bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dendritic Cells (DC) Activated by CpG DNA Ex Vivo Are Potent Inducers of Host Resistance to an Intracellular Pathogen That Is Independent of IL-12 Derived from the Immunizing DC
Authors: Ramírez-Pineda José R. , Fröhlich Anja , Berberich Christof , Moll Heidrun 
Published: April 2014

AbstractWe used the model of murine leishmaniasis to evaluate the signals enabling Ag-pulsed dendritic cells (DC) to prime a protective Th1 response in vivo. Bone marrow-derived DC (BMDC) that had been activated by TNF-α or CD40 ligation were not able to induce protection against leishmaniasis in susceptible BALB/c mice. In contrast, all mice vaccinated with a single dose of Leishmania major Ag-pulsed BMDC stimulated by prior in vitro exposure to CpG-containing oligodeoxynucleotides (ODN) were completely protected, had a dramatic reduction in parasite burden, and developed an Ag-specific Th1 response. Importantly, systemic administration of CpG ODN was not required. Protection mediated by ex vivo CpG ODN-activated and Ag-pulsed DC was solid, as documented by resistance to reinfection with a higher parasite dose, and long-lasting, as immunized mice were still protected against L. major challenge 16 wk after vaccination. A significantly increased level of protection could also be elicited in resistant C57BL/6 mice. Surprisingly, IL-12 expression by the immunizing BMDC was not required for induction of host resistance. In contrast, the availability of IL-12 derived from recipient cells was essential for the initial triggering of protective immunity by transferred BMDC. Together, these findings demonstrate that the type of stimulatory signal is critical for activating the potential of DC to induce a Th1 response in vivo that confers complete protection against an intracellular pathogen. Moreover, they show that the impact of activated DC on the initiation of a protective Th cell response in vivo may be independent of their ability to produce IL-12.
Mouse Strain Susceptibility to Trypanosome Infection: An Arginase-Dependent Effect
Authors: Duleu Sébastien , Vincendeau Philippe , Courtois Pierrette , Semballa Silla , Lagroye Isabelle , Daulouède Sylvie , Boucher Jean-Luc , Wilson Keith T. , Veyret Bernard , Gobert Alain P. 
Published: April 2014

AbstractWe previously reported that macrophage arginase inhibits NO-dependent trypanosome killing in vitro and in vivo. BALB/c and C57BL/6 mice are known to be susceptible and resistant to trypanosome infection, respectively. Hence, we assessed the expression and the role of inducible NO synthase (iNOS) and arginase in these two mouse strains infected with Trypanosoma brucei brucei. Arginase I and arginase II mRNA expression was higher in macrophages from infected BALB/c compared with those from C57BL/6 mice, whereas iNOS mRNA was up-regulated at the same level in both phenotypes. Similarly, arginase activity was more important in macrophages from infected BALB/c vs infected C57BL/6 mice. Moreover, increase of arginase I and arginase II mRNA levels and of macrophage arginase activity was directly induced by trypanosomes, with a higher level in BALB/c compared with C57BL/6 mice. Neither iNOS expression nor NO production was stimulated by trypanosomes in vitro. The high level of arginase activity in T. brucei brucei-infected BALB/c macrophages strongly inhibited macrophage NO production, which in turn resulted in less trypanosome killing compared with C57BL/6 macrophages. NO generation and parasite killing were restored to the same level in BALB/c and C57BL/6 macrophages when arginase was specifically inhibited with Nω-hydroxy-nor-l-arginine. In conclusion, host arginase represents a marker of resistance/susceptibility to trypanosome infections.
Dendritic Cells from Mice Neonatally Vaccinated with Modified Vaccinia Virus Ankara Transfer Resistance against Herpes Simplex Virus Type I to Naive One-Week-Old Mice
Authors: Franchini Marco , Hefti Hanspeter , Vollstedt Sabine , Glanzmann Bettina , Riesen Matthias , Ackermann Mathias , Chaplin Paul , Shortman Ken , Suter Mark 
Published: April 2014

