , Kida Yutaka , Kuwano Koichi 
Published: April 2014

AbstractThe pathogenesis of Mycoplasma pneumoniae infection is considered to be in part attributed to excessive immune responses. Recently, lipoproteins from mycoplasmas have been reported to induce NF-κB activation. In this study, we examined the ability of lipoproteins from M. pneumoniae to activate NF-κB, and the active component responsible for the NF-κB activation was identified. Lipid-associated membrane proteins from M. pneumoniae were found to induce NF-κB through TLR 2 in a human monocytic cell line, THP-1. The active component of the Lipid-associated membrane proteins was a subunit b of F0F1-type ATPase (F0F1-ATPase). The F0F1-ATPase is assumed to contain two palmitic acids. The activation of NF-κB by the F0F1-ATPase was inhibited by a dominant negative construct of TLR1 and TLR6. These results indicate that the activation of NF-κB by F0F1-ATPase is dependent on TLR1, TLR2, and TLR6. The activity of the F0F1-ATPase was decreased with pretreatment of lipoprotein lipase but not protease, indicating that the lipid moiety of the F0F1-ATPase was important for the NF-κB activation. Thus, a dipalmitoylated lipoprotein from M. pneumoniae was found to activate NF-κB through TLR1, TLR2, and TLR6.