bluuebunny/crossref_metadata_2025_split huggingface dataset:
ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival
Authors: Akbari Omid , Stock Philippe , Meyer Everett H. , Freeman Gordon J. , Sharpe Arlene H. , Umetsu Dale T. , DeKruyff Rosemarie H. 
Published: April 2014

Abstract
The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4+ iNKT than on CD4− iNKT cells. Furthermore, the number of CD4+ iNKT cells was significantly lower in spleens and livers of ICOS−/− and ICOSL−/− mice, and the remaining iNKT cells in ICOS−/− mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient Jα18−/− mice. In addition, direct activation of iNKT cells with α-GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS−/− mice. The failure of ICOS−/− iNKT cells to induce AHR was due in part to an inability of the ICOS−/− iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL−/− mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4+ iNKT cell function, homeostasis, and survival in the periphery.
The IL-1 Family Member 7b Translocates to the Nucleus and Down-Regulates Proinflammatory Cytokines
Authors: Sharma Sheetal , Kulk Nicole , Nold Marcel F. , Gräf Ralph , Kim Soo-Hyun , Reinhardt Dietrich , Dinarello Charles A. , Bufler Philip 
Published: April 2014

Abstract
The IL-1 family member 7b (IL-1F7b) is a novel homolog of the IL-1 cytokine family discovered by computational cloning. We have reported that IL-1F7b shares critical amino acid residues with IL-18 and binds the IL-18-binding protein; in doing so, IL-1F7b augments the inhibition of IFN-γ by the IL-18-binding protein. IL-1F7b also binds IL-18Rα but neither induces signal nor acts as a receptor antagonist. Hence, the function of IL-1F7b remains unknown. In the present study, we analyzed the intracellular expression pattern of IL-1F7b. Using two variants of GFP fusion constructs of human IL-1F7b stably expressed in RAW macrophages, only the postcleavage mature form of the IL-1F7b precursor—but not the N-terminal propiece—specifically translocates to the nucleus following LPS stimulation. IL-1F7b, like IL-1β, IL-18, and IL-33, is processed by caspase-1 to generate the mature cytokines. Therefore, we tested whether caspase-1-mediated cleavage of the IL-1F7b precursor is required for mature IL-1F7b to translocate actively into the nucleus. Indeed, a specific caspase-1 inhibitor markedly reduced nuclear entry of IL-1F7b. In stable transfectants of human IL-1F7b in RAW macrophages stimulated with LPS, levels of TNF-α, IL-1α, IL-6, as well as the chemokine MIP-2, were substantially reduced (72–98%) compared with LPS-stimulated cells transfected with the empty plasmid. These results demonstrate that IL-1F7b translocates to the nucleus after caspase-1 processing and may act as a transcriptional modulator reducing the production of LPS-stimulated proinflammatory cytokines, consistent with IL-1F7b being an anti-inflammatory member of the IL-1 family.
Targeting the Extracellular Membrane-Proximal Domain of Membrane-Bound IgE by Passive Immunization Blocks IgE Synthesis In Vivo
Authors: Feichtner Stefan , Inführ Daniela , Achatz-Straussberger Gertrude , Schmid Doris , Karnowski Alexander , Lamers Marinus , Rhyner Claudio , Crameri Reto , Achatz Gernot 
Published: April 2014

Abstract
The classical allergic reaction starts seconds or minutes after Ag contact and is committed by Abs produced by a special subset of B lymphocytes. These Abs belong to the IgE subclass and are responsible for Type I hyperreactivity reactions. Treatment of allergic diseases with humanized anti-IgE Abs leads primarily to a decrease of serum IgE levels. As a consequence, the number of high-affinity IgE receptors on mast cells and basophils decreases, leading to a lower excitability of the effector cells. The biological mechanism behind anti-IgE therapy remains partly speculative; however, it is likely that these Abs also interact with membrane IgE (mIgE) on B cells and possibly interfere with IgE production. In the present work, we raised a mouse mAb directed exclusively against the extracellular membrane-proximal domain of mIgE. The interaction between the monoclonal anti-mIgE Ab and mIgE induces receptor-mediated apoptosis in vitro. Passive immunization experiments lead to a block of newly synthesized specific IgEs during a parallel application of recombinant Bet v1a, the major birch pollen allergen. The decrease of allergen-specific serum IgE might be related to tolerance-inducing mechanisms stopping mIgE-displaying B cells in their proliferation and differentiation.
Chemokine and Cytokine Mediated Loss of Regulatory T Cells in Lymph Nodes during Pathogenic Simian Immunodeficiency Virus Infection
Authors: Qin Shulin , Sui Yongjun , Soloff Adam C. , Fallert Junecko Beth A. , Kirschner Denise E. , Murphey-Corb Michael A. , Watkins Simon C. , Tarwater Patrick M. , Pease James E. , Barratt-Boyes Simon M. , Reinhart Todd A. 
Published: April 2014

