bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Peptidyl-Prolyl Isomerase Pin1 Regulates Granulocyte-Macrophage Colony-Stimulating Factor mRNA Stability in T Lymphocytes
Authors: Esnault Stephane , Shen Zhong-Jian , Whitesel Emily , Malter James S. 
Published: April 2014

Abstract
Cytokine production is associated with both the normal and pathologic inflammatory response to injury. Previous studies have shown that the immunosuppressants cyclosporin A or FK506, which interact with the peptidyl-propyl isomerases cyclophilin A and FK506-binding protein (FKBP12), respectively, block cytokine expression. A third member of the peptidyl-propyl isomerase family, Pin1 is expressed by immune and other cells. Pin1 has been implicated in cell cycle progression, is overexpressed in human tumors, and may rescue neurons from τ-associated degeneration. However, the role of Pin1 in the immune system remains largely unknown. In this study, we analyze the role of Pin1 in GM-CSF expression by human PBMC and CD4+ lymphocytes. We show that Pin1 isomerase activity is necessary for activation-dependent, GM-CSF mRNA stabilization, accumulation, and protein secretion, but not non-AU-rich elements containing cytokine mRNAs, including TGF-β and IL-4. Mechanistically, Pin1 mediated the association of the AU-rich element-binding protein, AUF1, with GM-CSF mRNA, which determined the rate of decay by the exosome.
VH Replacement Rescues Progenitor B Cells with Two Nonproductive VDJ Alleles
Authors: Lutz Johannes , Müller Werner , Jäck Hans-Martin 
Published: April 2014

Abstract
Inaccurate VDJ rearrangements generate a large number of progenitor (pro)-B cells with two nonproductive IgH alleles. Such cells lack essential survival signals mediated by surface IgM heavy chain (μH chain) expression and are normally eliminated. However, secondary rearrangements of upstream VH gene segments into assembled VDJ exons have been described in mice transgenic for productive μH chains, a process known as VH replacement. If VH replacement was independent of μH chain signals, it could also modify nonproductive VDJ exons and thus rescue pro-B cells with unsuccessful rearrangements on both alleles. To test this hypothesis, we homologously replaced the JH cluster of a mouse with a nonproductive VDJ exon. Surprisingly, B cell development in IgHVDJ−/VDJ− mice was only slightly impaired and significant numbers of IgM-positive B cells were produced. DNA sequencing confirmed that all VDJ sequences from μH chain-positive B lymphoid cells were generated by VH replacement in a RAG-dependent manner. Another unique feature of our transgenic mice was the presence of IgH chains with unusually long CDR3-H regions. Such IgH chains were functional and only modestly counter-selected, arguing against a strict length constraint for CDR3-H regions. In conclusion, VH replacement can occur in the absence of a μH chain signal and provides a potential rescue mechanism for pro-B cells with two nonproductive IgH alleles.
Activating Transcription Factor/cAMP Response Element Binding Protein Family Member Regulated Transcription of CD1A
Authors: Colmone Angela , Li Sha , Wang Chyung-Ru 
Published: April 2014

Abstract
CD1a has a unique expression pattern among Ag-presenting molecules, expressed specifically on cortical thymocytes and APCs. As autoimmune disease, infection, and tumors can all result in alteration of CD1a expression, we are attempting to characterize the transcriptional regulation, and thus shed some light on specific expression, of CD1A. In this study, we have identified a minimal proximal promoter region required for CD1A transcription. Computer searches within this region identified numerous potential binding sites for lymphoid-specific transcription factors, including the ETS transcription factors, C/EBP, GATA, and CREB. Deletion and site-specific mutant analysis revealed a critical role of a potential cAMP response element (CRE) 965 bp upstream of the CD1A translation start site. Two activating transcription factor (ATF)/CREB family members, CREB-1 and ATF-2, are able to bind this site in vitro and in vivo. Notably, activation of ATF/CREB family members decreases CD1A transcription, while decrease in ATF-2 expression results in increased CD1A RNA level. The fact that these factors also bind the CD1A promoter in human monocytes strongly suggests a role for ATF/CREB family members in regulation of CD1A expression.
Fine Mapping of Collagen-Induced Arthritis Quantitative Trait Loci in an Advanced Intercross Line
Authors: Yu Xinhua , Bauer Kristin , Wernhoff Patrik , Koczan Dirk , Möller Steffen , Thiesen Hans-Jürgen , Ibrahim Saleh M. 
Published: April 2014

