bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scurfin (FoxP3) Controls T-Dependent Immune Responses In Vivo Through Regulation of CD4+ T Cell Effector Function
Authors: Kasprowicz Deborah J. , Smallwood P. Scott , Tyznik Aaron J. , Ziegler Steven F. 
Published: April 2014

AbstractScurfin, the protein product of the FoxP3 gene, is a forkhead-family transcription factor that negatively regulates T cell function. Mice carrying a loss-of-function mutation in FoxP3 (scurfy mice) present with fatal autoimmune-like disease caused by hyperresponsive CD4+ T cells. Mice that overexpress scurfin (FoxP3 Tg mice) possess fewer mature T cells with reduced functional capabilities compared with normal littermate control mice. We analyzed the ability of CD4+ T cells and B cells from FoxP3 Tg mice to respond to a T-dependent Ag and found that immunized FoxP3 Tg mice displayed reduced total and Ag-specific serum Ig and disorganized splenic architecture. However, when cultured in vitro, FoxP3 Tg B cells responded normally, suggesting that the poor Ab response was a result of defective T cell help in vivo. When challenged, CD4+ T cells from FoxP3 Tg mice display reduced up-regulation of CD40 ligand and fewer IFN-γ-producing cells. Overall, these findings show that overexpression of scurfin reduces T cell responses in vivo such that CD4+ T cells cannot provide help to B cells during a T cell-dependent Ab response.
l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes
Authors: Rodriguez Paulo C. , Zea Arnold H. , DeSalvo Joanna , Culotta Kirk S. , Zabaleta Jovanny , Quiceno David G. , Ochoa Juan B. , Ochoa Augusto C. 
Published: April 2014

Abstractl-Arginine plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by inducible nitric oxide synthase to produce nitric oxide, important in the cytotoxic mechanisms, and by arginase I (ASE I) and arginase II (ASE II) to synthesize l-ornithine and urea, the first being the precursor for the production of polyamines needed for cell proliferation. l-Arginine availability can modulate T cell function. Human T cells stimulated and cultured in the absence of l-arginine lose the expression of the TCR ζ-chain (CD3ζ) and have an impaired proliferation and a decreased cytokine production. The aim of this work was to test whether activated macrophages could modulate extracellular levels of l-arginine and alter T cell function, and to determine which metabolic pathway was responsible for this event. The results show that macrophages stimulated with IL-4 + IL-13 up-regulate ASE I and cationic amino acid transporter 2B, causing a rapid reduction of extracellular levels of l-arginine and inducing decreased expression of CD3ζ and diminished proliferation in normal T lymphocytes. Competitive inhibitors of ASE I or the addition of excess l-arginine lead to the re-expression of CD3ζ and recovery of T cell proliferation. In contrast, inducible nitric oxide synthase or ASE II failed to significantly reduce the extracellular levels of l-arginine and modulate CD3ζ expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regulation of CD3ζ in cancer and chronic infectious diseases.
Regulation of Polyclonal T Cell Responses by an MHC Anchor-Substituted Variant of Myelin Oligodendrocyte Glycoprotein 35-55
Authors: Ford Mandy L. , Evavold Brian D. 
Published: April 2014

AbstractAnalogs of immunogenic peptides containing substitutions at TCR contact residues (altered peptide ligands (APLs)) have been used to manipulate Ag-specific T cell responses in models of autoimmunity, including experimental autoimmune encephalomyelitis. However, recent clinical trials with APL of a myelin basic protein epitope revealed limitations of this therapy. In this study, we demonstrate that individual myelin oligodendrocyte glycoprotein (MOG) 35-55-specific T cell clones responded differentially to a MOG 35-55 APL, raising questions about the ability of peptide analogs containing amino acid substitutions at TCR contact residues to control polyclonal populations of T cells. In contrast, we found that a variant peptide containing a substitution at an MHC anchor residue uniformly affected multiple MOG 35-55-specific clones and polyclonal lines. Stimulation of polyclonal MOG 35-55-specific T cells with an MHC variant peptide resulted in the induction of anergy, as defined by a dramatic reduction in proliferation and IL-2 production upon challenge with wild-type peptide. Furthermore, treatment of T cell lines with this peptide in vitro resulted in a significant reduction in their encephalitogenicity upon adoptive transfer. These results indicate that the use of MHC anchor-substituted peptides may be efficacious in the regulation of polyclonal T cell responses such as those found in EAE.
A Giant GTPase, Very Large Inducible GTPase-1, Is Inducible by IFNs
Authors: Klamp Thorsten , Boehm Ulrich , Schenk Daniela , Pfeffer Klaus , Howard Jonathan C. 
Published: April 2014

