bluuebunny/crossref_metadata_2025_split huggingface dataset:
Downstream of Kinase, p62dok, Is a Mediator of FcγRIIB Inhibition of FcεRI Signaling
Authors: Ott Vanessa L. , Tamir Idan , Niki Masaru , Pandolfi Pier Paolo , Cambier John C. 
Published: April 2014

Abstract
The low-affinity receptor for IgG, FcγRIIB, is expressed widely in the immune system and functions to attenuate Ag-induced immune responses. In mast cells, coaggregation of FcγRIIB with the high-affinity IgE receptor, FcεRI, leads to inhibition of Ag-induced degranulation and cytokine production. FcγRIIB inhibitory activity requires a conserved motif within the FcγRIIB cytoplasmic domain termed the immunoreceptor tyrosine-based inhibition motif. When coaggregated with an activating receptor (e.g., FcεRI, B cell Ag receptor), FcγRIIB is rapidly phosphorylated on tyrosine and recruits the SH2 domain-containing inositol 5-phosphatase (SHIP). However, the mechanisms by which SHIP mediates FcγRIIB inhibitory function in mast cells remain poorly defined. In this report we demonstrate that FcγRIIB coaggregation with FcεRI stimulates enhanced SHIP tyrosine phosphorylation and association with Shc and p62dok. Concurrently, enhanced p62dok tyrosine phosphorylation and association with RasGAP are observed, suggesting that SHIP may mediate FcγRIIB inhibitory function in mast cells via recruitment of p62dok and RasGAP. Supporting this hypothesis, recruitment of p62dok to FcεRI is sufficient to inhibit FcεRI-induced calcium mobilization and extracellular signal-regulated kinase 1/2 activation. Interestingly, both the amino-terminal pleckstrin homology and phosphotyrosine binding domains and the carboxyl-terminal proline/tyrosine-rich region of p62dok can mediate inhibition, suggesting activation of parallel downstream signaling pathways that converge at extracellular signal-regulated kinase 1/2 activation. Finally, studies using gene-ablated mice indicate that p62dok is dispensable for FcγRIIB inhibitory signaling in mast cells. Taken together, these data suggest a role for p62dok as a mediator of FcγRIIB inhibition of FcεRI signal transduction in mast cells.
CD28 Costimulation Induces δ Opioid Receptor Expression During Anti-CD3 Activation of T Cells
Authors: Nguyen Khanh , Miller Bonnie C. 
Published: April 2014

Abstract
Previous studies have demonstrated that naive splenic mouse T cells express no or only very low levels of the δ-type opioid receptor (δOR), but stimulation of mouse splenocytes with Con A results in induction of δOR mRNA and protein. In this report we have shown that stimulation of highly purified populations of naive mouse T cells with anti-CD3 mAb alone results in T cell activation, as evidenced by sustained IL-2 secretion and cell proliferation, but fails to elicit δOR expression. However, δOR expression is induced by costimulation of these very pure T cells with anti-CD3 and anti-CD28 mAbs. The δOR induction by anti-CD3 and anti-CD28 costimulation was completely blocked by inhibition of phosphatidylinositol 3-kinase with wortmannin. Because phosphatidylinositol 3-kinase activation in T cells is linked to costimulation, these results suggest that induction of δOR expression during T cell activation is strictly dependent on costimulation. It also appears that costimulatory receptors other than CD28 can provide the signaling required for δOR expression because δOR mRNA was induced by Con A stimulation of splenocytes from CD28-deficient mice.
Prostaglandin E2 Inhibits IL-18-Induced ICAM-1 and B7.2 Expression Through EP2/EP4 Receptors in Human Peripheral Blood Mononuclear Cells
Authors: Takahashi Hideo K. , Iwagaki Hiromi , Yoshino Tadashi , Mori Shuji , Morichika Toshihiko , Itoh Hideyuki , Yokoyama Minori , Kubo Shinichiro , Kondo Eisaku , Akagi Tadaatsu , Tanaka Noriaki , Nishibori Masahiro 
Published: April 2014