AbstractThe generation of advanced intercross lines (AIL) is a powerful approach for high-resolution fine mapping of quantitative trait loci (QTLs), because they accumulate much more recombination events compared with conventional F2 intercross and N2 backcross. However, the application of this approach is severely hampered by the requirements of excessive resources to maintain such crosses, i.e., in terms of animal care, space, and time. Therefore, in this study, we produced an AIL to fine map collagen-induced arthritis (CIA) QTLs using comparatively limited resources. We used only 308 (DBA/1 × FVB/N)F11/12 AIL mice to refine QTLs controlling the severity and onset of arthritis as well as the Ab response and T cell subset in CIA, namely Cia2, Cia27, and Trmq3. These QTLs were originally identified in (DBA/1 × FVB/N)F2 progeny. The confidence intervals of the three QTLs were refined from 40, 43, and 48 Mb to 12, 4.1, and 12 Mb, respectively. The data were complemented by the use of another QTL fine-mapping approach, haplotype analysis, to further refine Cia2 into a 2-Mb genomic region. To aid in the search for candidate genes for the QTLs, genome-wide expression profiling was performed to identify strain-specific differentially expressed genes within the confidence intervals. Of the 1396 strain-specific differentially expressed genes, 3, 3, and 12 genes were within the support intervals of the Cia2, Cia27, and Trmq3, respectively. In addition, this study revealed that Cia27 and Trmq3 controlling anti-CII IgG2a Ab and CD4:CD8 T cell ratio, respectively, also regulated CIA clinical phenotypes.
TLR-Dependent Induction of IFN-β Mediates Host Defense against Trypanosoma cruzi
Authors: Koga Ritsuko , Hamano Shinjiro , Kuwata Hirotaka , Atarashi Koji , Ogawa Masahiro , Hisaeda Hajime , Yamamoto Masahiro , Akira Shizuo , Himeno Kunisuke , Matsumoto Makoto , Takeda Kiyoshi 
Published: April 2014

Abstract
Host resistance to the intracellular protozoan parasite Trypanosoma cruzi depends on IFN-γ production by T cells and NK cells. However, the involvement of innate immunity in host resistance to T. cruzi remains unclear. In the present study, we investigated host defense against T. cruzi by focusing on innate immunity. Macrophages and dendritic cells (DCs) from MyD88−/−TRIF−/− mice, in which TLR-dependent activation of innate immunity was abolished, were defective in the clearance of T. cruzi and showed impaired induction of IFN-β during T. cruzi infection. Neutralization of IFN-β in MyD88−/− macrophages led to enhanced T. cruzi growth. Cells from MyD88−/−IFNAR1−/− mice also showed impaired T. cruzi clearance. Furthermore, both MyD88−/−TRIF−/− and MyD88−/−IFNAR1−/− mice were highly susceptible to in vivo T. cruzi infection, highlighting the involvement of innate immune responses in T. cruzi infection. We further analyzed the molecular mechanisms for the IFN-β-mediated antitrypanosomal innate immune responses. MyD88−/−TRIF−/− and MyD88−/−IFNAR1−/− macrophages and DCs exhibited defective induction of the GTPase IFN-inducible p47 (IRG47) after T. cruzi infection. RNA interference-mediated reduction of IRG47 expression in MyD88−/− macrophages resulted in increased intracellular growth of T. cruzi. These findings suggest that TLR-dependent expression of IFN-β is involved in resistance to T. cruzi infection through the induction of IRG47.
Adoptive Transfer of CD8α+ Dendritic Cells (DC) Isolated from Mice Infected with Chlamydia muridarum Are More Potent in Inducing Protective Immunity Than CD8α− DC
Authors: Bilenki Laura , Wang Shuhe , Yang Jie , Fan Yijun , Jiao Lei , Joyee Antony George , Han Xiaobing , Yang Xi 
Published: April 2014