AbstractThe complex, partially overlapping, cellular responses to IFN type I (IFN-α and -β) and IFN type II (IFN-γ) involve several hundred genes that can be largely classified in terms of specific cellular programs functional in innate and adaptive immunity. Among these programs are previously unconsidered mechanisms of cell-autonomous resistance against various pathogens mediated by dedicated, largely novel families of GTPases. We report here the identification and characterization of a new GTPase family that contributes to the cellular response to both type I and type II IFNs. We name this family the very large inducible GTPases (VLIGs). The prototype VLIG, VLIG-1, is a strongly IFN-inducible, soluble, cytosolic and nuclear protein of 280 kDa. The open reading frame of VLIG-1 is encoded on a single very large exon, and outside the canonical GTP-binding motifs, sequence and structural prediction suggest a unique family without significant relationship to other known protein families. Within the GTPase superfamily the VLIG family is more closely related to IFN-inducible GTPases mediating cell-autonomous resistance than to other GTPase families. In addition, we provide evidence that VLIG-1 is polymorphic in mice of different genetic backgrounds and is a member of a small gene family on mouse chromosome 7 with a conserved homologue located on human chromosome 11.
Blockade of Programmed Death-1 Engagement Accelerates Graft-Versus-Host Disease Lethality by an IFN-γ-Dependent Mechanism
Authors: Blazar Bruce R. , Carreno Beatriz M. , Panoskaltsis-Mortari Angela , Carter Laura , Iwai Yoshiko , Yagita Hideo , Nishimura Hiroyuki , Taylor Patricia A. 
Published: April 2014

AbstractAcute graft-vs-host disease (GVHD) is influenced by pathways that can enhance or reduce lethality by providing positive or negative signals to donor T cells. To date, the only reported pathway to inhibit GVHD is the CTLA-4:B7 pathway. Because absence of the programmed death-1 (PD-1) pathway has been implicated in a predisposition to autoimmunity and hence a lack of negative signals, the effect of PD-1 pathway blockade on GVHD was explored using several distinct approaches. In each, GVHD lethality was markedly accelerated. Coblockade of CTLA-4 and PD-1 was additive in augmenting GVHD, indicating that these pathways are not fully redundant. Although neither perforin nor Fas ligand expression was required for GVHD enhancement, donor IFN-γ production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-γ production and suggest a novel therapeutic target for inhibiting GVHD lethality.
Chronic Exposure to Low Levels of Antigen in the Periphery Causes Reversible Functional Impairment Correlating with Changes in CD5 Levels in Monoclonal CD8 T Cells
Authors: Stamou Panagiota , de Jersey James , Carmignac Danielle , Mamalaki Clio , Kioussis Dimitris , Stockinger Brigitta 
Published: April 2014

AbstractThis study describes a double-transgenic model in which monoclonal CD8 F5 T cells are chronically exposed to self Ag (nucleoprotein) in the periphery, but are not affected during thymic development. Chronic exposure of CD8 T cells to their cognate Ag rendered them unable to proliferate or produce cytokines in response to antigenic stimulation in vitro. However, the cells still retained some killer function in vivo and continuously eliminated APC expressing high levels of Ag. In addition, when crossed with mice expressing Ag in the anterior pituitary gland (triple-transgenic mice), F5 T cells migrated to this site and killed growth hormone producing somatotrophs. The anergic state was reversible upon transfer into Ag-free recipients, resulting in full recovery of in vitro responsiveness to Ag. Anergic CD8 T cells express higher levels of CD5, a negative regulator of T cell signaling, whereas after transfer and residence in Ag-free hosts, CD5 levels returned to normal. This suggests that up-regulation of negative T cell regulators in peripheral T cells exposed to chronic stimulation by Ag may prevent full functionality and thus avoid overt autoreactivity.
Constitutively Active Protein Kinase B Enhances Lck and Erk Activities and Influences Thymocyte Selection and Activation
Authors: Na Shin-Young , Patra Amiya , Scheuring Yvonne , Marx Alexander , Tolaini Mauro , Kioussis Dimitris , Hemmings Brian , Hünig Thomas , Bommhardt Ursula 
Published: April 2014

