bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inflammatory Cytokines Regulate Function and Expression of Adenosine A2A Receptors in Human Monocytic THP-1 Cells
Authors: Khoa Nguyen D. , Montesinos M. Carmen , Reiss Allison B. , Delano David , Awadallah Nahel , Cronstein Bruce N. 
Published: April 2014

Abstract
Adenosine, acting at its receptors, particularly A2A receptors, is a potent endogenous anti-inflammatory agent that modulates the functions and differentiation of inflammatory and immune cells. Because the inflammatory milieu abounds in proinflammatory cytokines, we investigated the effects of Th1-inflammatory cytokines on function and expression of adenosine A2A receptors in the human monocytic cell line THP-1. We found that, consistent with previous reports, adenosine and 2-[p-(2-carnonylethyl)phenylethylamino]-5′-N-ethylcarboxamidoadenosine (CGS-21680), a selective A2A receptor agonist, suppress IL-12 production but increase IL-10 production in LPS-activated THP-1 cells. These effects were blocked by the A2A receptor antagonist 4-{2-[7-amino-2-(2-furyl)[1,2,4-triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol (ZM-241385). More importantly, the suppressive effect of adenosine and CGS-21680 on IL-12 production was significantly enhanced in cells pretreated with either IL-1 (10 U/ml) or TNF-α (100 U/ml) but markedly attenuated in cells pretreated with IFN-γ (100 U/ml). Similarly, IL-1 and TNF-α treatment potentiated the stimulatory effect of adenosine and CGS-21680 on IL-10 production, whereas IFN-γ treatment almost completely abolished this effect. CGS-21680 stimulated an increase in intracellular cAMP in a time- and dose-dependent manner in IL-1- and TNF-α-treated cells but not in control or IFN-γ-treated cells. Both IL-1 and TNF-α increased A2A receptor mRNA and protein. In parallel with its effect on A2A receptor function, IFN-γ down-regulated A2A receptor message and protein. Because adenosine mediates many of the antiinflammatory effects of drugs such as methotrexate, these observations suggest that local changes in the cytokine milieu may influence the therapeutic response to those drugs by altering the expression and function of adenosine receptors on inflammatory cells.
Reconstitution of the Complement Function in C1q-Deficient (C1qa−/−) Mice with Wild-Type Bone Marrow Cells
Authors: Petry Franz , Botto Marina , Holtappels Rafaela , Walport Mark J. , Loos Michael 
Published: April 2014

Abstract
Besides Ab-independent and Ab-dependent activation of the complement classical pathway in host defense, C1q plays a key role in the processing of immune complexes and in the clearance of apoptotic cells. In humans, C1q deficiency leads to systemic lupus erythematosus-like symptoms in over 90% of the cases, thus making this defect a strong disease susceptibility factor. Similarly, C1q-deficient mice (C1qa−/−) develop systemic lupus erythematosus-like symptoms, such as autoantibodies and glomerulonephritis. We have previously provided evidence that C1q is produced by cells of the monocyte-macrophage lineage. In this study, we have tested whether transplantation of bone marrow cells would be sufficient to reconstitute C1q levels in C1qa−/− mice. C1qa−/− mice received a single graft of 107 bone marrow cells from wild-type (wt) donors after irradiation doses of 6, 7, 8, or 9 Gy. Engraftment was monitored by a Y chromosome-specific PCR and a PCR that differentiated wt from C1qa−/− genotype. Serum levels of C1q Ag and C1 function increased rapidly in the recipient mice, and titers reached normal levels within 6 wk after bone marrow transplantation. In wt mice that received C1qa−/− bone marrow, serum levels of C1q decreased constantly over time and became C1q deficient within 55 wk. These data clearly demonstrate that bone marrow-derived cells are the source of serum C1q and are competent to reconstitute normal C1q serum levels in C1q-deficient mice. Therefore, stem cell transplantation could be a therapy for patients with hereditary C1q deficiency.
Clonal Biases of Peripheral CD8 T Cell Repertoire Directly Reflect Local Inflammation in Polymyositis
Authors: Nishio Junko , Suzuki Mihoko , Miyasaka Nobuyuki , Kohsaka Hitoshi 
Published: April 2014