AbstractModified vaccinia Ankara (MVA) is an attenuated virus. MVA induces the production of IFN and Flt3-L (FL), which results in the expansion of dendritic cells (DC) and enhanced resistance against viral infections. We report on the interplay among IFN, FL, and DC in the resistance against heterologous virus after injection of neonatal mice with MVA. The induction of serum FL was tested on day 2, and the expansion of DC was tested 1 wk after treatment with MVA. At this time point the resistance against infection with heterologous virus was also determined. After MVA treatment, serum FL was enhanced, and DC, including plasmacytoid cells in spleen, were increased in number. Mice that lacked functional IFN type I and II systems failed to increase both the concentration of FL and the number of DC. Treatment with MVA enhanced resistance against HSV-1 in wild-type animals 100-fold, but animals without a functional IFN system were not protected. Transfer of CD11c+ cells from MVA-treated mice into naive animals protected against lethal infection with HSV-1. Thus, although the increased resistance could be largely attributed to the increase in activation of IFN-producing plasmacytoid cells, this, in turn, depends on a complex interplay between the DC and T cell systems involving both FL and IFNs.
Viral FLIP Impairs Survival of Activated T Cells and Generation of CD8+ T Cell Memory
Authors: Wu Zhengqi , Roberts Margaret , Porter Melissa , Walker Fabianne , Wherry E. John , Kelly John , Gadina Massimo , Silva Elisabeth M. , DosReis George A. , Lopes Marcela F. , O’Shea John , Leonard Warren J. , Ahmed Rafi , Siegel Richard M. 
Published: April 2014

AbstractViral FLIPs (vFLIPs) interfere with apoptosis signaling by death-domain-containing receptors in the TNFR superfamily (death receptors). In this study, we show that T cell-specific transgenic expression of MC159-vFLIP from the human Molluscum contagiosum virus blocks CD95-induced apoptosis in thymocytes and peripheral T cells, but also impairs postactivation survival of in vitro activated primary T cells despite normal early activation parameters. MC159 vFLIP impairs T cell development to a lesser extent than does Fas-associated death domain protein deficiency or another viral FLIP, E8. In the periphery, vFLIP expression leads to a specific deficit of functional memory CD8+ T cells. After immunization with a protein Ag, Ag-specific CD8+ T cells initially proliferate, but quickly disappear and fail to produce Ag-specific memory CD8+ T cells. Viral FLIP transgenic mice exhibit impaired CD8+ T cell responses to lymphocytic choriomeningitis virus and Trypanosoma cruzi infections, and a specific defect in CD8+ T cell recall responses to influenza virus was seen. These results suggest that vFLIP expression in T cells blocks signals necessary for the sustained survival of CD8+ T cells and the generation of CD8+ T cell memory. Through this mechanism, vFLIP proteins expressed by T cell tropic viruses may impair the CD8+ T cell immune responses directed against them.
Ectopic CD40 Ligand Expression on B Cells Triggers Intestinal Inflammation
Authors: Kawamura Takahiro , Kanai Takanori , Dohi Taeko , Uraushihara Koji , Totsuka Teruji , Iiyama Ryoichi , Taneda Chikara , Yamazaki Motomi , Nakamura Tetsuya , Higuchi Tetsuya , Aiba Yuichi , Tsubata Takeshi , Watanabe Mamoru 
Published: April 2014