Abstract
Costimulatory molecules play important roles in immune responses. In the present study we investigated the effects of PGE2 on the expression of ICAM-1, B7.1, and B7.2 on monocytes in IL-18-stimulated PBMC using FACS analysis. Addition of PGE2 to PBMC inhibited ICAM-1 and B7.2 expression elicited by IL-18 in a concentration-dependent manner. We examined the involvement of four subtypes of PGE2 receptors, EP1, EP2, EP3, and EP4, in the modulatory effect of PGE2 on ICAM-1 and B7.2 expression elicited by IL-18, using subtype-specific agonists. ONO-AE1–259-01 (EP2R agonist) inhibited IL-18-elicited ICAM-1 and B7.2 expression in a concentration-dependent manner with a potency slightly less than that of PGE2, while ONO-AE1-329 (EP4R agonist) was much less potent than PGE2. The EP2/EP4R agonist 11-deoxy-PGE1 mimicked the effect of PGE2 with the same potency. ONO-D1-004 (EP1R agonist) and ONO-AE-248 (EP3R agonist) showed no effect on IL-18-elicited ICAM-1 or B7.2 expression. These results indicated that EP2 and EP4Rs were involved in the action of PGE2. Dibutyryl cAMP and forskolin down-regulated ICAM-1 and B7.2 expression in IL-18-stimulated monocytes. As EP2 and EP4Rs are coupled to adenylate cyclase, we suggest that PGE2 down-regulates IL-18-induced ICAM-1 and B7.2 expression in monocytes via EP2 and EP4Rs by cAMP-dependent signaling pathways. The fact that anti-B7.2 as well as anti-ICAM-1 Ab inhibited IL-18-induced cytokine production implies that PGE2 may modulate the immune response through regulation of the expression of particular adhesion molecules on monocytes via EP2 and EP4Rs.
Generation of CD8+ T Cell Memory in Response to Low, High, and Excessive Levels of Epitope
Authors: Wherry E. John , McElhaugh Michael J. , Eisenlohr Laurence C. 
Published: April 2014

AbstractThe magnitude of a virus-specific memory CTL population can dramatically influence the outcome of secondary infections, yet little is known about the determinants of memory size. We investigated the impact of epitope levels on CTL memory generation by using a recombinant vaccinia virus system that allows for a broad range of epitope expression with the same infectious dose of virus. The size of the memory pool was examined using MHC class I/peptide tetramer staining and IFN-γ ELISPOT analysis following priming with viruses expressing low, high, or excessive epitope levels. The size of the epitope-specific CD8+ T cell memory population correlates with Ag dose at the low and high levels of epitope expression. However, at excessive epitope levels, the number of functional, IFN-γ-producing, epitope-specific memory cells is significantly reduced compared with the number of tetramer+ cells. These results demonstrate that the level of epitope expressed during an acute viral infection in vivo can dramatically influence CTL memory size. Furthermore, when epitope is overexpressed, the quality of the response can be adversely affected. Therefore, epitope expression level is an important consideration when developing approaches to optimize CTL memory induction.
Alefacept, an Immunomodulatory Recombinant LFA-3/IgG1 Fusion Protein, Induces CD16 Signaling and CD2/CD16-Dependent Apoptosis of CD2+ Cells
Authors: da Silva Antonio J. , Brickelmaier Margot , Majeau Gerard R. , Li Zhifang , Su Lihe , Hsu Yen-Ming , Hochman Paula S. 
Published: April 2014

