bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD1d-Dependent NKT Cells Play a Protective Role in Acute and Chronic Arthritis Models by Ameliorating Antigen-Specific Th1 Responses
Authors: Teige Anna , Bockermann Robert , Hasan Maruf , Olofsson Katarina E. , Liu Yawei , Issazadeh-Navikas Shohreh 
Published: June 2010

Abstract
A protective and anti-inflammatory role for CD1d-dependent NKT cells (NKTs) has been reported in experimental and human autoimmune diseases. However, their role in arthritis has been unclear, with conflicting reports of CD1d-dependent NKTs acting both as regulatory and disease-promoting cells in arthritis. These differing modes of action might be due to genetic differences of inbred mice and incomplete backcrossing of gene-modified mice. We therefore put special emphasis on controlling the genetic backgrounds of the mice used. Additionally, we used two different murine arthritis models, Ag-induced arthritis (AIA) and collagen-induced arthritis (CIA), to evaluate acute and chronic arthritis in CD1d knockout mice and mice depleted of NK1.1+ cells. CD1d-deficient mice developed more severe AIA compared with wild-type littermates, with a higher degree of inflammation and proteoglycan depletion. Chronic arthritis in CIA was also worse in the absence of CD1d-dependent NKTs. Elevated levels of Ag-specific IFN-γ production accompanied these findings rather than changes in IL-17α. Depletion of NK1.1+ cells supported these findings in AIA and CIA. This report provides support for CD1d-dependent NKTs being suppressor cells in acute and chronic arthritis, likely via inhibition of arthritogenic Th1 cells. These results make CD1d-dependent NKTs an attractive target for therapeutic intervention.
TLR2- and Nucleotide-Binding Oligomerization Domain 2-Dependent Krüppel-Like Factor 2 Expression Downregulates NF-κB–Related Gene Expression
Authors: Zahlten Janine , Steinicke Robert , Opitz Bastian , Eitel Julia , N’Guessan Philippe Dje , Vinzing Maya , Witzenrath Martin , Schmeck Bernd , Hammerschmidt Sven , Suttorp Norbert , Hippenstiel Stefan 
Published: June 2010

Abstract
The release of potent proinflammatory mediators is not only central for mounting an efficient host response, but also bears the risk for deleterious excessive tissue-damaging inflammation. This is highlighted in severe pneumococcal pneumonia, in which the delicate balance between a robust inflammatory response to kill pneumococci and loss of organ function determines the outcome of disease. In this study, we tested the hypothesis that Krüppel-like factor (KLF)2 counterregulates pneumococci- and pattern recognition receptor-related human lung cell activation. Pneumococci induced KLF2 expression in vitro and in a murine pneumonia model. Activation of TLR2- and nucleotide-binding oligomerization domain protein 2-related signaling induced KLF2 expression in a PI3K-dependent manner. Overexpression of KLF2 downregulated pneumococci-, TLR2-, and nucleotide-binding oligomerization domain protein 2-related NF-κB–dependent gene expression and IL-8 release, whereas small interfering RNA-based silencing of KLF2 provoked an enhanced inflammatory response. KLF2-dependent downregulation of NF-κB activity is partly reversible by overexpression of the histone acetylase p300/CREB-binding protein-associated factor. In conclusion, KLF2 may act as a counterregulatory transcription factor in pneumococci- and pattern recognition receptor-related proinflammatory activation of lung cells, thereby preventing lung hyperinflammation and subsequent organ failure.
CD40 Expression Levels Modulate Regulatory T Cells inLeishmania donovaniInfection
Authors: Martin Sunil , Agarwal Reena , Murugaiyan Gopal , Saha Bhaskar 
Published: June 2010

