bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage Apoptosis in Response to High Intracellular Burden of Mycobacterium tuberculosis Is Mediated by a Novel Caspase-Independent Pathway
Authors: Lee Jinhee , Remold Heinz G. , Ieong Michael H. , Kornfeld Hardy 
Published: April 2014

Abstract
We previously reported that macrophage exposure to attenuated strains of pathogenic mycobacteria at multiplicities of infection (MOI) ≤ 10 triggers TNF-α-mediated apoptosis which reduces the viability of intracellular bacilli. Virulent strains were found to suppress macrophage apoptosis, and it was proposed that apoptosis is an innate defense against intracellular Mycobacterium tuberculosis analogous to apoptosis of virus-infected cells. The potential similarity of host cell responses to intracellular infection with mycobacteria and viruses suggests that M. tuberculosis might lyse infected macrophage when that niche is no longer needed. To investigate this question, we challenged murine macrophages with high intracellular bacillary loads. A sharp increase in cytolysis within 24 h was observed at MOI ≥ 25. The primary death mode was apoptosis, based on nuclear morphology and phosphatidyl serine exposure, although the apoptotic cells progressed rapidly to necrosis. Apoptosis at high MOI differs markedly from low MOI apoptosis: it is potently induced by virulent M. tuberculosis, it is TNF-α-independent, and it does not reduce mycobacterial viability. Caspase inhibitors failed to prevent high MOI apoptosis, and macrophages deficient in caspase-3, MyD88, or TLR4 were equally susceptible as wild type. Apoptosis was reduced in the presence of cathepsin inhibitors, suggesting the involvement of lysosomal proteases in this novel death response. We conclude that the presence of high numbers of intracellular M. tuberculosis bacilli triggers a macrophage cell death pathway that could promote extracellular spread of infection and contribute to the formation of necrotic lesions in tuberculosis.
IFN-Induced Attrition of CD8 T Cells in the Presence or Absence of Cognate Antigen during the Early Stages of Viral Infections
Authors: Bahl Kapil , Kim Sung-Kwon , Calcagno Claudia , Ghersi Dario , Puzone Roberto , Celada Franco , Selin Liisa K. , Welsh Raymond M. 
Published: April 2014

AbstractProfound lymphopenia has been observed during many acute viral infections, and our laboratory has previously documented a type I IFN-dependent loss of CD8 T cells immediately preceding the development of the antiviral T cell response. Most memory (CD44high) and some naive (CD44low) CD8 T cells are susceptible to IFN-induced attrition, and we show in this study that the IFN-induced attrition of CD8+CD44high T cells is associated with elevated activation of caspase-3 and caspase-8. We questioned whether TCR engagement by Ag would render CD8 T cells resistant to attrition. We tested whether a high concentration of Ag (GP33 peptide) would protect lymphocytic choriomeningitis (LCMV)-specific naive CD8 T cells (TCR transgenic P14 cells specific for the GP33 epitope of LCMV) and memory CD8 T cells (GP33-specific LCMV-immune cells) from depletion. Both naive P14 and memory GP33-specific donor CD8 T cells decreased substantially 16 h after inoculation with the Toll receptor agonist and IFN inducer, poly(I:C), regardless of whether a high concentration of GP33 peptide was administered to host mice beforehand. Moreover, donor naive P14 and LCMV-specific memory cells were depleted from day 2 LCMV-infected hosts by 16 h posttransfer. These results indicate that Ag engagement does not protect CD8 T cells from the IFN-induced T cell attrition associated with viral infections. In addition, computer models indicated that early depletion of memory T cells may allow for the generation for a more diverse T cell response to infection by reducing the immunodomination caused by cross-reactive T cells.
Contribution of CD8+ T Cells to Control of Mycobacterium tuberculosis Infection
Authors: Sud Dhruv , Bigbee Carolyn , Flynn JoAnne L. , Kirschner Denise E. 
Published: April 2014