AbstractSeveral studies indicate that CD4+ T cells, macrophages, and dendritic cells initially mediate intestinal inflammation in murine models of human inflammatory bowel disease. However, the initial role of B cells in the development of intestinal inflammation remains unclear. In this study we present evidence that B cells can trigger intestinal inflammation using transgenic (Tg) mice expressing CD40 ligand (CD40L) ectopically on B cells (CD40L/B Tg). We demonstrated that CD40L/B Tg mice spontaneously developed severe transmural intestinal inflammation in both colon and ileum at 8–15 wk of age. In contrast, CD40L/B Tg×CD40−/− double-mutant mice did not develop colitis, indicating the direct involvement of CD40-CD40L interaction in the development of intestinal inflammation. The inflammatory infiltrates consisted predominantly of massive aggregated, IgM-positive B cells. These mice were also characterized by the presence of anti-colon autoantibodies and elevated IFN-γ production. Furthermore, although mice transferred with CD4+ T cells alone or with both CD4+ T and B220+ B cells, but not B220+ cells alone, from diseased CD40L/B Tg mice, develop colitis, mice transferred with B220+ B cells from diseased CD40L/B Tg mice and CD4+ T cells from wild-type mice also develop colitis, indicating that the Tg B cells should be a trigger for this colitis model, whereas T cells are involved as effectors. As it has been demonstrated that CD40L is ectopically expressed on B cells in some autoimmune diseases, the present study suggests the possible contribution of B cells in triggering intestinal inflammation in human inflammatory bowel disease.
IFN-α Priming Results in a Gain of Proinflammatory Function by IL-10: Implications for Systemic Lupus Erythematosus Pathogenesis
Authors: Sharif M. Nusrat , Tassiulas Ioannis , Hu Yang , Mecklenbräuker Ingrid , Tarakhovsky Alexander , Ivashkiv Lionel B. 
Published: April 2014

Abstract
Interleukin-10 is a predominantly anti-inflammatory cytokine that inhibits macrophage and dendritic cell function, but can acquire proinflammatory activity during immune responses. We investigated whether type I IFNs, which are elevated during infections and in autoimmune diseases, modulate the activity of IL-10. Priming of primary human macrophages with low concentrations of IFN-α diminished the ability of IL-10 to suppress TNF-α production. IFN-α conferred a proinflammatory gain of function on IL-10, leading to IL-10 activation of expression of IFN-γ-inducible, STAT1-dependent genes such as IFN regulatory factor 1, IFN-γ-inducible protein-10 (CXCL10), and monokine induced by IFN-γ (CXCL9). IFN-α priming resulted in greatly enhanced STAT1 activation in response to IL-10, and STAT1 was required for IL-10 activation of IFN-γ-inducible protein-10 and monokine induced by IFN-γ expression in IFN-α-primed cells. In control, unprimed cells, IL-10 activation of STAT1 was suppressed by constitutive activity of protein kinase C and Src homology 2 domain-containing phosphatase 1. These results demonstrate that type I IFNs regulate the balance between IL-10 anti- and proinflammatory activity, and provide insight into molecular mechanisms that regulate IL-10 function. Gain of IL-10 proinflammatory functions may contribute to its pathogenic role in autoimmune diseases characterized by elevated type I IFN levels, such as systemic lupus erythematosus.
The Novel Cyclophilin-Binding Drug Sanglifehrin A Specifically Affects Antigen Uptake Receptor Expression and Endocytic Capacity of Human Dendritic Cells
Authors: Woltman Andrea M. , Schlagwein Nicole , van der Kooij Sandra W. , van Kooten Cees 
Published: April 2014

