bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Low Affinity Fc Receptor for IgG Functions as an Effective Cytolytic Receptor for Self-Specific CD8 T Cells
Authors: Dhanji Salim , Tse Kathy , Teh Hung-Sia 
Published: April 2014

AbstractWe have recently described a population of self-Ag-specific murine CD8+ T cells with a memory phenotype that use receptors of both the adaptive and innate immune systems in the detection of transformed and infected cells. In this study we show that upon activation with IL-2 with or without Ag, between 10 and 20% of the activated self-specific CD8+ T cells express the low affinity FcR for IgG. By contrast, all IL-2-activated NK cells express high levels of this FcR. The FcR comprises the FcγRIIIα and FcRγ subunits. However, the FcRγ subunit also associates with the CD3 complex, and this association probably contributes to the low expression of FcR in activated cells. Although the FcR is expressed at a low level on activated self-specific CD8+ T cells, it functions very efficiently as a cytolytic receptor in ADCC. FcR-dependent killing occurred in the absence of TCR stimulation, but could be augmented by concurrent stimulation of the TCR. In addition to mediating ADCC, engagement of the FcR on self-specific CD8+ T cells results in the production of both IFN-γ and TNF-α. This is the first report of an activating FcR on self-specific murine CD8+αβ TCR+ T cells and establishes the importance of innate immune system receptors in the function of these self-specific CD8+ T cells.
Synthetic TLR Agonists Reveal Functional Differences between Human TLR7 and TLR8
Authors: Gorden Keith B. , Gorski Kevin S. , Gibson Sheila J. , Kedl Ross M. , Kieper William C. , Qiu Xiaohong , Tomai Mark A. , Alkan Sefik S. , Vasilakos John P. 
Published: April 2014

Abstract
Although TLR7 and TLR8 are phylogenetically and structurally related, their relative functions are largely unknown. The role of TLR7 has been established using TLR7-deficient mice and small molecule TLR7 agonists. The absence of TLR8-selective agonists has hampered our understanding of the role of TLR8. In this study TLR agonists selective for TLR7 or TLR8 were used to determine the repertoire of human innate immune cells that are activated through these TLRs. We found that TLR7 agonists directly activated purified plasmacytoid dendritic cells and, to a lesser extent, monocytes. Conversely, TLR8 agonists directly activated purified myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells (GM-CSF/IL-4/TGF-β). Accordingly, TLR7-selective agonists were more effective than TLR8-selective agonists at inducing IFN-α- and IFN-regulated chemokines such as IFN-inducible protein and IFN-inducible T cell α chemoattractant from human PBMC. In contrast, TLR8 agonists were more effective than TLR7 agonists at inducing proinflammatory cytokines and chemokines, such as TNF-α, IL-12, and MIP-1α. Thus, this study demonstrated that TLR7 and TLR8 agonists differ in their target cell selectivity and cytokine induction profile.
Bone Marrow Is a Preferred Site for Homeostatic Proliferation of Memory CD8 T Cells
Authors: Becker Todd C. , Coley Shana M. , Wherry E. John , Ahmed Rafi 
Published: April 2014

Abstract
Proliferative renewal of memory CD8 T cells is essential for maintaining long-term immunity. In this study, we examined the contributions that various tissue microenvironments make toward the homeostatic proliferation of Ag-specific memory CD8 T cells. We found that dividing memory T cells were present in both lymphoid and nonlymphoid tissues. However, the bone marrow was the preferred site for proliferation and contained a major pool of the most actively dividing memory CD8 T cells. Adoptive transfer studies indicated that memory cells migrated through the bone marrow and divided there preferentially. These results show that the bone marrow is not only the source of stem cells for generating naive T cells but also provides the necessary signals for the self-renewal of memory T cells.
CD226 Expression Deficiency Causes High Sensitivity to Apoptosis in NK T Cells from Patients with Systemic Lupus Erythematosus
Authors: Tao Deng , Shangwu Liu , Qun Wu , Yan Liu , Wei Ju , Junyan Liu , Feili Gong , Boquan Jin , Jinquan Tan 
Published: April 2014