Abstract
Chlamydial infections are serious public health concerns worldwide. In this study, we examined the role of dendritic cell (DC) subsets in inducing protective immunity against chlamydial infection using an adoptive transfer approach. We found that CD11c+CD8α+ (double-positive, DP) DC, compared with CD11c+CD8α− (single-positive, SP) DC isolated from infected mice, are more potent inducers of protective immunity. Specifically, mice pretreated with DPDC from infected mice, upon infection with Chlamydia trachomatis mouse pneumonitis (MoPn), experienced significantly less severe body weight loss and in vivo chlamydial growth. Analysis of MoPn-driven cytokine production by immune cells revealed that mice that were treated with DPDC produced significantly higher levels of Th1 (TNF-α, IFN-γ, and IL-12) but lower levels of Th2 (IL-4, IL-5, and IL-13)-related cytokines than the recipients of SPDC following infection challenge. Moreover, DPDC-treated mice displayed significantly higher levels of MoPn-specific IgG2a production and delayed-type hypersensitivity responses compared with SPDC-treated mice. Furthermore, DPDC isolated from infected mice produced higher amounts of IL-12 and IL-10 in vitro in comparison with SPDC. These data indicate that CD8α+ DC have a significantly higher capacity in inducing protective immunity compared with CD8α− DC, demonstrating the crucial role of DC1-like cells in eliciting protection against C. trachomatis infection
NK Cell-Derived IFN-γ Differentially Regulates Innate Resistance and Neutrophil Response in T Cell-Deficient Hosts Infected with Mycobacterium tuberculosis
Authors: Feng Carl G. , Kaviratne Mallika , Rothfuchs Antonio Gigliotti , Cheever Allen , Hieny Sara , Young Howard A. , Wynn Thomas A. , Sher Alan 
Published: April 2014

Abstract
Although it is known that IFN-γ-secreting T cells are critical for control of Mycobacterium tuberculosis infection, the contribution of IFN-γ produced by NK cells to host resistance to the pathogen is less well understood. By using T cell-deficient RAG−/− mice, we showed that M. tuberculosis stimulates NK cell-dependent IFN-γ production in naive splenic cultures and in lungs of infected animals. More importantly, common cytokine receptor γ-chain−/−RAG−/− animals deficient in NK cells, p40−/−RAG−/−, or anti-IFN-γ mAb-treated RAG−/− mice displayed significantly increased susceptibility to M. tuberculosis infection compared with untreated NK-sufficient RAG−/− controls. Studies comparing IL-12 p40- and p35-deficient RAG−/− mice indicated that IL-12 plays a more critical role in the induction of IFN-γ-mediated antimycobacterial effector functions than IL-23 or other p40-containing IL-12 family members. The increased susceptibility of IL-12-deficient or anti-IFN-γ mAb-treated RAG−/− mice was associated not only with elevated bacterial loads, but also with the development of granulocyte-enriched foci in lungs. This tissue response correlated with increased expression of the granulocyte chemotactic chemokines KC and MIP-2 in NK as well as other leukocyte populations. Interestingly, depletion of granulocytes further increased bacterial burdens and exacerbated pulmonary pathology in these animals, revealing a compensatory function for neutrophils in the absence of IFN-γ. The above observations indicate that NK cell-derived IFN-γ differentially regulates T-independent resistance and granulocyte function in M. tuberculosis infection and suggest that this response could serve as an important barrier in AIDS patients or other individuals with compromised CD4+ T cell function.
Human Cytomegalovirus Envelope Glycoproteins B and H Are Necessary for TLR2 Activation in Permissive Cells
Authors: Boehme Karl W. , Guerrero Mario , Compton Teresa 
Published: April 2014