Abstract
Sanglifehrin A (SFA) is a recently developed immunosuppressant that belongs to the family of immunophilin-binding ligands. SFA is a cyclophilin A-binding immunosuppressive drug with a novel, but unidentified, mechanism of action. Several reports exist about the effect of SFA on T cells, but its effect on the initiators of the immune response, i.e., dendritic cells (DCs), is relatively unknown. Therefore, we examined the effect of SFA on the differentiation and function of human monocyte-derived DCs. Unlike the well-known cyclophilin A-binding immunosuppressant cyclosporin A, which did not affect DC phenotype, differentiation of DCs in the presence of SFA resulted in CD14-CD1a DCs with normal DC morphology, viability, and a proper capacity to activate allogeneic T cells. However, DCs generated in the presence of SFA demonstrated reduced macropinocytosis and lectin-mediated endocytosis, which was in line with a decreased expression of C-type lectins, including mannose receptor, C1qRP, DC-ASGPR, and especially, DC-SIGN. In contrast, FcαRI (CD89) and FcγRII (CD32) were increased by SFA. The explicit effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among immunophilin-binding immunosuppressive drugs.
Molecular Characterization of Polygalacturonases as Grass Pollen-Specific Marker Allergens: Expulsion from Pollen via Submicronic Respirable Particles
Authors: Swoboda Ines , Grote Monika , Verdino Petra , Keller Walter , Singh Mohan B. , De Weerd Nicole , Sperr Wolfgang R. , Valent Peter , Balic Nadja , Reichelt Rudolf , Suck Roland , Fiebig Helmut , Valenta Rudolf , Spitzauer Susanne 
Published: April 2014

AbstractGrass pollen belong to the most important allergen sources involved in the elicitation of allergic asthma. We have isolated cDNAs coding for Bermuda grass (Cynodon dactylon) and timothy grass (Phleum pratense) pollen allergens, belonging to a family of pectin-degrading enzymes (i.e., polygalacturonases). The corresponding allergens, termed Cyn d 13 and Phl p 13, represent glycoproteins of ∼42 kDa and isoelectric points of 7.5. rPhl p 13 was expressed in Escherichia coli and purified to homogeneity. Immunogold electron microscopy using rabbit anti-rPhl p 13 Abs demonstrated that in dry pollen group 13, allergens represent primarily intracellular proteins, whereas exposure of pollen to rainwater caused a massive release of cytoplasmic material containing submicronic particles of respirable size, which were coated with group 13 allergens. The latter may explain respiratory sensitization to group 13 allergens and represents a possible pathomechanism in the induction of asthma attacks after heavy rainfalls. rPhl p 13 was recognized by 36% of grass pollen allergic patients, showed IgE binding capacity comparable to natural Phl p 13, and induced specific and dose-dependent basophil histamine release. Epitope mapping studies localized major IgE epitopes to the C terminus of the molecule outside the highly conserved functional polygalacturonase domains. The latter result explains why rPhl p 13 contains grass pollen-specific IgE epitopes and may be used to diagnose genuine sensitization to grass pollen. Our finding that rabbit anti-rPhl p 13 Abs blocked patients’ IgE binding to the allergen suggests that rPhl p 13 may be used for immunotherapy of sensitized patients.
Promotion of Allograft Survival by CD4+CD25+ Regulatory T Cells: Evidence for In Vivo Inhibition of Effector Cell Proliferation
Authors: Lee Major K. , Moore Daniel J. , Jarrett Beth P. , Lian Moh Moh , Deng Shaoping , Huang Xiaolun , Markmann Joseph W. , Chiaccio Meredith , Barker Clyde F. , Caton Andrew J. , Markmann James F. 
Published: April 2014

Abstract
Regulatory T cells preserve tolerance to peripheral self-Ags and may control the response to allogeneic tissues to promote transplantation tolerance. Although prior studies have demonstrated prolonged allograft survival in the presence of regulatory T cells (T-reg), data documenting the capacity of these cells to promote tolerance in immunocompetent transplant models are lacking, and the mechanism of suppression in vivo remains unclear. We used a TCR transgenic model of allograft rejection to characterize the in vivo activity of CD4+CD25+ T-reg. We demonstrate that graft Ag-specific T-reg effectively intercede in the rejection response of naive T cells to established skin allografts. Furthermore, CFSE labeling demonstrates impaired proliferation of naive graft Ag-specific T cells in the draining lymph node in the presence of T-reg. These results confirm the efficacy of T-reg in promoting graft survival and suggest that their suppressive action is accomplished in part through inhibition of proliferation.
The Antigen-Presenting Activity of Fresh, Adult Parenchymal Microglia and Perivascular Cells from Retina
Authors: Gregerson Dale S. , Sam Thien N. , McPherson Scott W. 
Published: April 2014