Abstract
Regulatory T cells (Treg) play key roles in immune regulation through multiple modes of suppression. The effects of HIV-1 infection on Treg levels in lymphoid tissues remain incompletely understood. To explore this issue, we have measured the levels of forkhead box protein 3 (FOXP3)-positive cells and associated immunomodulatory genes in a pathogenic simian immunodeficiency virus/macaque model and found that a loss of Treg in lymph nodes occurred following simian immunodeficiency virus infection. Changes in expression of the ligands for CXCR3, CCR4, and CCR7 and the cytokines TGF-β and IL-2 were all linked to this loss of Treg, which in turn was linked with increased levels of cellular activation. Our findings identify three mechanisms that likely contribute to SIV-driven loss of Treg, including reduced levels of cytokines associated with Treg differentiation and altered expression of agonist and antagonist chemokines. The loss of Treg and the associated cellular activation in lymphoid tissues is consistent with the events in HIV-1-infected individuals and suggest that components of the Treg differentiation and trafficking network could be targets for therapeutic intervention.
UropathogenicEscherichia coliBlock MyD88-Dependent and Activate MyD88-Independent Signaling Pathways in Rat Testicular Cells
Authors: Bhushan Sudhanshu , Tchatalbachev Svetlin , Klug Jörg , Fijak Monika , Pineau Charles , Chakraborty Trinad , Meinhardt Andreas 
Published: April 2014

AbstractUropathogenic Escherichia coli (UPEC) is the most common etiological cause of urogenital tract infections and represents a considerable cause of immunological male infertility. We examined TLR 1–11 expression profiles in testicular cells and the functional response to infection with UPEC. All testicular cell types expressed mRNAs for at least two TLRs and, in particular, synthesis of TLR4 was induced in testicular macrophages (TM), Sertoli cells (SC), peritubular cells (PTC), and peritoneal macrophages (PM) after UPEC exposure. Even though MyD88-dependent pathways were activated as exemplified by phosphorylation of mitogen-activated protein kinases in TM, SC, PTC, and PM and by the degradation of IκBα and the nuclear translocation of NF-κB in PTC and PM, treatment with UPEC did not result in secretion of the proinflammatory cytokines IL-1α, IL-6, and TNF-α in any of the investigated cells. Moreover, stimulated production of these cytokines by nonpathogenic commensal E. coli or LPS in PM was completely abolished after coincubation with UPEC. Instead, in SC, PTC, TM, and PM, UPEC exposure resulted in activation of MyD88-independent signaling as documented by nuclear transfer of IFN-related factor-3 and elevated expression of type I IFNs α and β, IFN-γ-inducible protein 10, MCP-1, and RANTES. We conclude that in this in vitro model UPEC can actively suppress MyD88-dependent signaling at different levels to prevent proinflammatory cytokine secretion by testicular cells. Thus, testicular innate immune defense is shifted to an antiviral-like MyD88-independent response.
CD127 and CD25 Expression Defines CD4+ T Cell Subsets That Are Differentially Depleted during HIV Infection
Authors: Dunham Richard M. , Cervasi Barbara , Brenchley Jason M. , Albrecht Helmut , Weintrob Amy , Sumpter Beth , Engram Jessica , Gordon Shari , Klatt Nichole R. , Frank Ian , Sodora Donald L. , Douek Daniel C. , Paiardini Mirko , Silvestri Guido 
Published: April 2014