Abstract
Human CMV (HCMV) is a ubiquitous member of the Herpesviridae family and an opportunistic pathogen that poses significant health risks for immunocompromised patients. HCMV pathogenesis is intimately tied to the immune status of the host, thus characterization of the innate immune response to HCMV infection is critical for understanding disease progression. Previously, we identified TLR2 as a host factor that detects and initiates inflammatory cytokine secretion in response to HCMV independent of viral replication. In this study, we show that two entry-mediating envelope gp, gp B (gB) and gp H (gH), display determinants recognized by TLR2. Neutralizing Abs against TLR2, gB and gH inhibit inflammatory cytokine responses to HCMV infection, suggesting that inflammatory cytokine stimulation by HCMV is mediated by interactions between these envelope gp and TLR2. Furthermore, both gB and gH coimmunoprecipitate with TLR2 and TLR1, indicating that these envelope gp directly interact with TLR2 and that a TLR2/TLR1 heterodimer is a functional sensor for HCMV. Because our previous studies were conducted in model cell lines, we also show that TLR2 is expressed by HCMV permissive human fibroblast cell strains, and that TLR2 is a functional sensor in these cells. This study further elucidates the importance and potency of envelope gp as a class of molecules displaying pathogen-associated molecular patterns that are recognized with immediate kinetics by TLRs in permissive cells.
HIV Induces Maturation of Monocyte-Derived Dendritic Cells and Langerhans Cells
Authors: Harman Andrew N. , Wilkinson John , Bye Chris R. , Bosnjak Lidija , Stern J. Lewis , Nicholle Monique , Lai Joey , Cunningham Anthony L. 
Published: April 2014

Abstract
In HIV infection, dendritic cells (DCs) may play multiple roles, probably including initial HIV uptake in the anogenital mucosa, transport to lymph nodes, and subsequent transfer to T cells. The effects of HIV-1 on DC maturation are controversial, with several recent conflicting reports in the literature. In this study, microarray studies, confirmed by real-time PCR, demonstrated that the genes encoding DC surface maturation markers were among the most differentially expressed in monocyte-derived dendritic cells (MDDCs), derived from human blood, treated with live or aldrithriol-2-inactivated HIV-1BaL. These effects translated to enhanced cell surface expression of these proteins but differential expression of maturation markers was only partial compared with the effects of a conventional potent maturation stimulus. Such partially mature MDDCs can be converted to fully mature cells by this same potent stimulus. Furthermore, live HIV-1 stimulated greater changes in maturation marker surface expression than aldrithriol-2-inactivated HIV-1 and this enhanced stimulation by live HIV-1 was mediated via CCR5, thus suggesting both viral replication-dependent and -independent mechanisms. These partially mature MDDCs demonstrated enhanced CCR7-mediated migration and are also able to stimulate interacting T cells in a MLR, suggesting DCs harboring HIV-1 might prepare CD4 lymphocytes for transfer of HIV-1. Increased maturation marker surface expression was also demonstrated in native DCs, ex vivo Langerhans cells derived from human skin. Thus, HIV initiates maturation of DCs which could facilitate subsequent enhanced transfer to T cells.
Flavivirus Activation of Plasmacytoid Dendritic Cells Delineates Key Elements of TLR7 Signaling beyond Endosomal Recognition
Authors: Wang Jennifer P. , Liu Ping , Latz Eicke , Golenbock Douglas T. , Finberg Robert W. , Libraty Daniel H. 
Published: April 2014