Abstract
Although several observations show local T cell recognition of retinal Ag, there has been no direct demonstration that the APC were retinal derived, rather than recruited. In this study, CD45+ cells isolated from immunologically quiescent murine retina were tested in vitro for functional evidence of Ag presentation to naive and Ag-experienced CD4 T cells specific for β-galactosidase. Because CD45+ cells from brain have been reported to be efficient APC, they were included for comparison. Measures of activation included changes in CD4, CD25, CD44, CD45RB, CD62L, CD69, caspase-3 activation, CFSE dilution, size, number of cells recovered, and cytokine production. Retinal CD45+ cells gave no evidence of Ag-dependent TCR ligation in naive T cells, unlike splenic APC and CD45+ cells from brain, which supported potent responses. Instead, addition of retinal CD45+ cells to cocultures of naive 3E9 T cells plus splenic APC reduced the yield of activated T cells and cytokine production by limiting T cell activation at early time points. Ag-experienced T cells responded weakly to Ag presented by retinal CD45+ cells. Activating the retinal cells with IFN-γ, anti-CD40, or LPS incrementally increased their APC activity. Addition of neutralizing Abs to TGF-β did not reveal suppressed retinal APC activity. Because retina lacks tissue equivalents of meninges and choroid plexus, rich sources of dendritic cells in brain, cells from retina may better represent the APC activity of fresh, adult CNS parenchymal and perivascular cells. The activity of the retinal CD45+ cells appears to be directed to limiting T cell responses.
Extensive Replicative Capacity of Human Central Memory T Cells
Authors: Maus Marcela V. , Kovacs Birgit , Kwok William W. , Nepom Gerald T. , Schlienger Katia , Riley James L. , Allman David , Finkel Terri H. , June Carl H. 
Published: April 2014

Abstract
To characterize the replicative capacity of human central memory (TCM) CD4 T cells, we have developed a defined culture system optimized for the ex vivo expansion of Ag-specific CD4+ T cells. Artificial APCs (aAPCs) consisting of magnetic beads coated with Abs to HLA class II and a costimulatory Ab to CD28 were prepared; peptide-charged HLA class II tetramers were then loaded on the beads to provide Ag specificity. Influenza-specific DR*0401 CD4 TCM were isolated from the peripheral blood of normal donors by flow cytometry. Peptide-loaded aAPC were not sufficient to induce resting CD4 TCM to proliferate. In contrast, we found that the beads efficiently promoted the growth of previously activated CD4 TCM cells, yielding cultures with &gt;80% Ag-specific CD4 cells after two stimulations. Further stimulation with peptide-loaded aAPC increased purity to &gt;99% Ag-specific T cells. After in vitro culture for 3–12 wk, the flu-specific CD4 TCM had surface markers that were generally consistent with an effector phenotype described for CD8 T cells, except for the maintenance of CD28 expression. The TCM were capable of 20–40 mean population doublings in vitro, and the expanded cells produced IFN-γ, IL-2, and TNF-α in response to Ag, and a subset of cells also secreted IL-4 with PMA/ionomycin treatment. In conclusion, aAPCs expand TCM that have extensive replicative capacity, and have potential applications in adoptive immunotherapy as well as for studying the biology of human MHC class II-restricted T cells.
Comparative Genomic Analysis of Two Avian (Quail and Chicken) MHC Regions
Authors: Shiina Takashi , Shimizu Sayoko , Hosomichi Kazuyoshi , Kohara Sakae , Watanabe Seiki , Hanzawa Kei , Beck Stephan , Kulski Jerzy K. , Inoko Hidetoshi 
Published: April 2014