Abstract
Humans and mice with systemic lupus erythematosus (SLE) and related autoimmune diseases have reduced numbers of NK T cells. An association between NK T cell deficiency and autoimmune disease has been identified. However, the mechanisms for reduction of NK T cell number in patients with SLE are unknown. In the present study we report that NK T cells from active SLE patients are highly sensitive to anti-CD95-induced apoptosis compared with those from normal subjects and inactive SLE patients. CD226 expression is deficient on NK T cells from active SLE patients. The expression of one antiapoptotic member protein, survivin, is found to be selectively deficient in freshly isolated NK T cells from active SLE patients. CD226 preactivation significantly up-regulates survivin expression and activation, which can rescue active SLE NK T cells from anti-CD95-induced apoptosis. In transfected COS7 cells, we confirm that anti-CD95-mediated death signals are inhibited by activation of the CD226 pathway through stabilization of caspase-8 and caspase-3 and through activation of survivin. We therefore conclude that deficient expression of CD226 and survivin in NK T cells from active SLE is a molecular base of high sensitivity of the cells to anti-CD95-induced apoptosis. These observations offer a potential explanation for high apoptotic sensitivity of NK T cells from active SLE, and provide a new insight into the mechanism of reduction of NK T cell number in SLE and understanding the association between NK T cell deficiency and autoimmune diseases.
Heat Shock Protein 60: Specific Binding of Lipopolysaccharide
Authors: Habich Christiane , Kempe Karina , van der Zee Ruurd , Rümenapf Robert , Akiyama Hidehiko , Kolb Hubert , Burkart Volker 
Published: April 2014

Abstract
Human heat shock protein 60 (HSP60) has been shown to bind to the surface of innate immune cells and to elicit a proinflammatory response. In this study we demonstrate that the macrophage stimulatory property of recombinant human HSP60 is tightly linked to the HSP60 molecule and is lost after protease treatment. However, inhibition of macrophage stimulation was reached by the LPS-binding peptide magainin II amide. Indeed, HSP60 specifically bound [3H]LPS. [3H]LPS binding to HSP60 was saturable and competable by the unlabeled ligand. To identify the epitope region of the HSP60 molecule responsible for specific LPS binding, we analyzed the effect of several anti-HSP60 mAbs on HSP60-induced production of inflammatory mediators from macrophages. We identified only one mAb, clone 4B9/89, which blocked the macrophage stimulatory activity of the chaperone. The epitope specificity of this mAb points to the region aa 335–366 of HSP60. Clone 4B9/89 also strongly inhibited [3H]LPS binding to HSP60. A more detailed analysis was performed by screening with selected overlapping 20-mer peptides of the HSP60 sequence, covering the region aa 331–380. Only one peptide blocked LPS binding to HSP60, thereby restricting the potential LPS-binding region to aa 351–370 of HSP60. Finally, analysis of selected 15-mer peptides and a 13-mer peptide of the HSP60 sequence revealed that most of the LPS-binding region was accounted for by aa 354–365 of HSP60, with the motif LKGK being critical for binding. Our studies identified a defined region of HSP60 involved in LPS binding, thereby implicating a physiological role of human HSP60 as LPS-binding protein.
Limited Ability of Antigen-Specific Th1 Responses to Inhibit Th2 Cell Development In Vivo
Authors: Yasumi Takahiro , Katamura Kenji , Okafuji Ikuo , Yoshioka Takakazu , Meguro Taka-aki , Nishikomori Ryuta , Kusunoki Takashi , Heike Toshio , Nakahata Tatsutoshi 
Published: April 2014

AbstractTh1 and Th2 cells mutually antagonize each other’s differentiation. Consequently, allergen-specific Th1 cells are believed to be able to suppress the development of Th2 cells and to prevent the development of atopic disorders. To determine whether a pre-existing Ag-specific Th1 response can affect the development of Th2 cells in vivo, we used an immunization model of Ag-pulsed murine dendritic cell (DC) transfer to induce distinct Th responses. When transferred into naive mice, Ag-pulsed CD8α+ DCs induced a Th1 response and the production of IgG2a, whereas CD8α− DCs primed a Th2 response and the production of IgE. In the presence of a pre-existing Ag-specific Th2 environment due to Ag-pulsed CD8α− DC transfer, CD8α+ DCs failed to prime Th1 cells. In contrast, CD8α− DCs could prime a Th2 response in the presence of a pre-existing Ag-specific Th1 environment. Moreover, exogenous IL-4 abolished the Th1-inducing potential of CD8α+ DCs in vitro, but the addition of IFN-γ did not effectively inhibit the potential of CD8α− DCs to prime IL-4-producing cells. Thus, Th1 and Th2 cells differ in their potential to inhibit the development of the other. This suggests that the early induction of allergen-specific Th1 cells before allergy sensitization will not prevent the development of atopic disorders.
Dynamic Interactions of Fcγ Receptor IIB with Filamin-Bound SHIP1 Amplify Filamentous Actin-Dependent Negative Regulation of Fcε Receptor I Signaling
Authors: Lesourne Renaud , Fridman Wolf H. , Daëron Marc 
Published: April 2014