Abstract
Alefacept, an immunomodulatory recombinant fusion protein composed of the first extracellular domain of LFA-3 fused to the human IgG1 hinge, CH2, and CH3 domains, has recently been shown in phase II and III clinical trials to safely reduce disease expression in patients with chronic plaque psoriasis. Alefacept modulates the function of and selectively induces apoptosis of CD2+ human memory-effector T cells in vivo. We have sought to gain further understanding of the mechanisms of action that influence the biological activity of alefacept and may contribute to its efficacy and patient responsiveness. Specifically evaluated is the ability of alefacept to activate intracellular signals mediated via CD2 and/or FcγRIII (CD16). Experimentation using isoforms of alefacept engineered to have amino acid substitutions in the IgG1 CH2 domain that impact FcγR binding indicate that alefacept mediates cognate interactions between cells expressing human CD2 and CD16 to activate cells, e.g., increase extracellular signal-regulated kinase phosphorylation, up-regulate cell surface expression of the activation marker CD25, and induce release of granzyme B. In the systems used, this signaling is shown to require binding to CD2 and CD16 and be mediated through CD16, but not CD2. Experimentation using human CD2-transgenic mice and isoforms of alefacept confirmed the requirement for FcγR binding for detection of the pharmacological effects of alefacept in vivo. Thus alefacept acts as an effector molecule, mediating cognate interactions to activate FcγR+ cells (e.g., NK cells) to induce apoptosis of sensitive CD2+ target cells.
A Role for IFN-γ in Primary and Secondary Immunity Generated by NK Cell-Sensitive Tumor-Expressing CD80 In Vivo
Authors: Kelly Janice M. , Takeda Kazuyoshi , Darcy Phillip K. , Yagita Hideo , Smyth Mark J. 
Published: April 2014

Abstract
We have investigated the primary and secondary immunity generated in vivo by a MHC class I-deficient tumor cell line that expressed CD80 (B7-1). CD80 expression enhanced primary NK cell-mediated tumor rejection in vivo and T cell immunity against secondary tumor challenge. CD80 expression enhanced primary NK cell-mediated tumor rejection, and both NK cell perforin and IFN-γ activity were critical for the rejection of MHC class I-deficient RMA-S-CD80 tumor cells. This primary rejection process stimulated the subsequent development of specific CTL and Th1 responses against Ags expressed by the MHC class I-deficient RMA-S tumor cells. The development of effective secondary T cell immunity could be elicited by irradiated RMA-S-CD80 tumor cells and was dependent upon NK cells and IFN-γ in the priming response. Our findings demonstrate a key role for IFN-γ in innate and adaptive immunity triggered by CD80 expression on tumor cells.
The Src Family Kinase Fyn Mediates Signals Induced by TCR Antagonists
Authors: Tang Qizhi , Subudhi Sumit K. , Henriksen Kammi J. , Long Catherine G. , Vives Franklin , Bluestone Jeffrey A. 
Published: April 2014

Abstract
FcR nonbinding anti-CD3ε mAbs elicit partial TCR signaling that leads to T cell unresponsiveness and tolerance in vivo. In this study, the membrane-proximal events that promote T cell inactivation by FcR nonbinding anti-CD3 mAbs were examined. In the context of FcR nonbinding anti-CD3, TCR complexes did not aggregate and failed to translocate into glycolipid-enriched membrane microdomains. Furthermore, FcR nonbinding anti-CD3 mAbs induced tyrosine phosphorylation of the Fyn substrate Cbl, but not the ZAP-70 substrate linker for activation of T cells. Overexpression of Fyn, but not Lck, restored the mitogenicity of FcR nonbinding anti-CD3 in primary T cells. Taken together, these results suggest that Fyn mediates the partial signaling induced by TCR antagonists.
IFN Regulatory Factor-1 Regulates IFN-γ-Dependent Cathepsin S Expression
Authors: Storm van’s Gravesande Karin , Layne Matthew D. , Ye Qiang , Le Louis , Baron Rebecca M. , Perrella Mark A. , Santambrogio Laura , Silverman Eric S. , Riese Richard J. 
Published: April 2014