AbstractPolymyositis (PM) involves destruction of striated muscles by autoaggressive CD8 T cells, which accumulate and secrete cytotoxic effector molecules in the affected muscles. Previous studies of peripheral T cell repertoires from normal individuals and patients with viral infections have shown that primed CD8 T cells, unlike CD4 T cells, are prone to expand clonally and persist as large populations in the peripheral blood. These facts made us assume that autoaggressive myocytotoxic CD8 T cells would expand clonally in the peripheral blood from patients with PM. By clonal analyses of peripheral T cells from patients and age-matched controls, we show here that clonal expansion of CD8 T cells was more frequent in patients. This was not significant in CD4 T cells. In analogy to virus-specific T cells, the expanded T cells persisted as large populations over time. Analysis of the muscle biopsy specimens revealed that some of the expanded clones were infiltrating in the affected muscles from the same patients. These results provide the first evidence that local autoimmune reaction directly elicits significant biases in peripheral T cell repertoire. The expanded cells, which should be candidate autoaggressive T cells, were readily isolated from the peripheral blood for analysis of expressed genes including perforin. Thus, our findings should give us an immediate clue to analysis of the pathogenic T cells in PM.
IL-10 Improves Skin Disease and Modulates Endothelial Activation and Leukocyte Effector Function in Patients with Psoriatic Arthritis
Authors: McInnes Iain B. , Illei Gabor G. , Danning Carol L. , Yarboro Cheryl H. , Crane Marianne , Kuroiwa Takashi , Schlimgen Ryan , Lee Eric , Foster Barbara , Flemming Donald , Prussin Calman , Fleisher Thomas A. , Boumpas Dimitrios T. 
Published: April 2014

Abstract
Psoriatic arthritis (PsA) provides an ideal disease model in which to investigate the bioactivities of potentially therapeutic cytokines at multiple sites of tissue inflammation. We investigated the effects of IL-10, an antiinflammatory cytokine, given s.c. for 28 days in a double-blind, placebo-controlled study in PsA patients. Synovial/skin biopsies, peripheral blood leukocytes, articular magnetic resonance images, and clinical disease activity scores were obtained sequentially. Modest, but significant clinical improvement in skin, but not articular disease activity scores with only minor adverse effects was observed. Type 1, but not type 2 T cell cytokine production in vitro was suppressed in human rIL-10 compared with placebo recipients. Similarly, monokine production in vitro was reduced, whereas serum soluble TNFRII levels were elevated, indicating suppression of monocyte function. Decreased T cell and macrophage infiltration in synovial tissues was accompanied by reduced P-selectin expression. Moreover, suppressed synovial enhancement on magnetic resonance imaging and reduced αvβ3 integrin expression on von Willebrand factor+ vessels were observed. Together these data demonstrate that a short course of IL-10 modulates immune responses in vivo via diverse effects on endothelial activation, and leukocyte recruitment and effector function. Such biological changes may result in clinically meaningful improvement in disease activity.
Cutting Edge: Competition for APC by CTLs of Different Specificities Is Not Functionally Important During Induction of Antiviral Responses
Authors: Probst Hans Christian , Dumrese Tilman , van den Broek Maries F. 
Published: April 2014

Abstract
The hypothesis that T cell competition for access to APC influences priming of CTL responses is a controversial issue. A recent study using OVA as a model Ag supports this hypothesis and received considerable attention. However, using a comparable approach, we reached a different conclusion. We analyzed whether TCR transgenic T cells specific for lymphocytic choriomeningitis virus gp33–41/Db could inhibit the priming of endogenous responses against gp33–41 and against two other lymphocytic choriomeningitis virus glycoprotein-derived CTL epitopes. After priming with different stimuli, gp33–41/Db-specific TCR transgenic T cells reduced the endogenous gp33–41/Db response in a dose-dependent way, but all other endogenous responses were unaffected. Even when &gt;106 TCR transgenic cells were combined with weak priming, no reduction of responses other than of those specific for gp33–41/Db was observed. Thus, competition for APC by CTLs of different specificities is not of functional relevance in antiviral immune responses.
Cutting Edge: Immune Cells as Sources and Targets of the IL-10 Family Members?
Authors: Wolk Kerstin , Kunz Stefanie , Asadullah Khusru , Sabat Robert 
Published: April 2014