Abstract
Decreased CD4+ T cell counts are the best marker of disease progression during HIV infection. However, CD4+ T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4+ T cell subsets influences disease severity. CD4+ T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127+CD25low/− subset includes IL-2-producing naive and central memory T cells; the CD127−CD25− subset includes mainly effector T cells expressing perforin and IFN-γ; and the CD127lowCD25high subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4+CD127−CD25− T cells that is related to an absolute decline of CD4+CD127+CD25low/− T cells. Interestingly, this expansion of CD4+CD127− T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4+CD127−CD25− T cells correlated directly with the levels of total CD4+ T cell depletion and immune activation. CD4+CD127−CD25− T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4+ T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4+ T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4+ T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals.
Protein Kinase C-θ Critically Regulates the Proliferation and Survival of Pathogen-Specific T Cells in Murine Listeriosis
Authors: Sakowicz-Burkiewicz Monika , Nishanth Gopala , Helmuth Ulrike , Drögemüller Katrin , Busch Dirk H. , Utermöhlen Olaf , Naumann Michael , Deckert Martina , Schlüter Dirk 
Published: April 2014

Abstract
Protein kinase C-θ (PKC-θ) is essential for the activation of T cells in autoimmune disorders, but not in viral infections. To study the role of PKC-θ in bacterial infections, PKC-θ−/− and wild-type mice were infected with Listeria monocytogenes (LM). In primary and secondary listeriosis, the numbers of LM-specific CD8 and CD4 T cells were drastically reduced in PKC-θ−/− mice, resulting in increased CFUs in spleen and liver of both PKC-θ−/− C57BL/6 and BALB/c mice. Furthermore, immunization with peptide-loaded wild-type dendritic cells induced LM-specific CD4 and CD8 T cells in wild-type but not in PKC-θ−/− mice. In listeriosis, transfer of wild-type T cells into PKC-θ−/− mice resulted in a normal control of Listeria, and, additionally, a selective expression of PKC-θ in LM-specific T cells was sufficient to drive a normal proliferation and survival of these T cells in LM-infected PKC-θ−/− recipients, illustrating a cell-autonomous function of PKC-θ in LM-specific T cells. Conversely, adoptively transferred PKC-θ−/− T cells were partially rescued from cell death and proliferated in LM-infected wild-type recipients, demonstrating that a PKC-θ deficiency of LM-specific T cells can be partially compensated for by a wild-type environment. Additionally, in vitro experiments showed that only the addition of IL-2, but not an inhibition of caspase-3, induced proliferation and prevented death of PKC-θ−/− T cells stimulated with LM-infected wild-type dendritic cells, further demonstrating that the impaired proliferation and survival of PKC-θ−/− T cells in listeriosis is not intrinsically fixed and can be experimentally improved.
A Novel Proteolytic Cascade Generates an Extracellular Matrix-Derived Chemoattractant in Chronic Neutrophilic Inflammation
Authors: Gaggar Amit , Jackson Patricia L. , Noerager Brett D. , O’Reilly Philip J. , McQuaid D. Brent , Rowe Steven M. , Clancy J. P. , Blalock J. Edwin 
Published: April 2014