Abstract
Cathepsin S is a cysteine protease with potent endoproteolytic activity and a broad pH profile. Cathepsin S activity is essential for complete processing of the MHC class II-associated invariant chain within B cells and dendritic cells, and may also be important in extracellular matrix degradation in atherosclerosis and emphysema. Unique among cysteine proteases, cathepsin S activity is up-regulated by IFN-γ. Given its importance, we sought to elucidate the pathway by which IFN-γ increases cathepsin S expression. Our data demonstrate that the cathepsin S promoter contains an IFN-stimulated response element (ISRE) that is critical for IFN-γ-induced gene transcription in a cell line derived from type II alveolar epithelial (A549) cells. IFN response factor (IRF)-2 derived from A549 nuclear extracts associates with the ISRE oligonucleotide in gel shift assays, but is quickly replaced by IRF-1 following stimulation with IFN-γ. The time course of IRF-1/ISRE complex formation correlates with increased levels of IRF-1 protein and cathepsin S mRNA. Overexpression of IRF-1, but not IRF-2, markedly augments cathepsin S promoter activity in A549 cells. Furthermore, overexpression of IRF-1 increases endogenous cathepsin S mRNA levels in 293T epithelial cells. Finally, freshly isolated bone marrow cells from IRF-1−/− mice fail to up-regulate cathepsin S activity in response to IFN-γ. Thus, IRF-1 is the critical transcriptional mediator of IFN-γ-dependent cathepsin S activation. These data elucidate a new pathway by which IRF-1 may affect MHC class II processing and presentation.
Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway
Authors: Stephensen Charles B. , Rasooly Reuven , Jiang Xiaowen , Ceddia Michael A. , Weaver Casey T. , Chandraratna Roshantha A. S. , Bucy R. Patterson 
Published: April 2014

Abstract
Vitamin A deficiency diminishes Th2-mediated Ab responses, and high-level dietary vitamin A or treatment with the vitamin A metabolite retinoic acid (RA) enhances such responses. To identify a potential mechanism(s) underlying this in vivo activity of vitamin A, we examined the effects of all-trans and 9-cis RA on development of Th1 and Th2 cell populations using in vitro stimulation of Ag-naive Th0 cells from the DO11.10 TCR-transgenic mouse. Treatment with 9-cis, but not with all-trans RA, at primary stimulation strongly enhanced Th2 development. IL-4-neutralizing Ab blocked this activity, but IL-12- and IFN-γ-neutralizing Ab did not. Because 9-cis RA regulates gene transcription via either RA receptors or retinoid X receptors (RXRs), we tested the Th2-enhancing activities of the RXR- and RA receptor-selective agonists AGN194204 and 4-((E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TTNPB). AGN194204 strongly enhanced Th2 development, whereas TTNPB did not. This RXR agonist also enhanced Th2 development when purified, naive Th0 cells (L-selectinhigh/CD4+) were stimulated with CD3 and CD28 Abs in the absence of APCs. During primary antigenic stimulation of naive Th0 cells from DO11.10 mice, AGN194204 increased IL-4 and IL-5 production, decreased IFN-γ production, increased mRNA in responding T cells for genes involved in Th2 development (IL-4, GATA-3, and c-maf), and decreased mRNA for genes involved in Th1 development (IFN-γ, T-bet, and IL-12R). These data show that stimulation of the RXR pathway enhances Th2 development, perhaps by affecting the relative expression of pertinent transcription factors, cytokines, and cytokine receptors.
Tissue-Level Regulation of Th1 and Th2 Primary and Memory CD4 T Cells in Response to Listeria Infection
Authors: Marzo Amanda L. , Vezys Vaiva , Williams Kristina , Tough David F. , Lefrançois Leo 
Published: April 2014

Abstract
Ag-specific Th1 and Th2 cytokine-producing CD4 T cells were quantitated in secondary lymphoid and tertiary tissues following oral Listeria monocytogenes infection. Although the response to Listeria was previously believed to be predominately Th1 like, CD4 T cells producing IL-4 or IL-5 comprised a substantial proportion of the overall primary and memory response. The frequency of IFN-γ-, IL-4-, or IL-5-producing primary effector or memory CD4 T cells was significantly higher in lung, liver, and intestinal lamina propria (LP) as compared with spleen and lymph node. However, maximum numbers of IL-4- and IL-5-producing cells were detected in the LP several days after the peak of the Th1 response, and IL-5 production was skewed toward the mucosal tissues. Remarkably, the recall response resulted in sustained Th1 and Th2 responses in tertiary, but not lymphoid tissues and long-term retention of Th1 and Th2 memory cells in equal proportions in the LP. Finally, CD40 ligand was essential for induction of IFN-γ in the spleen and LP, but not in the liver and lung, while the IL-4 response required CD40 ligand only in the spleen. Therefore, the rules governing the effector phenotype, and the overall magnitude of the CD4 response, are regulated at the level of individual tissues.
Expression of the Tyrosine Phosphatase Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 1 Determines T Cell Activation Threshold and Severity of Experimental Autoimmune Encephalomyelitis
Authors: Deng Caishu , Minguela Alfredo , Hussain Rehana Z. , Lovett-Racke Amy E. , Radu Caius , Ward E. Sally , Racke Michael K. 
Published: April 2014