Abstract
TLR7 senses RNA in endosomal compartments. TLR7 expression and signaling have been demonstrated in plasmacytoid and myeloid dendritic cells, B cells, and T cells. The regulation of TLR7 signaling can play a crucial role in shaping the immune response to RNA viruses with different cellular tropisms, and in developing adjuvants capable of promoting balanced humoral and cell-mediated immunity. We used unique characteristics of two ssRNA viruses, dengue virus and influenza virus, to delineate factors that regulate viral RNA-human TLR7 signaling beyond recognition in endosomal compartments. Our data show that TLR7 recognition of enveloped RNA virus genomes is linked to virus fusion or uncoating from the endosome. The signaling threshold required to activate TLR7-type I IFN production is greater than that required to activate TLR7-NF-κB-IL-8 production. The higher order structure of viral RNA appears to be an important determinant of TLR7-signaling potency. A greater understanding of viral RNA-TLR7 activity relationships will promote rational approaches to interventional and vaccine strategies for important human viral pathogens.
Sertoli Cells Initiate Testicular Innate Immune Responses through TLR Activation
Authors: Riccioli Anna , Starace Donatella , Galli Roberta , Fuso Andrea , Scarpa Sigfrido , Palombi Fioretta , De Cesaris Paola , Ziparo Elio , Filippini Antonio 
Published: April 2014

Abstract
TLRs play a crucial role in early host defense against invading pathogens. In the seminiferous epithelium, Sertoli cells are the somatic nurse cells that mechanically segregate germ cell autoantigens by means of the blood-tubular barrier and create a microenvironment that protects germ cells from both interstitial and ascending invading pathogens. The objective of this study was to examine TLR expression and their functional responses to specific agonists in mouse Sertoli cells. We measured the expression of TLR2, TLR4, TLR5, and TLR6 mRNAs and confirmed by FACS analysis the presence of proteins TLR2 and TLR5 on which we focused our study. Stimulation of Sertoli cells with macrophage-activating lipopeptide-2, agonist of TLR2/TLR6, and with flagellin, agonist of TLR5, induces augmented secretion of the chemokine MCP-1. To assess the functional significance of MCP-1 production following TLR stimulation, conditioned medium from either macrophage-activating lipopeptide-2 or flagellin-treated Sertoli cells was tested for in vitro chemotaxis assay, and a significant increase of macrophage migration was observed in comparison with unstimulated conditioned medium. Moreover, we studied the role of NF-κB and of MAPKs in regulating TLR-mediated MCP-1 secretion by using inhibitors specific for each transduction pathway and we demonstrated a pivotal role of the IκB/NF-κB and JNK systems. In addition, TLR2/TLR6 and TLR5 stimulation induces increased ICAM-1 expression in Sertoli cells. Collectively, this study demonstrates the novel ability of Sertoli cells to potentially respond to a wide variety of bacteria through TLR stimulation.
Bordetella bronchiseptica Modulates Macrophage Phenotype Leading to the Inhibition of CD4+ T Cell Proliferation and the Initiation of a Th17 Immune Response
Authors: Siciliano Nicholas A. , Skinner Jason A. , Yuk Ming H. 
Published: April 2014

Abstract
Bordetella bronchiseptica is a Gram-negative bacterium equipped with several colonization factors that allow it to establish a persistent infection of the murine respiratory tract. Previous studies indicate that B. bronchiseptica adenylate cyclase toxin (ACT) and the type III secretion system (TTSS) synergize to drive dendritic cells into an altered phenotype to down-regulate the host immune response. In this study, we examined the effects of B. bronchiseptica ACT and TTSS on murine bone marrow-derived macrophages. We demonstrate that ACT and TTSS are required for the inhibition of Ag-driven CD4+ T cell proliferation by bacteria-infected macrophages. We identify PGE2 as the mediator of this inhibition, and we show that ACT and the TTSS synergize to increase macrophage production of PGE2. We further demonstrate that B. bronchiseptica can modulate normal macrophage function and drive the immune response toward a Th17 phenotype classified by the significant production of IL-17. In this study, we show that B. bronchiseptica-infected macrophages can induce IL-17 production from naive CD4+ splenocytes, and that lung tissues from B. bronchiseptica-infected mice exhibit a strong Th17 immune response. ACT inhibited surface expression of CD40 and CD86, suppressed TNF-α production, and up-regulated IL-6 production. TTSS also synergized with ACT to up-regulate IL-10 and PGE2 secretion. These findings indicate that persistent colonization by B. bronchiseptica may rely on the ability of the bacteria to differentially modulate both macrophage and dendritic cell function leading to an altered adaptive immune response and subsequent bacterial colonization.
Lipopolysaccharide-Activated CD4+CD25+ T Regulatory Cells Inhibit Neutrophil Function and Promote Their Apoptosis and Death
Authors: Lewkowicz Przemysław , Lewkowicz Natalia , Sasiak Andrzej , Tchórzewski Henryk 
Published: April 2014