AbstractProtein kinase B (PKB), a serine threonine kinase is critically involved in cellular proliferation and survival. To characterize its role in T cell development in vivo, we have analyzed transgenic mice that express a membrane-targeted constitutively active version of PKB (myr PKB) in thymocytes and peripheral T cells. We report that myr PKB renders proliferative responses of thymocytes more sensitive to TCR signals by increased and sustained activation of Src kinase Lck and the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In addition, the proliferative response of myr PKB T cells is relatively independent of calcium mobilization and calcineurin activity. We also find that myr PKB enhances phosphorylation of glycogen synthase kinase 3, a negative regulator of NFAT and T cell activation, and the recruitment of the adapter protein Cbl-c. Interestingly, we demonstrate that upon TCR/CD3 stimulation of wild-type T cells PKB is translocated into lipid rafts, adding a new role for PKB in TCR-initiated signalosome formation in T cell activation. Localization of transgenic PKB in lipid rafts could contribute to the higher TCR sensitivity of myr PKB thymocytes which is reflected in an increase in positive selection toward the CD4 lineage and variable effects on negative selection depending on the model system analyzed. Thus, our observations clearly indicate a cross-talk between PKB and important signaling molecules downstream of TCR that modulate the thresholds of thymocyte selection and T cell activation.
The Onecut Transcription Factor Hepatocyte Nuclear Factor-6 Controls B Lymphopoiesis in Fetal Liver
Authors: Bouzin Caroline , Clotman Frédéric , Renauld Jean-Christophe , Lemaigre Frédéric P. , Rousseau Guy G. 
Published: April 2014

AbstractMouse genetic models have helped to identify transcription factors that are expressed by hemopoietic cells and control their differentiation into lymphoid cells. However, little is known on transcription factors that are involved in this process, but are expressed in nonhemopoietic cells of the microenvironment. We show in this study that inactivation of the gene coding for hepatocyte nuclear factor-6 (HNF-6) in mice led to B lymphopenia in the bone marrow and spleen. This phenotype disappeared shortly after birth when fetal B lymphopoiesis is no longer active, pointing to a defect in fetal liver. Indeed, the number of B cells was decreased in this organ as well. An analysis of B cell developmental markers in fetal liver cells showed that B lymphopoiesis was impaired just beyond the pre-pro B cell stage. Hemopoietic cells from hnf6−/− fetal liver could reconstitute the lymphoid system when injected into scid mice. Because parenchymal cells, but not hemopoietic cells, expressed hnf6 in normal liver, we concluded that HNF-6 controls B lymphopoiesis in fetal liver and that HNF-6 exerts this control indirectly by acting in parenchymal cells. The involvement, in the B cell defect of hnf6−/− fetuses, of genes known to exert such an indirect control was ruled out by expression analysis, including microarrays, and by in vivo rescue experiments. This work identifies HNF-6 as the first noncell-intrinsic transcription factor known to control B lymphopoiesis specifically in fetal liver.
The Porcine Ig δ Gene: Unique Chimeric Splicing of the First Constant Region Domain in its Heavy Chain Transcripts
Authors: Zhao Yaofeng , Pan-Hammarström Qiang , Kacskovics Imre , Hammarström Lennart 
Published: April 2014

Abstract
The pig δ gene is located ∼3.4 kb downstream of the second transmembrane exon of the μ gene and shows a similar genomic structure to its counterpart in cow with three exons encoding the CH1, CH2, and CH3 domains. The porcine genomic δCH1 exon has been replaced by a recent duplication of the μCH1 and its flanking sequences, a genetic event that also led to the formation of a short switch δ region, immediately upstream of the δ gene. The δCH1 exhibits a 98.7% similarity (314 of 318 bp) to the μCH1 at the DNA level, whereas the homologies between the δCH2 and μCH3, and the δCH3 and μCH4 are only 33.3 and 35.8%, respectively. Either of the two CH1 exons (μ and δ) could be observed in the expressed porcine IgD H chain cDNA sequences VDJ-μCH1-H-δCH2-δCH3 or VDJ-δCH1-H-δCH2-δCH3, showing a pattern that has not been observed previously in vertebrates. In addition, transfection of a human B cell line, using artificial constructs resembling the porcine Cμ-Cδ locus, also generated both VDJ-μCH1-δCH1-H1-δCH2 and VDJ -δCH1-H1-δCH2 transcripts. An examination of the pig δ genomic sequence shows a putative, second hinge region-encoding exon. Due to the lack of a normal branchpoint sequence for RNA splicing, this exon is not present in the normal pig δ cDNA. However, the exon could be spliced into most of the expressed transcripts in vitro in cell transfection experiments after introduction of a single T nucleotide to restore the branchpoint sequence upstream of the putative H2 exon.
Complexes of HLA-G Protein on the Cell Surface Are Important for Leukocyte Ig-Like Receptor-1 Function
Authors: Gonen-Gross Tsufit , Achdout Hagit , Gazit Roi , Hanna Jacob , Mizrahi Sa’ar , Markel Gal , Goldman-Wohl Debra , Yagel Simcha , Hořejší Václav , Levy Ofer , Baniyash Michal , Mandelboim Ofer 
Published: April 2014