AbstractDendritic cell (DC)-expressed CD40 is shown to play crucial roles in eliciting effector T cell responses, primarily the proinflammatory CD4+ Th subsets and cytotoxic CD8+ T cells that eliminate various infections and tumors, respectively. In contrast, DCs are also implied in the generation of regulatory T cells (Tregs) that counteract the functions of the proinflammatory Th subsets and exacerbate infections. However, the role of DC-expressed CD40 in the generation of Tregs is unknown. In this study, we generated bone marrow-derived DCs from mice (on a BALB/c background) expressing different levels of CD40 and tested their relative efficiency in generating Tregs. We observed that low levels of CD40 expression were required for efficient Treg generation. DCs expressing low levels of CD40 induced Tregs, whereas DCs expressing high levels of CD40 induced effector T cells, possibly CD8+CD40+ T cells with a contraregulatory activity; the adoptive transfer of the former DC exacerbated whereas the latter significantly reduced Leishmania donovani infection in BALB/c mice. Similarly, priming of mice with leishmanial Ag-pulsed DCs expressing high levels of CD40 induced host protection against L. donovani challenge infection. In contrast, priming with the low CD40-expressing DC resulted in aggravated infection as compared with the control mice. The results establish that CD40 can play differential roles in Treg differentiation and determine the course of infection. We demonstrate that the knowledge can be efficiently used in adoptive cell transfer therapy against an infectious disease.
Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-γ Production
Authors: Matsuda Hiroyuki , Takeda Katsuyuki , Koya Toshiyuki , Okamoto Masakazu , Shiraishi Yoshiki , Miyahara Nobuaki , Dakhama Azzeddine , Matsuda Jennifer L. , Gapin Laurent , Gelfand Erwin W. 
Published: June 2010

Abstract
Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA–α-galactosylceramide (OVA/αGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/αGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/αGalCer BMDCs into IFN-γ–deficient (IFN-γ−/−) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-γ treatment following OVA-BMDC transfer. Further, Jα18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/αGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-γ−/− mice restored the development of these responses in Jα18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/αGalCer BMDC transfer. iNKT cells from these IFN-γ−/− mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-γ as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.
Identification of an Important Immunological Difference between Virulent Varicella-Zoster Virus and Its Avirulent Vaccine: Viral Disruption of Dendritic Cell Instruction
Authors: Gutzeit Cindy , Raftery Martin J. , Peiser Matthias , Tischer Karsten B. , Ulrich Martina , Eberhardt Melanie , Stockfleth Eggert , Giese Thomas , Sauerbrei Andreas , Morita Craig T. , Schönrich Günther 
Published: June 2010

Abstract
Virulent varicella-zoster virus (VZV) can spread in immunocompetent humans, resulting in symptoms mostly of the skin. In contrast, vaccine Oka (V-Oka), the attenuated VZV vaccine strain, only rarely causes clinical reactions. The mechanisms underlying these pathogenetic differences are unclear. In this study, we comparatively analyzed the ability of virulent VZV and V-Oka to modulate instruction of dendritic cells (DCs) by innate signals. DCs isolated from normal human skin were susceptible to infection with VZV and V-Oka. Moreover, inflammatory DCs, which play a crucial role in the stimulation of Th1 immune responses, accumulated in herpes zoster lesions. Infection of inflammatory DCs generated in vitro with virulent VZV or V-Oka resulted in upregulation of CD1c. Upon coculture with CD1c-restricted innate cells, DCs developed a mature phenotype whether infected with virulent VZV or V-Oka. Intriguingly, a striking difference was detected on the functional level. The release of IFN-γ and IL-12, the signature cytokines of Th1 responses, was enhanced by V-Oka but blocked by virulent VZV. V-Oka and virulent VZV efficiently synergized with CD40L, eliminating the possibility that CD40 signaling was a target of VZV-associated immune evasion. Instead, virulent VZV selectively interfered with signaling through TLR2, which is known to sense VZV. Thus, virulent VZV subverts Th1-promoting instruction of human DCs by blocking TLR2-mediated innate signals that prime IL-12 production by DCs. Taken together, our results demonstrate a novel immune-evasion mechanism of virulent VZV that has been lost during the attenuation process leading to the VZV vaccine strain.
Prevention of Experimental Colitis by a Selective Inhibitor of the Immunoproteasome
Authors: Basler Michael , Dajee Maya , Moll Carlo , Groettrup Marcus , Kirk Christopher J. 
Published: June 2010