Abstract
CD4+CD25+ T regulatory (Treg) cells play a central role in the suppression of immune response and prevention of autoimmune reactions. Pathogen recognition receptors expressed by immune cells, such as TLRs, may provide a critical link between the innate and adaptive immune systems. There is also evidence that TLR ligands can directly modulate the suppressive capacity of Treg cells. Here, we showed that CD4+CD25+ Treg cells affect neutrophil function and survival and that the TLR4 ligand is involved in the regulation of the cell interactions. We found that LPS-activated Treg cells inhibit reactive oxygen intermediates and cytokine production by neutrophils. Moreover, Treg cells reverse LPS-induced survival of neutrophils and promote their apoptosis and death. We also found that TCR-activated Treg cells induce the same effects on polymorphonuclear neutrophils as those achieved by TLR4 stimulation. Importantly, the suppressive potential of CD4+CD25+ Treg cells induced by LPS seems to be partially IL-10 and TGF-β dependent, whereas anti-CD3/CD28 stimulation is rather contact dependent. Together, these observations suggest that Treg cells have the ability to directly regulate neutrophil function and life span when both types of the cells are exposed to LPS.
Airway Epithelial Cells Produce B Cell-Activating Factor of TNF Family by an IFN-β-Dependent Mechanism
Authors: Kato Atsushi , Truong-Tran Ai Q. , Scott Alan L. , Matsumoto Kenji , Schleimer Robert P. 
Published: April 2014

Abstract
Activation of B cells in the airways is now believed to be of great importance in immunity to pathogens, and it participates in the pathogenesis of airway diseases. However, little is known about the mechanisms of local activation of B cells in airway mucosa. We investigated the expression of members of the B cell-activating TNF superfamily (B cell-activating factor of TNF family (BAFF) and a proliferation-inducing ligand (APRIL)) in resting and TLR ligand-treated BEAS-2B cells and primary human bronchial epithelial cells (PBEC). In unstimulated cells, expression of BAFF and APRIL was minimal. However, BAFF mRNA was significantly up-regulated by TLR3 ligand (dsRNA), but not by other TLR ligands, in both BEAS-2B cells (376-fold) and PBEC (224-fold). APRIL mRNA was up-regulated by dsRNA in PBEC (7-fold), but not in BEAS-2B cells. Membrane-bound BAFF protein was detectable after stimulation with dsRNA. Soluble BAFF protein was also induced by dsRNA (&gt;200 pg/ml). The biological activity of the epithelial cell-produced BAFF was verified using a B cell survival assay. BAFF was also strongly induced by IFN-β, a cytokine induced by dsRNA. Induction of BAFF by dsRNA was dependent upon protein synthesis and IFN-αβ receptor-JAK-STAT signaling, as indicated by studies with cycloheximide, the JAK inhibitor I, and small interfering RNA against STAT1 and IFN-αβ receptor 2. These results suggest that BAFF is induced by dsRNA in airway epithelial cells and that the response results via an autocrine pathway involving IFN-β. The production of BAFF and APRIL by epithelial cells may contribute to local accumulation, activation, class switch recombination, and Ig synthesis by B cells in the airways.