Abstract
Tuberculosis is the number one cause of death due to infectious disease in the world today. Understanding the dynamics of the immune response is crucial to elaborating differences between individuals who contain infection vs those who suffer active disease. Key cells in an adaptive immune response to intracellular pathogens include CD8+ T cells. Once stimulated, these cells provide a number of different effector functions, each aimed at clearing or containing the pathogen. To explore the role of CD8+ T cells in an integrative way, we synthesize both published and unpublished data to build and test a mathematical model of the immune response to Mycobacterium tuberculosis in the lung. The model is then used to perform a series of simulations mimicking experimental situations. Selective deletion of CD8+ T cell subsets suggests a differential contribution for CD8+ T cell effectors that are cytotoxic as compared with those that produce IFN-γ. We also determined the minimum levels of effector memory cells of each T cell subset (CD4+ and CD8+) in providing effective protection following vaccination.
Distinct Roles of TLR2 and the Adaptor ASC in IL-1β/IL-18 Secretion in Response to Listeria monocytogenes
Authors: Özören Nesrin , Masumoto Junya , Franchi Luigi , Kanneganti Thirumala-Devi , Body-Malapel Mathilde , Ertürk İlkim , Jagirdar Rajesh , Zhu Li , Inohara Naohiro , Bertin John , Coyle Anthony , Grant Ethan P. , Núñez Gabriel 
Published: April 2014

Abstract
Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) is an adaptor molecule that has recently been implicated in the activation of caspase-1. We have studied the role of ASC in the host defense against the intracellular pathogen Listeria monocytogenes. ASC was found to be essential for the secretion of IL-1β/IL-18, but dispensable for IL-6, TNF-α, and IFN-β production, in macrophages infected with Listeria. Activation of caspase-1 was abolished in ASC-deficient macrophages, whereas activation of NF-κB and p38 was unaffected. In contrast, secretion of IL-1β, IL-6, and TNF-α was reduced in TLR2-deficient macrophages infected with Listeria; this was associated with impaired activation of NF-κB and p38, but normal caspase-1 processing. Analysis of Listeria mutants revealed that cytosolic invasion was required for ASC-dependent IL-1β secretion, consistent with a critical role for cytosolic signaling in the activation of caspase-1. Secretion of IL-1β in response to lipopeptide, a TLR2 agonist, was greatly reduced in ASC-null macrophages and was abolished in TLR2-deficient macrophages. These results demonstrate that TLR2 and ASC regulate the secretion of IL-1β via distinct mechanisms in response to Listeria. ASC, but not TLR2, is required for caspase-1 activation independent of NF-κB in Listeria-infected macrophages.
Oncostatin-M Up-Regulates VCAM-1 and Synergizes with IL-4 in Eotaxin Expression: Involvement of STAT6
Authors: Fritz Dominik K. , Kerr Christine , Tong Li , Smyth David , Richards Carl D. 
Published: April 2014

AbstractOncostatin-M (OSM) is an IL-6/gp130 family member that can stimulate the eosinophil-selective CC chemokine eotaxin-1 in vitro and eosinophil accumulation in mouse lung in vivo. The adhesion molecule VCAM-1 and eotaxin have been implicated in extravasation and accumulation of eosinophils into tissue in animal models of asthma. In this study, we investigated the role of OSM in regulation of VCAM-1 expression, and STAT6 tyrosine 641 phosphorylation in murine fibroblasts. OSM induced VCAM-1 expression in C57BL/6 mouse lung fibroblasts (MLF) and NIH 3T3 fibroblasts at the protein and mRNA level in vitro. OSM also induced STAT6 Y641 phosphorylation in MLF and NIH 3T3 fibroblasts, an activity not observed with other IL-6/gp130 cytokine family members (IL-6, leukemia inhibitory factor, cardiotropin-1, and IL-11) nor in cells derived from STAT6−/− mice (STAT6−/− MLF). STAT6 was not essential for OSM-induced VCAM-1 or eotaxin-1 as assessed in STAT6−/− MLF. Combination of IL-4 and OSM synergistically enhanced eotaxin-1 expression in MLF. IL-4 induction and the IL-4/OSM synergistic induction of eotaxin-1 was abrogated in STAT6−/− MLF, however, regulation of IL-6 was similar in −/− or wild-type MLF. Induction of VCAM-1 by OSM was diminished by pharmacological inhibitors of PI3K (LY294002) but not inhibitors of ERK1/2 (PD98059) or p38 MAPK (SB203580). These data support the role of OSM in eosinophil accumulation into lung tissue through eotaxin-1 and VCAM-1 expression and the notion that OSM is able to induce unique signal transduction events through its receptor complex of OSMR β-chain and gp130.
IL-4-Induced Peroxisome Proliferator-Activated Receptor γ Activation Inhibits NF-κB Trans Activation in Central Nervous System (CNS) Glial Cells and Protects Oligodendrocyte Progenitors under Neuroinflammatory Disease Conditions: Implication for CNS-Demyelinating Diseases
Authors: Paintlia Ajaib S. , Paintlia Manjeet K. , Singh Inderjit , Singh Avtar K. 
Published: April 2014