Abstract
This study investigated the expression of five novel human IL-10-related molecules and their receptors in blood mononuclear cells. IL-19 and IL-20 were found to be preferentially expressed in monocytes. IL-22 and IL-26 (AK155) expression was exclusively detected in T cells, especially upon type 1 polarization, and in NK cells. IL-24 (melanoma differentiation-associated gene 7) expression was restricted to monocytes and T cells. Detection of these molecules in lymphocytes was predominantly linked to cellular activation. Regarding T cells, IL-26 was primarily produced by memory cells, and its expression was independent on costimulation. In contrast to the high expression of receptors for IL-10 homologs in different tissues and cell lines, monocytes and NK, B, and T cells showed clear expression only of IL-10R1, IL-10R2, and IL-20R2. In these cells, IL-20R2 might be part of a still-unknown receptor complex. Therefore, immune cells may represent a major source but a minor target of the novel IL-10 family members.
Inhibitory Effects of Cytomegalovirus Proteins US2 and US11 Point to Contributions from Direct Priming and Cross-Priming in Induction of Vaccinia Virus-Specific CD8+ T Cells
Authors: Basta Sameh , Chen Weisan , Bennink Jack R. , Yewdell Jonathan W. 
Published: April 2014

AbstractThe extent to which naive CD8+ CTLs (TCD8+) are primed by APCs presenting endogenous Ags (direct priming) or Ags acquired from other infected cells (cross-priming) is a critical topic in basic and applied immunology. To examine the contribution of direct priming in the induction of VV-specific TCD8+, we generated recombinant vaccinia viruses that express human CMV proteins (US2 and US11) that induce the destruction of newly synthesized MHC class I molecules. Expression of US2 or US11 was associated with a 24–63% decrease in numbers of primary or secondary VV-specific TCD8+ responding to i.p. infection. Using HPLC-isolated peptides from VV-infected cells, we show that US2 and US11 selectively inhibit TCD8+ responses to a subset of immunogenic VV determinants. Moreover, VV-US2 and lysates from VV-infected histoincompatible cells elicit TCD8+ specific for a similar subset of VV determinants. These findings indicate that US2 and US11 can function in vivo to interfere with the activation of virus-specific TCD8+. Furthermore, they suggest that 1) both cross-priming and direct priming contribute significantly to the generation of VV-specific TCD8+, 2) the sets of immunogenic vaccinia virus determinants generated by cross-priming and direct priming are not completely overlapping, and 3) cross-priming overrides the effects of cis-acting viral interference with the class I Ag presentation pathway.
Recycling CD1d1 Molecules Present Endogenous Antigens Processed in an Endocytic Compartment to NKT Cells
Authors: Roberts Tonya J. , Sriram Venkataraman , Spence Philip M. , Gui Ming , Hayakawa Kyoko , Bacik Igor , Bennink Jack R. , Yewdell Jonathan W. , Brutkiewicz Randy R. 
Published: April 2014

AbstractMouse CD1d1 molecules present endogenous glycolipids to NKT cells. Although glycolipid presentation requires CD1d1 transport through the endocytic pathway, the processing requirements for such endogenous Ag presentation by CD1d1 molecules are undefined. We examined CD1d1 Ag presentation to NKT cells by disrupting endocytic trafficking and function in cells expressing normal and mutated CD1d1 expressed by recombinant vaccinia viruses. Consistent with previous studies, we found that preventing CD1d1 localization to endosomes by altering its cytoplasmic targeting sequences abrogated recognition by Vα14Jα281+ NKT cells without affecting recognition by Vα14− NKT cells. Increasing the pH of acidic compartments by incubating cells with chloroquine or bafilomycin A1 blocked CD1d1 recognition by Vα14+ (but not Vα14−) NKT cells without reducing levels of cell surface CD1d1. Similar results were obtained with primaquine, which interferes with the recycling of cell surface glycoproteins. These results suggest that the loading of a subset of glycolipid ligands onto CD1d1 molecules entails the delivery of cell surface CD1d1 molecules and an acidic environment in the endocytic pathway.
Ligand-Induced TCR Down-Regulation Is Not Dependent on Constitutive TCR Cycling
Authors: Dietrich Jes , Menné Charlotte , Lauritsen Jens Peter H. , von Essen Marina , Rasmussen Anette B. , Ødum Niels , Geisler Carsten 
Published: April 2014