Abstract
Experimental autoimmune encephalomyelitis (EAE) is a CD4 Th1-mediated inflammatory demyelinating disorder of the CNS and a well-established animal model for multiple sclerosis. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic tyrosine phosphatase that is involved in regulating the T cell activation cascade from signals initiated through the TCR. To study the role of SHP-1 in EAE pathogenesis, we immunized B10.PL mice heterozygous for deletion of the SHP-1 gene (mev+/−) and B10.PL wild-type mice with the immunodominant epitope of myelin basic protein (MBP Ac1-11). T cell proliferation and IFN-γ production were significantly increased in mev+/− mice after immunization with MBP Ac1-11. The frequency of MBP Ac1-11-specific CD4 T cells, analyzed by staining with fluorescently labeled tetramers (MBP1-11[4Y]: I-Au complexes), was increased in the draining lymph node cells of mev+/− mice compared with wild-type mice. In addition, mev+/− mice developed a more severe course of EAE with epitope spreading to proteolipid protein peptide 43-64. Finally, expansion of MBP Ac1-11-specific T cells in response to Ag was enhanced in mev+/− T cells, particularly at lower Ag concentrations. These data demonstrate that the level of SHP-1 plays an important role in regulating the activation threshold of autoreactive T cells.
The CD3γ Leucine-Based Receptor-Sorting Motif Is Required for Efficient Ligand-Mediated TCR Down-Regulation
Authors: von Essen Marina , Menné Charlotte , Nielsen Bodil L. , Lauritsen Jens Peter H. , Dietrich Jes , Andersen Peter S. , Karjalainen Klaus , Ødum Niels , Geisler Carsten 
Published: April 2014

Abstract
TCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. At least two distinct pathways exist for down-regulation of the TCR. One pathway is activated following TCR ligation and is dependent on tyrosine phosphorylation. The other pathway is dependent on protein kinase C (PKC)-mediated activation of the CD3γ di-leucine-based receptor-sorting motif. Previous studies have failed to demonstrate a connection between ligand- and PKC-induced TCR down-regulation. Thus, although an apparent paradox, the dogma has been that ligand- and PKC-induced TCR down-regulations are not interrelated. By analyses of a newly developed CD3γ-negative T cell variant, freshly isolated and PHA-activated PBMC, and a mouse T cell line, we challenged this dogma and demonstrate in this work that PKC activation and the CD3γ di-leucine-based motif are indeed required for efficient ligand-induced TCR down-regulation.
Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells
Authors: Dabbagh Karim , Dahl Martin E. , Stepick-Biek Pamela , Lewis David B. 
Published: April 2014