Abstract
The engagement of high affinity receptors for IgE (FcεRI) generates both positive and negative signals whose integration determines the intensity of mast cell responses. FcεRI-positive signals are also negatively regulated by low affinity receptors for IgG (FcγRIIB). Although the constitutive negative regulation of FcεRI signaling was shown to depend on the submembranous F-actin skeleton, the role of this compartment in FcγRIIB-dependent inhibition is unknown. We show in this study that the F-actin skeleton is essential for FcγRIIB-dependent negative regulation. It contains SHIP1, the phosphatase responsible for inhibition, which is constitutively associated with the actin-binding protein, filamin-1. After coaggregation, FcγRIIB and FcεRI rapidly interact with the F-actin skeleton and engage SHIP1 and filamin-1. Later, filamin-1 and F-actin dissociate from FcR complexes, whereas SHIP1 remains associated with FcγRIIB. Based on these results, we propose a dynamic model in which the submembranous F-actin skeleton forms an inhibitory compartment where filamin-1 functions as a donor of SHIP1 for FcγRIIB, which concentrate this phosphatase in the vicinity of FcεRI and thereby extinguish activation signals.
Kinase-Independent Functions for Itk in TCR-Induced Regulation of Vav and the Actin Cytoskeleton
Authors: Dombroski Derek , Houghtling Richard A. , Labno Christine M. , Precht Patricia , Takesono Aya , Caplen Natasha J. , Billadeau Daniel D. , Wange Ronald L. , Burkhardt Janis K. , Schwartzberg Pamela L. 
Published: April 2014

Abstract
The Tec family kinase Itk is an important regulator of Ca2+ mobilization and is required for in vivo responses to Th2-inducing agents. Recent data also implicate Itk in TCR-induced regulation of the actin cytoskeleton. We have evaluated the requirements for Itk function in TCR-induced actin polarization. Reduction of Itk expression via small interfering RNA treatment of the Jurkat human T lymphoma cell line or human peripheral blood T cells disrupted TCR-induced actin polarization, a defect that correlated with decreased recruitment of the Vav guanine nucleotide exchange factor to the site of Ag contact. Vav localization and actin polarization could be rescued by re-expression of either wild-type or kinase-inactive murine Itk but not by Itk containing mutations affecting the pleckstrin homology or Src homology 2 domains. Additionally, we find that Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. Expression of membrane-targeted Vav, Vav-CAAX, can rescue the small interfering RNA to Itk-induced phenotype, implicating the alteration in Vav localization as directly contributing to the actin polarization defect. These data suggest a kinase-independent scaffolding function for Itk in the regulation of Vav localization and TCR-induced actin polarization.
Ig-Independent Igβ Expression on the Surface of B Lymphocytes after B Cell Receptor Aggregation
Authors: Kremyanskaya Marina , Monroe John G. 
Published: April 2014

Abstract
In order for humoral immune responses to develop, B cells must be able to recognize, bind, and internalize Ags. These functions are performed by the BCR, which is also responsible for initiating and transducing activation signals necessary for B cell proliferation and differentiation. We have examined surface expression patterns of individual components of the BCR following anti-Ig- and Ag-induced aggregation. Specifically, the localization and expression levels of the Ag-binding component, surface Ig (sIg), and the Igβ component of the Igα/Igβ signaling unit were investigated to determine their individual participation in the internalization and signal transduction. Using primary murine B cells, we found that while &gt;95% of the sIg is internalized following anti-Ig-induced aggregation, 20–30% of Igβ remains on the surface. These results suggest that sIg and Igβ may function independently following the initial stages of signal transduction.
A20 Is a Negative Regulator of IFN Regulatory Factor 3 Signaling
Authors: Saitoh Tatsuya , Yamamoto Masahiro , Miyagishi Makoto , Taira Kazunari , Nakanishi Makoto , Fujita Takashi , Akira Shizuo , Yamamoto Naoki , Yamaoka Shoji 
Published: April 2014