Abstract
Chronic neutrophilic inflammation is a manifestation of a variety of lung diseases including cystic fibrosis (CF). There is increasing evidence that fragments of extracellular matrix proteins, such as collagen and elastin, play an important role in inflammatory cell recruitment to the lung in animal models of airway inflammation. Unfortunately, the association of these peptides with human disease and the identification of therapeutic targets directed toward these inflammatory pathways have remained elusive. In this study, we demonstrate that a novel extracellular matrix-derived neutrophil chemoattractant, proline-glycine-proline (PGP), acts through CXC receptors 1 and 2 on neutrophils, similar to N-acetylated proline-glycine-proline (N-α-PGP). We describe the specific multistep proteolytic pathway involved in PGP generation from collagen, involving matrix metalloproteases 8 and 9 and prolyl endopeptidase, a serine protease for which we identify a novel role in inflammation. PGP generation correlates closely with airway neutrophil counts after administration of proteases in vivo. Using CF as a model, we show that CF sputum has elevated levels of PGP peptides and that PGP levels decline during the course of CF inpatient therapy for acute pulmonary exacerbation, pointing to its role as a novel biomarker for this disease. Finally, we demonstrate that CF secretions are capable of generating PGP from collagen ex vivo and that this generation is significantly attenuated by the use of inhibitors directed toward matrix metalloprotease 8, matrix metalloprotease 9, or prolyl endopeptidase. These experiments highlight unique protease interactions with structural proteins regulating innate immunity and support a role for these peptides as novel biomarkers and therapeutic targets for chronic, neutrophilic lung diseases.
FcγRIIB Deficiency Leads to Autoimmunity and a Defective Response to Apoptosis in Mrl-MpJ Mice
Authors: McGaha Tracy L. , Karlsson Mikael C. I. , Ravetch Jeffrey V. 
Published: April 2014

AbstractData suggests that modulation of FcγRIIB expression represents a significant risk factor for the development of autoimmunity. In this study, we investigated this notion in mice that possess genetics permissible for the development of autoimmunity. To this end, Mrl-MpJ Fcgr2b−/− mice were monitored for the development of autoreactivity. We found that FcγRIIB deficiency led to chronic B cell activation associated with increased germinal center and plasma cell accumulation in the spleen. Likewise, Mrl-MpJ Fcgr2b−/− mice exhibited significant serum IgG reactivity against DNA. We further analyzed the IgG isotype contribution to the anti-dsDNA response and found increases in all subtypes with the exception of IgG3. In particular, we found large increases in IgG1 and IgG2b autoreactivity correlating with significant increases in immune complex deposition and kidney pathology. Finally, we found dendritic cells derived from Mrl-MpJ Fcgr2b−/− mice greatly increased IL-12 expression upon coincubation with apoptotic thymocytes compared with wild-type controls. The results indicate that FcγRIIB is an important regulator of peripheral tolerance and attenuation of the inhibitory signal it provides enhances autoimmune disease on susceptible backgrounds. Additionally, the data indicates FcγRIIB function has a significant impact on APC activity, suggesting a prominent role in dendritic cell activity in response to interaction with particulate autoantigens.
Costimulation of Dectin-1 and DC-SIGN Triggers the Arachidonic Acid Cascade in Human Monocyte-Derived Dendritic Cells
Authors: Valera Isela , Fernández Nieves , Trinidad Antonio García , Alonso Sara , Brown Gordon D. , Alonso Andrés , Crespo Mariano Sánchez 
Published: April 2014

AbstractInflammatory mediators derived from arachidonic acid (AA) alter the function of dendritic cells (DC), but data regarding their biosynthesis resulting from stimulation of opsonic and nonopsonic receptors are scarce. To address this issue, the production of eicosanoids by human monocyte-derived DC stimulated via receptors involved in Ag recognition was assessed. Activation of FcγR induced AA release, short-term, low-grade PG biosynthesis, and IL-10 production, whereas zymosan, which contains ligands of both the mannose receptor and the human β-glucan receptor dectin-1, induced a wider set of responses including cyclooxygenase 2 induction and biosynthesis of leukotriene C4 and IL-12p70. The cytosolic phospholipase A2 inhibitor pyrrolidine 1 completely inhibited AA release stimulated via all receptors, whereas the spleen tyrosine kinase (Syk) inhibitors piceatannol and R406 fully blocked AA release in response to immune complexes, but only partially blocked the effect of zymosan. Furthermore, anti-dectin-1 mAb partially inhibited the response to zymosan, and this inhibition was enhanced by mAb against DC-specific ICAM-3-grabbing nonintegrin (SIGN). Immunoprecipitation of DC lysates showed coimmunoprecipitation of DC-SIGN and dectin-1, which was confirmed using Myc-dectin-1 and DC-SIGN constructs in HEK293 cells. These data reveal a robust metabolism of AA in human DC stimulated through both opsonic and nonopsonic receptors. The FcγR route depends on the ITAM/Syk/cytosolic phospholipase A2 axis, whereas the response to zymosan involves the interaction with the C-type lectin receptors dectin-1 and DC-SIGN. These findings help explain the distinct functional properties of DC matured by immune complexes vs those matured by β-glucans.
Evidence for a Selective Migration of Fetus-Specific CD4+CD25bright Regulatory T Cells from the Peripheral Blood to the Decidua in Human Pregnancy
Authors: Tilburgs Tamara , Roelen Dave L. , van der Mast Barbara J. , de Groot-Swings Godelieve M. , Kleijburg Carin , Scherjon Sicco A. , Claas Frans H. 
Published: April 2014