Abstract
LPS potently induces dendritic cell maturation and the production of proinflammatory cytokines, such as IL-12, by activation of Toll-like receptor 4 (TLR4). Since IL-12 is important for the generation and maintenance of Th1 responses and may also inhibit Th2 cell generation from naive CD4 T cell precursors, it has been inferred that TLR4 signaling would have similar effects via the induction of IL-12 secretion. Surprisingly, we found that TLR4-defective mice subjected to sensitization and pulmonary challenge with a protein allergen had reductions in airway inflammation with eosinophils, allergen-specific IgE levels, and Th2 cytokine production, compared with wild-type mice. These reduced responses were attributable, at least in part, to decreased dendritic cell function: Dendritic cells from TLR4-defective mice expressed lower levels of CD86, a costimulatory molecule important for Th2 responses. They also induced less Th2 cytokine production by antigenically naive CD4 T cells in vitro and mediated diminished CD4 T cell Ag-specific pulmonary inflammation in vivo. These results indicate that TLR4 is required for optimal Th2 responses to Ags from nonpathogenic sources and suggest a role for TLR4 ligands, such as LPS derived from commensal bacteria or endogenously derived ligands, in maturation of the innate immune system before pathogen exposure.
Quantitative Expression of Toll-Like Receptor 1–10 mRNA in Cellular Subsets of Human Peripheral Blood Mononuclear Cells and Sensitivity to CpG Oligodeoxynucleotides
Authors: Hornung Veit , Rothenfusser Simon , Britsch Stefanie , Krug Anne , Jahrsdörfer Bernd , Giese Thomas , Endres Stefan , Hartmann Gunther 
Published: April 2014

AbstractThe Toll-like receptor (TLR)9 is critical for the recognition of immunostimulatory CpG motifs but may cooperate with other TLRs. We analyzed TLR1–10 mRNA expression by using quantitative real-time PCR in highly purified subsets of human PBMC and determined the sensitivity of these subsets to CpG oligodeoxynucleotides (ODN). TLR1 and TLR6 were expressed in all cell types examined. TLR10 was highly expressed in B cells and weakly expressed in plasmacytoid dendritic cells (PDC). High expression of TLR2 was characteristic for monocytes. PDC and B cells expressed marked levels of TLR7 and TLR9 and were directly sensitive to CpG ODN. In CpG ODN-stimulated PDC and B cells, TLR9 expression rapidly decreased, as opposed to TLR7, which was up-regulated in PDC and decreased in B cells. In monocytes, NK cells, and T cells, TLR7 was absent. Despite low expression of TLR9, monocytes, NK cells, and T cells did not respond to CpG ODN in the absence of PDC but were activated in the presence of PDC. In conclusion, our studies provide evidence that PDC and B cells, but not monocytes, NK cells, or T cells, are primary targets of CpG ODN in peripheral blood. The characteristic expression pattern of TLR1–10 in cellular subsets of human PBMC is consistent with the concept that TLR9 is essential in the recognition of CpG ODN in PDC and B cells. In addition, selective regulation of TLR7 expression in PDC and B cells by CpG ODN revealed TLR7 as a candidate TLR potentially involved in modulating the recognition of CpG motifs.
Friend of GATA Is Expressed in Naive Th Cells and Functions As a Repressor of GATA-3-Mediated Th2 Cell Development
Authors: Kurata Hirokazu , Lee Hyun-Jun , McClanahan Terri , Coffman Robert L. , O’Garra Anne , Arai Naoko 
Published: April 2014

Abstract
The commitment of naive T cells to polarized Th cells requires specific changes in their transcription factors. Retrovirally overexpressed GATA-3 has been reported to induce the Th2 cytokine profile in developing Th1 cells. In this study, we examined the role of the N-terminal finger (Nf) of GATA-3 in Th2 cell development. The Nf, as well as the C-terminal finger and the transactivation domain, is critical for the induction of the Th2 phenotype. Using the GATA-3-Nf as a bait, our yeast two-hybrid screening identified friend of GATA (FOG) in the Th2 cell-specific library. Naive T cells express significant levels of FOG mRNA, which was rapidly down-regulated upon commitment to both Th1 and Th2 lineages. In reporter assays, FOG blocked the GATA-3-mediated activation of several cytokine promoters. Finally, retroviral expression of FOG in developing Th2 cells suppressed both IL-4 and IL-5 and allowed for IFN-γ production, which was accompanied by a significant level of T-bet mRNA expression. Serial deletion mutation analysis indicated that the N-terminal region, but not the consensus C-terminal binding protein-binding motif, of FOG is critical for the effects. Our results clearly indicate that 1) FOG is a repressor of GATA-3 in naive T cells and 2) the down-regulation of FOG induces Th2 cell differentiation by releasing GATA-3 from its repression.