Abstract
We mapped two different quail Mhc haplotypes and sequenced one of them (haplotype A) for comparative genomic analysis with a previously sequenced haplotype of the chicken Mhc. The quail haplotype A spans 180 kb of genomic sequence, encoding a total of 41 genes compared with only 19 genes within the 92-kb chicken Mhc. Except for two gene families (B30 and tRNA), both species have the same basic set of gene family members that were previously described in the chicken “minimal essential” Mhc. The two Mhc regions have a similar overall organization but differ markedly in that the quail has an expanded number of duplicated genes with 7 class I, 10 class IIB, 4 NK, 6 lectin, and 8 B-G genes. Comparisons between the quail and chicken Mhc class I and class II gene sequences by phylogenetic analysis showed that they were more closely related within species than between species, suggesting that the quail Mhc genes were duplicated after the separation of these two species from their common ancestor. The proteins encoded by the NK and class I genes are known to interact as ligands and receptors, but unlike in the quail and the chicken, the genes encoding these proteins in mammals are found on different chromosomes. The finding of NK-like genes in the quail Mhc strongly suggests an evolutionary connection between the NK C-type lectin-like superfamily and the Mhc, providing support for future studies on the NK, lectin, class I, and class II interaction in birds.
Differential Requirement for Adapter Proteins Src Homology 2 Domain-Containing Leukocyte Phosphoprotein of 76 kDa and Adhesion- and Degranulation-Promoting Adapter Protein in FcεRI Signaling and Mast Cell Function
Authors: Wu Jennifer N. , Jordan Martha S. , Silverman Michael A. , Peterson Erik J. , Koretzky Gary A. 
Published: April 2014

Abstract
The adapter molecule Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is essential for FcεRI-mediated signaling, degranulation and IL-6 production in mast cells. To test the structural requirements of SLP-76 in mast cell signaling and function, we have studied the functional responses of murine bone marrow-derived mast cells (BMMCs) expressing mutant forms of SLP-76. We found that the N-terminal tyrosines as well as the central proline-rich region of SLP-76 are required for participation of SLP-76 in FcεRI-mediated signaling and function. The C-terminal SH2 domain of SLP-76 also contributes to optimal function of SLP-76 in mast cells. Another adapter molecule, adhesion- and degranulation-promoting adapter protein (ADAP), is known to bind the SH2 domain of SLP-76, and cell line studies have implicated ADAP in mast cell adhesion and FcεRI-induced degranulation. Surprisingly, we found that mast cells lacking ADAP expression demonstrate no defects in FcεRI-induced adhesion, granule release, or IL-6 production, and that ADAP-deficient mice produce a normal passive systemic anaphylactic response. Thus, failure to bind ADAP does not underlie the functional defects exhibited by SLP-76 SH2 domain mutant-expressing mast cells.
Early Target Genes of IL-12 and STAT4 Signaling in Th Cells
Authors: Lund Riikka J. , Chen Zhi , Scheinin Joonas , Lahesmaa Riitta 
Published: April 2014

Abstract
IL-12 signaling through STAT4 is essential for induction of optimal levels of IFN-γ production and commitment of Th1 cells. The molecular mechanism that controls how IL-12 and STAT4 signaling induces Th1 differentiation is poorly described. To identify the early target genes of IL-12 and STAT4 signaling, oligonucleotide arrays were used to compare the gene expression profiles of wild-type and STAT4-knockout murine Th cells during the early Th1 differentiation. According to the results, 20 genes were regulated in an IL-12- and STAT4-dependent manner. Importantly, Ifnγ was clearly the first gene induced by IL-12 in a STAT4-dependent manner. Most of the other defects in gene expression in STAT4-knockout cells were seen after 48 h of Th1 polarization. In addition to IL-12 signaling mediated by STAT4, STAT4-independent induction of a number of genes was observed immediately in response to Th1 induction. This induction was at least in part driven by IFN-γ independently of STAT4. Importantly, addition of exogenous IFN-γ into Th1 cell cultures of STAT4-knockout cells restored the defect in IFN-γ production further demonstrating the critical role of IFN-γ in early Th1 differentiation.