AbstractTCR internalization takes place both in resting T cells as part of constitutive TCR cycling, after PKC activation, and during TCR triggering. It is still a matter of debate whether these pathways represent distinct pathways. Thus, some studies have indicated that ligand-induced TCR internalization is regulated by mechanisms distinct from those involved in constitutive internalization, whereas other studies have suggested that the ligand-induced TCR internalization pathway is identical with the constitutive pathway. To resolve this question, we first identified requirements for constitutive TCR cycling. We found that in contrast to PKC-induced TCR internalization where both CD3γ-S126 and the CD3γ leucine-based internalization motif are required, constitutive TCR cycling required neither PKC nor CD3γ-S126 but only the CD3γ leucine-based motif. Having identified these requirements, we next studied ligand-induced internalization in cells with abolished constitutive TCR cycling. We found that ligand-induced TCR internalization was not dependent on constitutive TCR internalization. Likewise, constitutive internalization and recycling of the TCR were independent of an intact ligand-induced internalization of the TCR. In conclusion, ligand-induced TCR internalization and constitutive cycling of the TCR represents two independent pathways regulated by different mechanisms.
In Vivo Differentiated Cytokine-Producing CD4+ T Cells Express Functional CCR7
Authors: Debes Gudrun F. , Höpken Uta E. , Hamann Alf 
Published: April 2014

AbstractChemokines and their receptors fulfill specialized roles in inflammation and under homeostatic conditions. CCR7 and its ligands, CCL19 and CCL21, are involved in lymphocyte recirculation through secondary lymphoid organs and additionally navigate lymphocytes into distinct tissue compartments. The role of CCR7 in the migration of polarized T effector/memory cell subsets in vivo is still poorly understood. We therefore analyzed murine and human CD4+ cytokine-producing cells developed in vivo for their chemotactic reactivity to CCR7 ligands. The responses of cells producing cytokines, such as IFN-γ, IL-4, and IL-10, as well as of subsets defined by memory or activation markers were comparable to that of naive CD4+ cells, with slightly lower reactivity in cells expressing IL-10 or CD69. This indicates that CCR7 ligands are able to attract naive as well as the vast majority of activated and effector/memory T cell stages. Chemotactic reactivity of these cells toward CCL21 was absent in CCR7-deficient cells, proving that effector cells do not use alternative receptors for this chemokine. Th1 cells generated from CCR7−/− mice failed to enter lymph nodes and Peyer’s patches, but did enter a site of inflammation. These findings indicate that CD4+ cells producing effector cytokines upon stimulation retain the capacity to recirculate through lymphoid tissues via CCR7.
Identification of Naive or Antigen-Experienced Human CD8+ T Cells by Expression of Costimulation and Chemokine Receptors: Analysis of the Human Cytomegalovirus-Specific CD8+ T Cell Response
Authors: Wills Mark R. , Okecha Georgina , Weekes Michael P. , Gandhi Maher K. , Sissons Patrick J. G. , Carmichael Andrew J. 
Published: April 2014

AbstractHuman CMV (HCMV) infection provides an informative model of how long term human CD8+ T cell memory is maintained in the presence of Ag. To clarify the phenotypic identity of Ag-experienced human CD8+ T cells in vivo, we determined the expression of costimulation and chemokine receptors on Ag-specific CD8+ T cells by quantifying individual virus-specific clones in different cell populations using TCR clonotypic probing. In healthy HCMV carriers, expanded CD8+ clones specific for either HCMV tegument protein pp65 or immediate-early protein IE72 are found in both CD45ROhigh cells and the subpopulation of CD45RAhigh cells that lack the costimulatory molecule CD28. In contrast to previous suggested models of CD8+ T cell memory, we found that in healthy virus carriers highly purified CD28−CD45RAhighCCR7− cells are not terminally differentiated, because following stimulation in vitro with specific HCMV peptide these cells underwent sustained clonal proliferation, up-regulated CD45RO and CCR5, and showed strong peptide-specific cytotoxic activity. In an individual with acute primary HCMV infection, HCMV pp65-specific CD8+ T cells are predominantly CD28−CD45ROhighCCR7−. During convalescence, an increasing proportion of pp65-specific CD8+ T cells were CD28−CD45RAhighCCR7−. We conclude that naive human CD8+ T cells are CD28+CD45RAhigh, express CCR7 but not CCR6, and are predominantly CD27+ and L-selectin CD62 ligand-positive. The phenotype CD27+CD45RAhigh should not be used to identify naive human CD8+ T cells, because CD27+CD45RAhigh cells also contain a significant subpopulation of CD28−CD27+ Ag-experienced expanded clones. Thus CD8+ T cell memory to HCMV is maintained by cells of expanded HCMV-specific clones that show heterogeneity of activation state and costimulation molecular expression within both CD45ROhigh and CD28−CD45RAhigh T cell pools.
Reduced Expression of STAT4 and IFN-γ in Macrophages from BALB/c Mice
Authors: Kuroda Etsushi , Kito Tomohiro , Yamashita Uki 
Published: April 2014