AbstractThe nonclassical class I MHC molecule HLA-G is selectively expressed on extravillous cytotrophoblast cells at the maternal-fetal interface during pregnancy. HLA-G can inhibit the killing mediated by NK cells via interaction with the inhibitory NK cell receptor, leukocyte Ig-like receptor-1 (LIR-1). Comparison of the sequence of the HLA-G molecule to other class I MHC proteins revealed two unique cysteine residues located in positions 42 and 147. Mutating these cysteine residues resulted in a dramatic decrease in LIR-1 Ig binding. Accordingly, the mutated HLA-G transfectants were less effective in the inhibition of NK killing and RBL/LIR-1 induced serotonin release. Immunoprecipitation experiments demonstrated the involvement of the cysteine residues in the formation of HLA-G protein oligomers on the cell surface. The cysteine residue located at position 42 is shown to be critical for the expression of such complexes. These oligomers, unique among the class I MHC proteins, probably bind to LIR-1 with increased avidity, resulting in an enhanced inhibitory function of LIR-1 and an impaired killing function of NK cells.
Promiscuous CTL Recognition of Viral Epitopes on Multiple Human Leukocyte Antigens: Biological Validation of the Proposed HLA A24 Supertype
Authors: Burrows Scott R. , Elkington Rebecca A. , Miles John J. , Green Katherine J. , Walker Susan , Haryana Sofia M. , Moss Denis J. , Dunckley Heather , Burrows Jacqueline M. , Khanna Rajiv 
Published: April 2014

AbstractMultiple HLA class I alleles can bind peptides with common sequence motifs due to structural similarities in the peptide binding cleft, and these groups of alleles have been classified into supertypes. Nine major HLA supertypes have been proposed, including an A24 supertype that includes A*2301, A*2402, and A*3001. Evidence for this A24 supertype is limited to HLA sequence homology and/or similarity in peptide binding motifs for the alleles. To investigate the immunological relevance of this proposed supertype, we have examined two viral epitopes (from EBV and CMV) initially defined as HLA-A*2301-binding peptides. The data clearly demonstrate that each peptide could be recognized by CTL clones in the context of A*2301 or A*2402; thus validating the inclusion of these three alleles within an A24 supertype. Furthermore, CTL responses to the EBV epitope were detectable in both A*2301+ and A*2402+ individuals who had been previously exposed to this virus. These data substantiate the biological relevance of the A24 supertype, and the identification of viral epitopes with the capacity to bind promiscuously across this supertype could aid efforts to develop CTL-based vaccines or immunotherapy. The degeneracy in HLA restriction displayed by some T cells in this study also suggests that the dogma of self-MHC restriction needs some refinement to accommodate foreign peptide recognition in the context of multiple supertype alleles.
Clearance ofPneumocystis cariniiin Mice Is Dependent on B Cells But Not onP. carinii-Specific Antibody
Authors: Lund Frances E. , Schuer Kevin , Hollifield Melissa , Randall Troy D. , Garvy Beth A. 
Published: April 2014