Abstract
Th2 phenotype cytokine, IL-4, plays an important role in the regulation of Th1 cell responses and spontaneous remission of inflammatory CNS demyelinating diseases such as multiple sclerosis (MS). In this study we demonstrate IL-4-induced down-regulation of inducible NO synthase (iNOS) expression and survival of differentiating oligodendrocyte progenitors (OPs) in proinflammatory cytokine (Cyt-Mix)-treated CNS glial cells, which is a condition similar to that observed in the brain of a patient with MS. IL-4 treatment of Cyt-Mix-treated CNS glial cells significantly decreased iNOS expression/NO release with a parallel increase in survival of differentiating OPs. IL-4 effects were concentration-dependent and could be reversed by anti-IL-4R Abs. The use of inhibitors for Akt, p38 MAPK, and peroxisome proliferator-activated receptor γ (PPAR-γ) antagonist revealed that inhibition of Cyt-Mix-induced iNOS expression and survival of differentiating OPs by IL-4 is via PPAR-γ activation. There was a coordinate increase in the expression of both PPAR-γ and its natural ligand-producing enzyme 12/15-lipoxygenase (12/15-LOX) in IL-4-treated cells. Next, EMSA, immunoblots, and transient cotransfection studies with reporter plasmids (pNF-κB-Luc and pTK-PPREx3-Luc) and 12/15-LOX small interfering RNA revealed that IL-4-induced PPAR-γ activation antagonizes NF-κB transactivation in Cyt-Mix-treated astrocytes. In support of this finding, similarly treated 12/15-LOX−/− CNS glial cells further corroborated the result. Furthermore, there was reversal of IL-4 inductive effects in the brain of LPS-challenged 12/15-LOX−/− mice when compared with LPS-challenged wild-type mice. Together, these data for the first time demonstrate the inhibition of Cyt-Mix-induced NF-κB transactivation in CNS glial cells by IL-4 via PPAR-γ activation, hence its implication for the protection of differentiating OPs during MS and other CNS demyelinating diseases.
Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation
Authors: Kim Daniel C. , Hsu F. Ida , Barrett Nora A. , Friend Daniel S. , Grenningloh Roland , Ho I-Cheng , Al-Garawi Amal , Lora Jose M. , Lam Bing K. , Austen K. Frank , Kanaoka Yoshihide 
Published: April 2014

Abstract
The Th2 cell-dependent inflammatory response is a central component of asthma, and the ways in which it is regulated is a critical question. The cysteinyl leukotrienes (cys-LTs) are 5-lipoxygenase pathway products implicated in asthma, in particular, by their function as smooth muscle constrictors of airways and microvasculature. To elucidate additional roles for cys-LTs in the pathobiology of pulmonary inflammation, we used an OVA sensitization and challenge protocol with mice lacking leukotriene C4 synthase (LTC4S), the terminal enzyme for cys-LT generation. Ag-induced pulmonary inflammation, characterized by eosinophil infiltration, goblet cell hyperplasia with mucus hypersecretion, and accumulation and activation of intraepithelial mast cells was markedly reduced in LTC4Snull mice. Furthermore, Ag-specific IgE and IgG1 in serum, Th2 cell cytokine mRNA expression in the lung, and airway hyperresponsiveness to methacholine were significantly reduced in LTC4Snull mice compared with wild-type controls. Finally, the number of parabronchial lymph node cells from sensitized LTC4Snull mice and their capacity to generate Th2 cell cytokines ex vivo after restimulation with Ag were also significantly reduced. In contrast, delayed-type cutaneous hypersensitivity, a prototypic Th1 cell-dependent response, was intact in LTC4Snull mice. These findings provide direct evidence of a role for cys-LTs in regulating the initiation and/or amplification of Th2 cell-dependent pulmonary inflammation.
Functional Study of CD4+CD25+ Regulatory T Cells in Health and Autoimmune Hepatitis
Authors: Longhi Maria Serena , Hussain Munther J. , Mitry Ragai R. , Arora Sunil K. , Mieli-Vergani Giorgina , Vergani Diego , Ma Yun 
Published: April 2014