AbstractBALB/c mice have been shown to easily induce Th2 type responses in several infection models. In this study, to examine the mechanisms of Th2 dominant responses in BALB/c mice, we assessed several macrophage functions using C3H/HeN, C57BL/6, and BALB/c mouse strains. Peritoneal macrophages from three strains of mice equally produced IL-12 by stimulation with LPS plus IFN-γ. However, IFN-γ production in response to IL-12 or IL-12 plus IL-18 was much lower in macrophages from BALB/c mice than other strains. IFN-γ produced by activated macrophages induced IL-12R mRNA expression in T cells and macrophages themselves depending on their amount of IFN-γ; namely, macrophages from BALB/c mice induced lower expression of IL-12R. Intracellular levels of STAT4 were much lower in macrophages from BALB/c mice. However, other STATs, such as STAT1 or STAT6, were expressed similarly in the three mouse strains. STAT4 and IFN-γ production by other cell types such as T cells and B cells were equal in C3H/HeN and BALB/c mice. These results indicate that macrophages from Th2-dominant BALB/c mice have different functional characters compared with other mouse strains; that is, STAT4 expression and IFN-γ production are reduced, which is one of the causes to shift to Th2-type responses.
Immune Responses in 4-1BB (CD137)-Deficient Mice
Authors: Kwon Byoung S. , Hurtado Jose C. , Lee Zang H. , Kwack Kyu B. , Seo Su K. , Choi Beom K. , Koller Beverly H. , Wolisi Godwin , Broxmeyer Hal E. , Vinay Dass S. 
Published: April 2014

AbstractThe 4-1BB (a TNFR superfamily member) is an inducible costimulatory molecule that can exert regulatory effects on T cells independently of CD28 stimulation. The in vitro expression of 4-1BB (CD137) is induced following activation of T cells with various stimuli, including anti-TCR mAbs, lectins, and a combination of PMA and ionomycin. To delineate further the physiological role of 4-1BB in immunity, mice deficient in this receptor were generated. These mutant mice developed normally, and were viable and fertile. Humoral responses to vesicular stomatitis virus were comparable with those seen in wild-type mice, whereas the IgG2a and IgG3 isotype responses to keyhole limpet hemocyanin were somewhat reduced in the mutant mice. The 4-1BB-deficient mice demonstrated enhanced T cell proliferation in response to mitogens or anti-CD3 even in the environment of reduced ability to secrete growth-supporting cytokines (IL-2 and IL-4). Although T cells from 4-1BB-deficient mice showed enhanced proliferation, the T cell immune responses of these animals, such as cytokine production and CTL activity, were diminished. In addition, 4-1BB deletion appears to play a role in the regulation of myeloid progenitor cell growth, leading to an increase in these precursor cells in peripheral blood, bone marrow, and spleen.
Vα24-JαQ-Independent, CD1d-Restricted Recognition of α-Galactosylceramide by Human CD4+ and CD8αβ+ T Lymphocytes
Authors: Gadola Stephan D. , Dulphy Nicolas , Salio Mariolina , Cerundolo Vincenzo 
Published: April 2014

AbstractHuman CD1d molecules present an unknown ligand, mimicked by the synthetic glycosphingolipid α-galactosylceramide (αGC), to a highly conserved NKT cell subset expressing an invariant TCR Vα24-JαQ paired with Vβ11 chain (Vα24+Vβ11+ invariant NK T cell (NKTinv)). The developmental pathway of Vα24+Vβ11+NKTinv is still unclear, but recent studies in mice were consistent with a TCR instructive, rather than a stochastic, model of differentiation. Using CD1d-αGC-tetramers, we demonstrate that in humans, TCR variable domains other than Vα24 and Vβ11 can mediate specific recognition of CD1d-αGC. In contrast to Vα24+Vβ11+NKTinv cells, Vα24−/CD1d-αGC-specific T cells express either CD8αβ or CD4 molecules, but they are never CD4 CD8 double negative. We show that CD8αβ+Vα24−/CD1d-αGC-specific T cells exhibit CD8-dependent specific cytotoxicity and have lower affinity TCRs than Vα24+/CD1d-αGC-specific T cells. In conclusion, our results demonstrate that, contrary to the currently held view, recognition of CD1d-αGC complex in humans is not uniformly restricted to the Vα24-JαQ/Vβ11 NKT cell subset, but can be mediated by a diverse range of Vα and Vβ domains. The existence of a diverse repertoire of CD1d-αGC-specific T cells in humans strongly supports their Ag-driven selection.