Abstract
IFN regulatory factor 3 (IRF-3) is a critical transcription factor that regulates an establishment of innate immune status following detection of viral pathogens. Recent studies have revealed that two IκB kinase (IKK)-like kinases, NF-κB-activating kinase/Traf family member-associated NF-κB activator-binding kinase 1 and IKK-i/IKKε, are responsible for activation of IRF-3, but the regulatory mechanism of the IRF-3 signaling pathway has not been fully understood. In this study, we report that IRF-3 activation is suppressed by A20, which was initially identified as an inhibitor of apoptosis and inducibly expressed by dsRNA. A20 physically interacts with NF-κB-activating kinase/Traf family member-associated NF-κB activator-binding kinase 1 and IKK-i/IKKε, and inhibits dimerization of IRF-3 following engagement of TLR3 by dsRNA or Newcastle disease virus infection, leading to suppression of the IFN stimulation response element- and IFN-β promoter-dependent transcription. Importantly, knocking down of A20 expression by RNA interference results in enhanced IRF-3-dependent transcription triggered by the stimulation of TLR3 or virus infection. Our study thus demonstrates that A20 is a candidate negative regulator of the signaling cascade to IRF-3 activation in the innate antiviral response.
A Common Polymorphism in the SFTPD Gene Influences Assembly, Function, and Concentration of Surfactant Protein D
Authors: Leth-Larsen Rikke , Garred Peter , Jensenius Henriette , Meschi Joseph , Hartshorn Kevan , Madsen Jens , Tornoe Ida , Madsen Hans O. , Sørensen Grith , Crouch Erika , Holmskov Uffe 
Published: April 2014

Abstract
Surfactant protein D (SP-D) plays important roles in the host defense against infectious microorganisms and in regulating the innate immune response to a variety of pathogen-associated molecular pattern. SP-D is mainly expressed by type II cells of the lung, but SP-D is generally found on epithelial surfaces and in serum. Genotyping for three single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met11Thr), 160 (Ala160Thr), and 270 (Ser270Thr) of the SP-D gene was performed and related to the SP-D levels in serum. Individuals with the Thr/Thr11-encoding genotype had significantly lower SP-D serum levels than individuals with the Met/Met11 genotype. Gel filtration chromatography revealed two distinct m.w. peaks with SP-D immunoreactivity in serum from Met/Met11-encoding genotypes. In contrast, Thr/Thr11 genotypes lacked the highest m.w. form. A similar SP-D size distribution was found for recombinant Met11 and Thr11 expressed in human embryonic kidney cells. Atomic force microscopy of purified SP-D showed that components eluting in the position of the high m.w. peak consist of multimers, dodecamers, and monomers of subunits, whereas the second peak exclusively contains monomers. SP-D from both peaks bound to mannan-coated ELISA plates. SP-D from the high m.w. peak bound preferentially to intact influenza A virus and Gram-positive and Gram-negative bacteria, whereas the monomeric species preferentially bound to isolated LPS. Our data strongly suggest that polymorphic variation in the N-terminal domain of the SP-D molecule influences oligomerization, function, and the concentration of the molecule in serum.
Antigen-Specific T Cells Maintain an Effector Memory Phenotype during Persistent Trypanosoma cruzi Infection
Authors: Martin Diana L. , Tarleton Rick L. 
Published: April 2014

Abstract
Infection with the protozoan parasite Trypanosoma cruzi is a major cause of morbidity and mortality in Central and South America. Control of acute experimental infection with T. cruzi is dependent on a robust T cell and type 1 cytokine response. However, little evidence exists demonstrating the development and persistence of a potent antiparasite T cell memory response, and there has been much speculation that the majority of the immune response to T. cruzi infection is not directed against the parasite. In this study, we used an experimental mouse model of T. cruzi infection to test both the Ag specificity and the functional and phenotypic characteristics of the responding T cell population. We observed a vigorous antiparasite response from both CD4+ and CD8+ T cells that was maintained in the face of persistent infection. T cells from infected mice also proliferated in response to re-exposure to Ag, and CD8+ T cells underwent spontaneous proliferation when transferred to naive congenic mice, both characteristic of central memory T cells. Interestingly, T cells from infected mice showed significant down-regulation of CD62L, a characteristic associated with an effector memory phenotype. These results suggest that T cells maintained in mice with chronic T. cruzi infection are fully functional memory cells that cannot be easily categorized in the current central/effector memory paradigm.
A Chemotactic Peptide from Laminin α5 Functions as a Regulator of Inflammatory Immune Responses via TNFα-mediated Signaling
Authors: Adair-Kirk Tracy L. , Atkinson Jeffrey J. , Kelley Diane G. , Arch Robert H. , Miner Jeffrey H. , Senior Robert M. 
Published: April 2014