Abstract
Regulatory CD4+CD25+ T cells (Tregs) are defective numerically and functionally in autoimmune hepatitis (AIH). We have investigated and compared the mechanism of action of Tregs in healthy subjects and in AIH patients using Transwell experiments, where Tregs are cultured either in direct contact with or separated from their targets by a semipermeable membrane. We also studied Treg FOXP3 expression and effect on apoptosis. Direct contact is necessary for Tregs to suppress proliferation and IFN-γ production by CD4+CD25− and CD8+ T cells in patients and controls. Moreover, in both, direct contact of Tregs with their targets leads to increased secretion of regulatory cytokines IL-4, IL-10, and TGF-β, suggesting a mechanism of linked immunosuppression. Tregs/CD4+CD25− T cell cocultures lead to similar changes in IFN-γ and IL-10 secretion in patients and controls, whereas increased TGF-β secretion is significantly lower in patients. In contrast, in patients, Tregs/CD8+ T cell cocultures lead to a higher increase of IL-4 secretion. In AIH, Treg FOXP3 expression is lower than in normal subjects. Both in patients and controls, FOXP3 expression is present also in CD4+CD25− T cells, although at a low level and not associated to suppressive function. Both in patients and controls, addition of Tregs does not influence target cell apoptosis, but in AIH, spontaneous apoptosis of CD4+CD25− T cells is reduced. In conclusion, Tregs act through a direct contact with their targets by modifying the cytokine profile and not inducing apoptosis. Deficient CD4+CD25− T cell spontaneous apoptosis may contribute to the development of autoimmunity.
Mycobacteria Induce IFN-γ Production in Human Dendritic Cells via Triggering of TLR2
Authors: Fricke Ingo , Mitchell Daniell , Mittelstädt Jessica , Lehan Nadine , Heine Holger , Goldmann Torsten , Böhle Andreas , Brandau Sven 
Published: April 2014

Abstract
IFN-γ is of central importance for the induction of robust cell-mediated immunity and for the activation of APC. Recent studies using experimental murine systems have now suggested a fundamental role for APC-derived IFN-γ during infection with intracellular pathogens. It is currently unknown whether human dendritic cells (DC) can respond to bacterial stimulation with production of IFN-γ. To test this question, we used human monocyte-derived DC stimulated by Mycobacterium bovis bacillus Calmette-Guérin as a model system. We demonstrate production of IFN-γ mRNA and protein on the single cell level. IFN-γ in DC cultures was not simply produced by contaminating lymphocytes because production of DC-IFN-γ could also be demonstrated in highly purified DC cultures containing virtually no T, B, and NK cells. TLR2 was identified as a key receptor involved in triggering production of DC-IFN-γ. Interestingly, DC-IFN-γ seems to participate in an autocrine DC activation loop, and production of DC-IFN-γ could be enhanced by costimulation of DC with IL-12/IL-15/IL-18. In conclusion, we have demonstrated production of IFN-γ by human DC on the single cell level, identified TLR2 as a pattern recognition receptor involved in this process, and elucidated some of the functional consequences of autocrine IFN-γ production by human DC.
Dendritic Cells Require Multidrug Resistance Protein 1 (ABCC1) Transporter Activity for Differentiation
Authors: van de Ven Rieneke , de Jong Mariska C. , Reurs Anneke W. , Schoonderwoerd Antoinet J. N. , Jansen Gerrit , Hooijberg Jan H. , Scheffer George L. , de Gruijl Tanja D. , Scheper Rik J. 
Published: April 2014