AbstractBoth CD4+ T cells and B cells are critical for defense against Pneumocystis carinii infection; however, the mechanism by which B cells mediate protection is unknown. We show that P. carinii-specific IgM is not sufficient to mediate clearance of P. carinii from the lungs since CD40-deficient mice produced normal levels of specific IgM, but were unable to clear the organisms. Using chimeric mice in which the B cells were deficient in CD40 (CD40KO chimeras) we found that clearance of P. carinii infection is delayed compared with wild-type controls. These CD40KO chimeric mice produced normal levels of P. carinii-specific IgM, but did not produce class-switched IgG or IgA. Similarly, clearance of P. carinii was delayed in mice deficient in FcγRI and III (FcγRKO), indicating that P. carinii-specific IgG partially mediates opsonization and clearance of P. carinii. Opsonization of organisms by complement did not compensate for the lack of specific IgG or FcγR, since C3-deficient and C3-depleted FcγRKO mice were still able to clear P. carinii. Finally, μMT and CD40KO chimeric mice had reduced numbers of activated CD4+ T cells in the lungs and lymph nodes compared with wild-type mice, suggesting that B cells are important for activation of T cells in response to P. carinii. Together these data indicate that P. carinii-specific IgG plays an important, but not critical, role in defense against P. carinii. Moreover, these data suggest that B cells also mediate host defense against P. carinii by facilitating CD4+ T cell activation or expansion.
Porcine Pulmonary Collectins Show Distinct Interactions with Influenza A Viruses: Role of theN-Linked Oligosaccharides in the Carbohydrate Recognition Domain
Authors: van Eijk Martin , White Mitchell R. , Crouch Erika C. , Batenburg Joseph J. , Vaandrager Arie B. , van Golde Lambert M. G. , Haagsman Henk P. , Hartshorn Kevan L. 
Published: April 2014

AbstractInfluenza A virus (IAV) infections are a major cause of respiratory disease of humans and animals. Pigs can serve as important intermediate hosts for transmission of avian IAV strains to humans, and for the generation of reassortant strains; this may result in the appearance of new pandemic IAV strains in humans. We have studied the role of the porcine lung collectins surfactant proteins D and A (pSP-D and pSP-A), two important components of the innate immune response against IAV. Hemagglutination inhibition assays revealed that both pSP-D and pSP-A display substantially greater inhibitory activity against IAV strains isolated from human, swine, and horse, than lung collectins from other animal species. The more potent activity of pSP-D results from interactions mediated by the asparagine-linked oligosaccharide located in the carbohydrate recognition domain of pSP-D, which is absent in SP-Ds from other species characterized to date. Presence of this sialylated oligosaccharide moiety enhances the anti-influenza activity of pSP-D, as demonstrated by assays of viral aggregation, inhibition of infectivity, and neutrophil response to IAV. The greater hemagglutination inhibitory activity of pSP-A is due to porcine-specific structural features of the conserved asparagine-linked oligosaccharide in the carbohydrate recognition domain of SP-A. A more efficient lung collectin-mediated immune response against IAV in pigs may play a role in providing conditions by which pigs can act as “mixing vessel” hosts that can lead to the production of reassortant, pandemic strains of IAV.
Heat-KilledBrucella abortusInduces TNF and IL-12p40 by Distinct MyD88-Dependent Pathways: TNF, Unlike IL-12p40 Secretion, Is Toll-Like Receptor 2 Dependent
Authors: Huang Li-Yun , Aliberti Julio , Leifer Cynthia A. , Segal David M. , Sher Alan , Golenbock Douglas T. , Golding Basil 
Published: April 2014

AbstractCattle and humans are susceptible to infection with the Gram-negative intracellular bacterium Brucella abortus. Heat-killed B. abortus (HKBA) is a strong Th1 adjuvant and carrier. Previously, we have demonstrated that dendritic cells produce IL-12 in response to HKBA stimulation. In the present study, we use knockout mice and in vitro reconstitution assays to examine the contribution of signaling by Toll-like receptors (TLRs) and their immediate downstream signaling initiator, myeloid differentiation protein MyD88, in the activation following stimulation by HKBA. Our results show that HKBA-mediated induction of IL-12p40 and TNF is dependent on the adapter molecule MyD88. To identify the TLR involved in HKBA recognition, we examined HKBA responses in TLR2- and TLR4-deficient animals. TNF responses to HKBA were TLR4 independent; however, the response in TLR2-deficient mice was significantly delayed and reduced, although not completely abolished. Studies using Chinese hamster ovary/CD14 reporter cell lines stably transfected with either human TLR2 or human TLR4 confirmed the results seen with knockout mice, namely TLR2, but not TLR4, can mediate cellular activation by HKBA. In addition, human embryonic kidney 293 cells, which do not respond to HKBA, were made responsive by transfecting TLR2, but not TLR4 or TLR9. Taken together, our data demonstrate that MyD88-dependent pathways are crucial for activation by HKBA and that TLR2 plays a role in TNF, but not IL-12p40 pathways activated by this microbial product.