Abstract
Tissue injury triggers inflammatory responses that may result in release of degradation products or exposure of cryptic domains of extracellular matrix components. Previously, we have shown that a cryptic peptide (AQARSAASKVKVSMKF) in the α-chain of laminin-10 (α5β1γ1), a prominent basement membrane component, is chemotactic for both neutrophils (PMNs) and macrophages (Mφs) and induces matrix metalloproteinase-9 (MMP-9) production. To determine whether AQARSAASKVKVSMKF has additional effects on inflammatory cells, we performed microarray analysis of RNA from RAW264.7 Mφs stimulated with AQARSAASKVKVSMKF. Several cytokines and cytokine receptors were increased &gt;3-fold in response to the laminin α5 peptide. Among these were TNF-α and one of its receptors, the p75 TNFR (TNFR-II), increasing 3.5- and 5.7-fold, respectively. However, the peptide had no effect on p55 TNFR (TNFR-I) expression. Corroborating the microarray data, the protein levels of TNF-α and TNFR-II were increased following stimulation of RAW264.7 cells with AQARSAASKVKVSMKF. In addition, we determined that the production of TNF-α and TNFR-II in response to AQARSAASKVKVSMKF preceded the production of MMP-9. Furthermore, using primary Mφs from mice deficient in TNFR-I, TNFR-II, or both TNF-α receptors (TNFRs), we determined that AQARSAASKVKVSMKF induces MMP-9 expression by Mφs through a pathway triggered by TNFR-II. However, TNF-α signaling is not required for AQARSAASKVKVSMKF-induced PMN release of MMP-9 or PMN emigration. These data suggest that interactions of inflammatory cells with basement membrane components may orchestrate immune responses by inducing expression of cytokines, recruitment of inflammatory cells, and release of proteinases.
Sle1ab Mediates the Aberrant Activation of STAT3 and Ras-ERK Signaling Pathways in B Lymphocytes
Authors: Liu Kui , Liang Chaoying , Liang Zhiyan , Tus Katalin , Wakeland Edward K. 
Published: April 2014

Abstract
The Sle1ab genomic interval on murine chromosome 1 mediates the loss of immune tolerance to chromatin resulting in antinuclear Abs (ANA) production in the lupus-prone NZM2410 mouse. Global gene expression analysis was used to identify the molecular pathways that are dysregulated at the initiation of B lymphocyte autoimmunity in B6.Sle1ab mice. This analysis identified that STAT3 and ras-ERK signaling pathways are aberrantly activated in Sle1ab B lymphocytes, consistent with increased production of IL-6 by splenic B lymphocytes and monocytes in B6.Sle1ab mice. In vitro treatment of splenic mononuclear cells isolated from ANA-positive Sle1ab mice with anti-IL-6 Ab or AG490, an inhibitor of STAT3 signaling pathway, suppressed ANA production in short-term culture, indicating that this pathway was essential to the production of autoantibodies. In vivo treatment of ANA-positive B6.Sle1ab mice with the ras pathway inhibitor, perillyl alcohol, suppressed the increase of ANA. These findings identify IL-6 as a early key cytokine in Sle1ab-mediated disease development and indicate that the STAT3 and ras-ERK signaling pathways are potential therapeutic targets for treating systemic lupus erythematosus.
Decoy Receptor 3 Increases Monocyte Adhesion to Endothelial Cells via NF-κB-Dependent Up-Regulation of Intercellular Adhesion Molecule-1, VCAM-1, and IL-8 Expression
Authors: Yang Chia-Ron , Hsieh Shie-Liang , Ho Feng-Ming , Lin Wan-Wan 
Published: April 2014

AbstractDecoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT and TL1A, is highly expressed in cancer cells. We show that pretreatment of HUVECs with DcR3 enhances the adhesion of THP-1 and U937 cells and primary monocytes. A similar stimulatory effect of DcR3 on THP-1 adhesion was also observed in human microvascular endothelial cells (HMVECs). Flow cytometry and ELISA showed that DcR3-treated HUVECs exhibited significant increases in ICAM-1 and VCAM-1 expression. We also demonstrate the ability of DcR3 to stimulate the secretion of IL-8 by HUVECs. RT-PCR and reporter assays revealed that the expression of adhesion molecules and IL-8 are regulated at the level of gene transcription. Experiments with pyrrolidine dithiocarbamate indicated the involvement of an NF-κB signaling pathway. DcR3 was found to induce IκB kinase activation, IκB degradation, p65 nuclear translocation, and NF-κB DNA-binding activity. The enhancement by DcR3 of cell adhesion to HUVECs was not mimicked by the TL1A-Ab, which has been shown in our previous work to be a neutralizing Ab against TL1A, thereby inducing HUVECs angiogenesis. Moreover, DcR3-induced cell adhesion could be detected in human aortic endothelial cells (ECs) in which TL1A expression is lacking. Together, our data demonstrate that DcR3 increases monocyte adhesion to ECs via NF-κB activation, leading to the transcriptional up-regulation of adhesion molecules and IL-8 in ECs. This novel action appears not to be due to TL1A neutralization, but occurs through an as yet undefined target(s). This study implicates DcR3 in the relationship between inflammation and cancer development.