Abstract
Dendritic cells (DC) express the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and multidrug resistance protein 1 (MRP1; ABCC1). Functionally, both these transporters have been described to be required for efficient DC and T cell migration. In this study, we report that MRP1 activity is also crucial for differentiation of DC. Inhibition of MRP1, but not P-glycoprotein, transporter activity with specific antagonists during in vitro DC differentiation interfered with early DC development. Impaired interstitial and Langerhans DC differentiation was characterized by 1) morphological changes, reflected by dropped side scatter levels in flow cytometric analysis and 2) phenotypic changes illustrated by maintained expression of the monocytic marker CD14, lower expression levels of CD40, CD86, HLA-DR, and a significant decrease in the amount of cells expressing CD1a, CD1c, and Langerin. Defective DC differentiation also resulted in their reduced ability to stimulate allogeneic T cells. We identified the endogenous CD1 ligands sulfatide and monosialoganglioside GM1 as MRP1 substrates, but exogenous addition of these substrates could not restore the defects caused by blocking MRP1 activity during DC differentiation. Although leukotriene C4 was reported to restore migration of murine Mrp1-deficient DC, the effects of MRP1 inhibition on DC differentiation appeared to be independent of the leukotriene pathway. Though MRP1 transporter activity is important for DC differentiation, the relevant MRP1 substrate, which is required for DC differentiation, remains to be identified. Altogether, MRP1 seems to fulfill an important physiological role in DC development and DC functions.
Immunological and Antitumor Effects of IL-23 as a Cancer Vaccine Adjuvant
Authors: Overwijk Willem W. , de Visser Karin E. , Tirion Felicia H. , de Jong Laurina A. , Pols Thijs W. H. , van der Velden Yme U. , van den Boorn Jasper G. , Keller Anna M. , Buurman Wim A. , Theoret Marc R. , Blom Bianca , Restifo Nicholas P. , Kruisbeek Ada M. , Kastelein Robert A. , Haanen John B. A. G. 
Published: April 2014

AbstractThe promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory cytokine, IL-23, in gp100 peptide vaccine therapy of established murine melanoma. Neither systemic nor local IL-23 alone had any impact on tumor growth or tumor-specific T cell numbers. Upon specific vaccination, however, systemic IL-23 greatly increased the relative and absolute numbers of vaccine-induced CD8+ T cells and enhanced their effector function at the tumor site. Although IL-23 specifically increased IFN-γ production by tumor-specific T cells, IFN-γ itself was not a primary mediator of the vaccine adjuvant effect. The IL-23-induced antitumor effect and accompanying reversible weight loss were both partially mediated by TNF-α. In contrast, local expression of IL-23 at the tumor site maintained antitumor activity in the absence of weight loss. Under these conditions, it was also clear that enhanced effector function of vaccine-induced CD8+ T cells, rather than increased T cell number, is a primary mechanism underlying the antitumor effect of IL-23. Collectively, these results suggest that IL-23 is a potent vaccine adjuvant for the induction of therapeutic, tumor-specific CD8+ T cell responses.
Conversion of Alloantigen-Specific CD8+ T Cell Anergy to CD8+ T Cell Priming through In Vivo Ligation of Glucocorticoid-Induced TNF Receptor
Authors: Kim Juyang , Choi Woon S. , Kang Hyun , Kim Hye J. , Suh Jae-Hee , Sakaguchi Shimon , Kwon Byungsuk 
Published: April 2014

Abstract
In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-γ and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.
Chlamydia Infection Induces ICOS Ligand-Expressing and IL-10-Producing Dendritic Cells That Can Inhibit Airway Inflammation and Mucus Overproduction Elicited by Allergen Challenge in BALB/c Mice
Authors: Han Xiaobing , Wang Shuhe , Fan Yijun , Yang Jie , Jiao Lei , Qiu Hongyu , Yang Xi 
Published: April 2014

Abstract
Our previous study has shown that the adoptive transfer of dendritic cells (DCs) freshly isolated from Chlamydia-infected mice (iIDCs), unlike those from control naive mice (iNDCs), can inhibit systemic and cutaneous eosinophilia induced by OVA exposure. In the present study, we examined the mechanism by which iIDC inhibits allergen-specific Th2 cell differentiation in vitro and in vivo. The study revealed that iIDCs exhibited higher surface expression of CD8α and the ICOS ligand (ICOS-L), as well as higher IL-10 and IL-12 production than iNDCs. In vitro DC:CD4+ T cell coculture experiments showed that iIDCs could inhibit allergen-specific Th2 cell differentiation and that the inhibitory effect could be abolished by the blockage of IL-10 or IL-12 activity. More interestingly, the coblockade of IL-10 and the ICOS-L showed synergistic effect in enhancing allergen-driven Th2 cytokine production. Furthermore, adoptive transfer of iIDCs, but not iNDCs, to OVA sensitized mice significantly inhibited airway eosinophilia and mucus overproduction following intranasal challenge with OVA. Overall, the data demonstrate a critical role played by ICOS-L-expressing and IL-10-producing DCs from Chlamydia-infected mice in the infection-mediated inhibition of allergic responses.