AbstractThe proteasome, a multicatalytic protease, is responsible for the degradation of intracellular proteins. Stimulation of cells with inflammatory cytokines, such as IFN-γ, leads to the replacement of the constitutive catalytic proteasome subunits by the inducible subunits low molecular mass polypeptide (LMP)2 (β1i), multicatalytic endopeptidase complex-like-1 (β2i), and LMP7 (β5i), which are required for the production of certain MHC class I-restricted T cell epitopes. In this study, we investigated the effect of immunoproteasomes on the development of dextran sulfate sodium-induced colitis. Colitis induction in LMP2-, LMP7-, and multicatalytic endopeptidase complex-like-1–deficient mice caused reduced weight loss compared with wild-type mice. Although colon lengths were shortened in wild-type mice, no reduction was observed in immunoproteasome-deficient mice. In accordance with this, proinflammatory cytokines, such as TNF-α and IL-1β, were not upregulated in these mice. Blockage of LMP7 by a novel LMP7-selective inhibitor (PR-957) strongly reduced pathological symptoms of dextran sulfate sodium-induced colitis. Production of numerous cytokines in PR-957–treated mice was suppressed, resulting in reduced inflammation and tissue destruction. Taken together, these results demonstrate that an immunoproteasome-specific inhibitor can be used to attenuate autoimmune diseases like colitis.
Germinal Center T Follicular Helper Cell IL-4 Production Is Dependent on Signaling Lymphocytic Activation Molecule Receptor (CD150)
Authors: Yusuf Isharat , Kageyama Robin , Monticelli Laurel , Johnston Robert J. , DiToro Daniel , Hansen Kyle , Barnett Burton , Crotty Shane 
Published: June 2010

Abstract
CD4 T cell help is critical for the generation and maintenance of germinal centers (GCs), and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP [SH2D1A]) expression in CD4 T cells is essential for GC development. However, SAP-deficient mice have only a moderate defect in TFH differentiation, as defined by common TFH surface markers. CXCR5+ TFH cells are found within the GC, as well as along the boundary regions of T/B cell zones. In this study, we show that GC-associated T follicular helper (GC TFH) cells can be identified by their coexpression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. GC TFH cells are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH cell subset and SAP− TFH cells are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that uses SAP signaling, is specifically required for IL-4 production by GC TFH cells. GC TFH cells require IL-4 and -21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by GC CD4 T cells but not in TFH cell and GC TFH cell differentiation.
Expression of Costimulatory TNFR2 Induces Resistance of CD4+FoxP3− Conventional T Cells to Suppression by CD4+FoxP3+ Regulatory T Cells
Authors: Chen Xin , Hamano Ryoko , Subleski Jeffrey J. , Hurwitz Arthur A. , Howard O. M. Zack , Oppenheim Joost J. 
Published: June 2010

Abstract
Our previous study showed that TNFR2 is preferentially expressed by CD4+FoxP3+ regulatory T cells (Tregs), and expression of this receptor identified maximally suppressive Tregs. TNFR2 is also expressed by a small fraction of CD4+FoxP3− conventional T cells (Tconvs) in normal mice, and its expression is upregulated by T cell activation. This raises questions about the role of TNFR2 signaling in the function of Tconv cells. In this study, by using FoxP3/gfp knock-in mice, we showed that TNFR2 signaling did not induce FoxP3− CD4 cells to become suppressive. Ki-67, a marker of proliferation, was concomitantly expressed with TNFR2 by CD4 cells, independent of forkhead box P3 expression, in normal mice and Lewis lung carcinoma-bearing mice. TNFR2 is associated with greater suppressive functions when expressed by Tregs and is associated with greater resistance to suppression when expressed by Tconv cells. In mice bearing 4T1 breast tumor or Lewis lung carcinoma, intratumoral Tconv cells expressing elevated levels of TNFR2 acquired the capacity to resist suppression by lymph node-derived Tregs. However, they remained susceptible to inhibition by more suppressive tumor-infiltrating Tregs, which expressed higher levels of TNFR2. Our data indicate that TNFR2 also costimulates Tconv cells. However, intratumoral Tregs expressing more TNFR2 are able to overcome the greater resistance to suppression of intratumoral Tconv cells, resulting in a dominant immunosuppressive tumor environment.
CD49d Is a New Marker for Distinct Myeloid-Derived Suppressor Cell Subpopulations in Mice
Authors: Haile Lydia A. , Gamrekelashvili Jaba , Manns Michael P. , Korangy Firouzeh , Greten Tim F. 
Published: June 2010

Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells that negatively regulate the immune response during tumor progression, inflammation, and infection. In this study, through gene-expression analysis, we have identified a new marker, CD49d, which is expressed exclusively on CD11b+Gr-1dull/int. MDSCs. We have characterized two subpopulations of MDSCs based on CD49d expression in two different settings, a mouse model of inflammatory bowel disease and tumor-bearing mice. The CD49d+ subset of MDSCs was mainly monocytic and strongly suppressed Ag-specific T cell proliferation in an NO-dependent mechanism similar to Gr-1dull/int. MDSCs. Alternatively, CD49d− cells were granulocytic and poorly inhibited T cell proliferation compared with CD11b+Gr-1high cells. Both mouse models showed preferential expansion of the granulocytic CD49d− subset. We suggest that CD49d can be used as an alternative marker for Gr-1 to differentiate between the subpopulations of MDSCs together with CD11b, which will ultimately help in understanding the mechanisms of immune suppression by MDSCs.
Combined Genotypic and Phenotypic Killer Cell Ig-Like Receptor Analyses Reveal KIR2DL3 Alleles Displaying Unexpected Monoclonal Antibody Reactivity: Identification of the Amino Acid Residues Critical for Staining
Authors: Falco Michela , Romeo Elisa , Marcenaro Stefania , Martini Stefania , Vitale Massimo , Bottino Cristina , Mingari Maria Cristina , Moretta Lorenzo , Moretta Alessandro , Pende Daniela 
Published: June 2010

Abstract
In humans, recent clinical and experimental data from hematopoietic stem cell transplantation revealed that donor-derived alloreactive NK cells exert a beneficial graft versus leukemia effect. The existence of donor-derived alloreactive NK cells can be predicted on the basis of donor killer cell Ig-like receptor (KIR) gene profile and HLA class I typing of both donor and recipient. Moreover, the size of the alloreactive NK cell population can be directly assessed by the combined use of anti–KIR-specific mAb. In this study, in an attempt to improve the definition of alloreactive NK cell subsets, we assessed the KIR genotype and phenotype in a cohort of 44 donors. This approach allowed the identification of two different KIR2DL3 alleles (KIR2DL3*005 and the novel allele KIR2DL3*015) that did not react with the anti–KIR2DL3-specific ECM41 mAb. In contrast, both alleles were recognized at the cell surface by several mAb reacting with KIR2DL2/L3/S2. Notably, KIR2DL3*005 was also stained by the anti–KIR2DL1/S1-specific EB6B and 11PB6 mAb. Functional analysis revealed that, despite its particular mAb reactivity, the specificity of KIR2DL3*005 for HLA-C molecules did not differ from that of other KIR2DL2/L3 alleles. Finally, site-directed mutagenesis demonstrated that glutamine at position 35 is required for ECM41 staining, whereas glutamic acid 35 and arginine 50 are relevant for staining with EB6B or 11PB6 mAb. Our present data represent a substantial progress in the characterization of the NK cell repertoire and an improved phenotypic/functional definition of given KIR+ subsets.
Naturally Activated Vγ4 γδ T Cells Play a Protective Role in Tumor Immunity through Expression of Eomesodermin
Authors: He Weifeng , Hao Jianlei , Dong Siyuan , Gao Yunfei , Tao Jian , Chi Hongbo , Flavell Richard , O’Brien Rebecca L. , Born Willi K. , Craft Joseph , Han Jihong , Wang Puyue , Zhao Liqing , Wu Jun , Yin Zhinan 
Published: June 2010

Abstract
We previously demonstrated that γδ T cells played an important role in tumor immune surveillance by providing an early source of IFN-γ. The precise role of different subsets of γδ T cells in the antitumor immune response, however, is unknown. Vγ1 and Vγ4 γδ T cells are the principal subsets of peripheral lymphoid γδ T cells and they might play distinct roles in tumor immunity. In support of this, we observed that reconstitution of TCRδ−/− mice with Vγ4, but not Vγ1, γδ T cells restored the antitumor response. We also found that these effects were exerted by the activated (CD44high) portion of Vγ4 γδ T cells. We further determined that IFN-γ and perforin are critical elements in the Vγ4-mediated antitumor immune response. Indeed, CD44high Vγ4 γδ T cells produced significantly more IFN-γ and perforin on activation, and showed greater cytolytic activity than did CD44high Vγ1 γδ T cells, apparently due to the high level of eomesodermin (Eomes) in these activated Vγ4 γδ T cells. Consistently, transfection of dominant-negative Eomes in Vγ4 γδ T cells diminished the level of IFN-γ secretion, indicating a critical role of Eomes in the effector function of these γδ T cells. Our results thus reveal distinct functions of Vγ4 and Vγ1 γδ T cells in antitumor immune response, and identify a protective role of activated Vγ4 γδ T cells, with possible implications for tumor immune therapy.
Human T-Lymphotropic Virus Type 1-Induced CC Chemokine Ligand 22 Maintains a High Frequency of Functional FoxP3+ Regulatory T Cells
Authors: Toulza Frederic , Nosaka Kisato , Tanaka Yuetsu , Schioppa Tiziana , Balkwill Frances , Taylor Graham P. , Bangham Charles R. M. 
Published: June 2010