Abstract
During pregnancy, the maternal immune system has to tolerate the persistence of fetal alloantigens. Many mechanisms contribute to the prevention of a destructive immune response mediated by maternal alloreactive lymphocytes directed against the allogeneic fetus. Murine studies suggest that CD4+CD25+ T cells provide mechanisms of specific immune tolerance to fetal alloantigens during pregnancy. Previous studies by our group demonstrate that a significantly higher percentage of activated T cells and CD4+CD25bright T cells are present in decidual tissue in comparison with maternal peripheral blood in human pregnancy. In this study, we examined the phenotypic and functional properties of CD4+CD25bright T cells derived from maternal peripheral blood and decidual tissue. Depletion of CD4+CD25bright T cells from maternal peripheral blood demonstrates regulation to third party umbilical cord blood cells comparable to nonpregnant controls, whereas the suppressive capacity to umbilical cord blood cells of her own child is absent. Furthermore, maternal peripheral blood shows a reduced percentage of CD4+CD25brightFOXP3+ and CD4+CD25brightHLA-DR+ cells compared with peripheral blood of nonpregnant controls. In contrast, decidual lymphocyte isolates contain high percentages of CD4+CD25bright T cells with a regulatory phenotype that is able to down-regulate fetus-specific and fetus-nonspecific immune responses. These data suggest a preferential recruitment of fetus-specific regulatory T cells from maternal peripheral blood to the fetal-maternal interface, where they may contribute to the local regulation of fetus-specific responses.
Dendritic Cells as Killers: Mechanistic Aspects and Potential Roles
Authors: Chauvin Camille , Josien Régis 
Published: April 2014

Abstract
Dendritic cells (DC) are professional APC endowed with the unique capacity to activate naive T cells. DC also have important effector functions during the innate immune response, such as pathogen recognition and cytokine production. In fact, DC represent the crucial link between innate and adaptive immune responses. However, DC are quite heterogeneous and various subsets endowed with specific pathogen recognition mechanisms, locations, phenotypes, and functions have been described both in rodents and in humans. A series of studies indicated that rodent as well as human DC could also mediate another important innate function, i.e., cell-mediated cytotoxicity, mostly toward tumor cells. In this article, we will review the phenotypes of these so-called killer DC, their killing mechanism, and putative implication in the immune response.
Identification of a Novel Immunogenic HLA-A*0201-Binding Epitope of HER-2/neu with Potent Antitumor Properties
Authors: Gritzapis Angelos D. , Voutsas Ioannis F. , Lekka Eftychia , Tsavaris Nikolaos , Missitzis Ioannis , Sotiropoulou Panagiota , Perez Sonia , Papamichail Michael , Baxevanis Constantin N. 
Published: April 2014

Abstract
HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for MHC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/neu decamer LIAHNQVRQV spanning residues 85–94 (HER-2(1085)). HER-2(1085) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(1085) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu+ HLA-A2.1+ breast cancer patients analyzed had HER-2(1085)-reactive T cells ranging from 0.35–0.70% of CD8+ T cells. Depletion of T regulatory cells from PBMC enabled the rapid expansion of HLA-A2.1/HER-2(1085)pentamer+/CD8+ cells (PENT+/CD8+), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(1085)-specific human CTL recognized the HER-2/neu+ HLA-A2.1+ tumor cell line SKBR3.A2, as determined by IFN-γ intracellular staining and in the high sensitivity CD107α degranulation assay. Finally, HER-2(1085) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(1085) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(1085) as a possible target for anticancer immunotherapy.