Abstract
We recently reported that human T-lymphotropic virus type 1 (HTLV-1) infection is accompanied by a high frequency of CD4+FoxP3+ cells in the circulation. In asymptomatic carriers of HTLV-1 and in patients with HTLV-1–associated inflammatory and malignant diseases, a high FoxP3+ cell frequency correlated with inefficient cytotoxic T cell-mediated killing of HTLV-1–infected cells. In adult T cell leukemia/lymphoma (ATLL), the FoxP3+ population was distinct from the leukemic T cell clones. However, the cause of the increase in FoxP3+ cell frequency in HTLV-1 infection was unknown. In this study, we report that the plasma concentration of the chemokine CCL22 is abnormally high in HTLV-1–infected subjects and that the concentration is strongly correlated with the frequency of FoxP3+ cells, which express the CCL22 receptor CCR4. Further, we show that CCL22 is produced by cells that express the HTLV-1 transactivator protein Tax, and that the increased CCL22 enhances the migration and survival of FoxP3+ cells in vitro. Finally, we show that FoxP3+ cells inhibit the proliferation of ex vivo, autologous leukemic clones from patients with ATLL. We conclude that HTLV-1–induced CCL22 causes the high frequency of FoxP3+ cells observed in HTLV-1 infection; these FoxP3+ cells may both retard the progression of ATLL and HTLV-1–associated inflammatory diseases and contribute to the immune suppression seen in HTLV-1 infection, especially in ATLL.
Dilute Doping, Defects, and Ferromagnetism in Metal Oxide Systems
Authors: Ogale Satishchandra B. 
Published: June 2010

AbstractOver the past decade intensive research efforts have been carried out by researchers around the globe on exploring the effects of dilute doping of magnetic impurities on the physical properties of functional non‐magnetic metal oxides such as TiO2 and ZnO. This effort is aimed at inducing spin functionality (magnetism, spin polarization) and thereby novel magneto‐transport and magneto‐optic effects in such oxides. After an early excitement and in spite of some very promising results reported in the literature, this field of diluted magnetic semiconducting oxides (DMSO) has continued to be dogged by concerns regarding uniformity of dopant incorporation, the possibilities of secondary ferromagnetic phases, and contamination issues. The rather sensitive dependence of magnetism of the DMSO systems on growth methods and conditions has led to interesting questions regarding the specific role played by defects in the attendant phenomena. Indeed, it has also led to the rapid re‐emergence of the field of defect ferromagnetism. Many theoretical studies have contributed to the analysis of diverse experimental observations in this field and in some cases to the predictions of new systems and scenarios. In this review an attempt is made to capture the scope and spirit of this effort highlighting the successes, concerns, and questions.
Biological Nutrient Removal Using a Novel Laboratory‐Scale Twin Fluidized‐Bed Bioreactor
Authors: Andalib M. , Nakhla G. , Zhu J. 
Published: June 2010

AbstractThe capability of biological nutrient removal from wastewater of a novel laboratory‐scale twin fluidized‐bed bioreactor (TFBBR) was studied. The work showed approximately 96 % organic matter, 84 % nitrogen, and 12 % phosphorus removal efficiencies in the first three phases of the study at influent synthetic municipal wastewater (SMW) flow rates of 150, 190, and 240 L/d, with corresponding organic loading rates of 1.3, 1.7, and 2.3 kg COD m–3 d–1 and nitrogen loading rates of 0.14, 0.18 and 0.25 kg N m–3 d–1. The TFBBR effluent was characterized by <1.0 mg NH4‐N/L, <4.3 mg NO3‐N/L, <6 mg TN/L, <6 mg SBOD/L, and 6–10 mg VSS/L. For the three phases, biomass yields of 0.06, 0.066, and 0.071 g VSS/g COD were observed, respectively, which was a significant further reduction in yield compared to the liquid‐solid circulating fluidized‐bed bioreactor technology developed and patented by this research group, of 0.12–0.16 g VSS/g COD. The very low yield was due to a longer solid retention time of 72–108 d.