bluuebunny/crossref_metadata_2025_split huggingface dataset:
TNF Receptor-Associated Factor 2-Dependent Canonical Pathway Is Crucial for the Development of Peyer’s Patches
Authors: Piao Jiang-Hu , Yoshida Hisahiro , Yeh Wen-Chen , Doi Takahiro , Xue Xin , Yagita Hideo , Okumura Ko , Nakano Hiroyasu 
Published: April 2014

Abstract
Activation of the noncanonical pathway through the interaction of lymphotoxin (LT)-α1β2 and LT-βR is essential for the development of secondary lymphoid organs including lymph nodes (LN) and Peyer’s patches (PP). Although TNFR-associated factor (TRAF) 2 and TRAF5 were identified as signal transducers for the LT-βR, roles for TRAF2 and TRAF5 in the development of secondary lymphoid organs remain obscure. In this study, we show that PP but not mesenteric LN development is severely impaired in traf2−/− and traf2−/−traf5−/− mice. Development of VCAM-1+ and ICAM-1+ mesenchymal cells and expression of CXCL13, a crucial chemokine for the development of PP, are severely impaired in PP anlagen in the intestines of traf2−/− mice. Surprisingly, TNF-α stimulation potently up-regulates cxcl13 mRNA expression in wild-type murine embryonic fibroblasts, which is impaired in traf2−/− and relA−/− murine embryonic fibroblasts. Moreover, RelA is recruited to the promoter of cxcl13 gene upon TNF-α stimulation and PP development is impaired in TNFR type 1 (tnfr1)−/− mice. These results underscore a crucial role for the TNFR1-TRAF2-RelA-dependent canonical pathway in the development of PP through up-regulation of cxcl13 mRNA.
CXC Chemokine Ligand 9/Monokine Induced by IFN-γ Production by Tumor Cells Is Critical for T Cell-Mediated Suppression of Cutaneous Tumors
Authors: Gorbachev Anton V. , Kobayashi Hirohito , Kudo Daisuke , Tannenbaum Charles S. , Finke James H. , Shu Suyu , Farber Joshua M. , Fairchild Robert L. 
Published: April 2014

Abstract
The role of tumor-produced chemokines in the growth of malignancies remains poorly understood. We retrieved an in vivo growing MCA205 fibrosarcoma and isolated tumor cell clones that produce both CXCL9/monokine induced by IFN-γ (Mig) and CXCL10/IFN-γ-inducible protein 10 following stimulation with IFN-γ and clones that produce IFN-γ-inducible protein 10 but not Mig. The Mig-deficient variants grew more aggressively as cutaneous tumors in wild-type mice than the Mig-producing tumor cells. The growth of Mig-expressing, but not Mig-deficient, tumor cells was suppressed by NK and T cell activity. Transduction of Mig-negative variants to generate constitutive tumor cell production of Mig resulted in T cell-dependent rejection of the tumors and in induction of protective tumor-specific CD8+ T cell responses to Mig-deficient tumors. The results indicate a critical role for tumor-derived Mig in T cell-mediated responses to cutaneous fibrosarcomas and suggest the loss of Mig expression as a mechanism used by tumor cells to evade these responses.
Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis
Authors: Stel Alja J. , ten Cate Bram , Jacobs Susan , Kok Jan Willem , Spierings Diana C. J. , Dondorff Monica , Helfrich Wijnand , Kluin-Nelemans Hanneke C. , de Leij Lou F. M. H. , Withoff Sebo , Kroesen Bart Jan 
Published: April 2014

Abstract
Ab binding to CD20 has been shown to induce apoptosis in B cells. In this study, we demonstrate that rituximab sensitizes lymphoma B cells to Fas-induced apoptosis in a caspase-8-dependent manner. To elucidate the mechanism by which Rituximab affects Fas-mediated cell death, we investigated rituximab-induced signaling and apoptosis pathways. Rituximab-induced apoptosis involved the death receptor pathway and proceeded in a caspase-8-dependent manner. Ectopic overexpression of FLIP (the physiological inhibitor of the death receptor pathway) or application of zIETD-fmk (specific inhibitor of caspase-8, the initiator-caspase of the death receptor pathway) both specifically reduced rituximab-induced apoptosis in Ramos B cells. Blocking the death receptor ligands Fas ligand or TRAIL, using neutralizing Abs, did not inhibit apoptosis, implying that a direct death receptor/ligand interaction is not involved in CD20-mediated cell death. Instead, we hypothesized that rituximab-induced apoptosis involves membrane clustering of Fas molecules that leads to formation of the death-inducing signaling complex (DISC) and downstream activation of the death receptor pathway. Indeed, Fas coimmune precipitation experiments showed that, upon CD20-cross-linking, Fas-associated death domain protein (FADD) and caspase-8 were recruited into the DISC. Additionally, rituximab induced CD20 and Fas translocation to raft-like domains on the cell surface. Further analysis revealed that, upon stimulation with rituximab, Fas, caspase-8, and FADD were found in sucrose-gradient raft fractions together with CD20. In conclusion, in this study, we present evidence for the involvement of the death receptor pathway in rituximab-induced apoptosis of Ramos B cells with concomitant sensitization of these cells to Fas-mediated apoptosis via Fas multimerization and recruitment of caspase-8 and FADD to the DISC.
p21CIP1/WAF1 Controls Proliferation of Activated/Memory T Cells and Affects Homeostasis and Memory T Cell Responses
Authors: Arias Cristina F. , Ballesteros-Tato André , García María Isabel , Martín-Caballero Juan , Flores Juana M. , Martínez-A Carlos , Balomenos Dimitrios 
Published: April 2014

Abstract
Development of autoantibodies and lupus-like autoimmunity by 129/Sv × C57BL/6 p21−/− mice has established that cell cycle deregulation is one the defective pathways leading to break of tolerance. Memory T cell accumulation is thought to be related to tolerance loss in murine lupus models. We studied T cell memory responses in C57BL/6 p21−/− mice that develop lupus-like disease manifestations. p21 did not affect primary proliferation of naive T cells, and was required for cycling control, but not for apoptosis of activated/memory T cells. When we induced apoptosis by secondary TCR challenge, surviving memory T cells depended on p21 for proliferation control. Under conditions of secondary T cell stimulation that did not cause apoptosis, p21 was also needed for regulation of activated/memory T cell expansion. The requirement for p21 in the control of T cell proliferation of activated/memory T cells suggests that in addition to apoptosis, cycling regulation by p21 constitutes a new pathway for T cell homeostasis. Concurring with this view, we found accumulation in p21−/− mice of memory CD4+ T cells that showed increased proliferative potential after TCR stimulation. Furthermore, OVA immunization of p21−/− mice generated hyperresponsive OVA-specific T cells. Overall, the data show that p21 controls the proliferation of only activated/memory T cells, and suggest that p21 forms part of the memory T cell homeostasis mechanism, contributing to maintenance of tolerance.
A Novel Postpriming Regulatory Check Point of Effector/Memory T Cells Dictated through Antigen Density Threshold-Dependent Anergy
Authors: Oved Kfir , Ziv Omer , Jacob-Hirsch Jasmine , Noy Roy , Novak Hila , Makler Oryan , Galit Denkberg , Keren Sinik , Segal Dina , Gefen-Dor Chen , Amariglio Ninette , Rechavi Gideon , Reiter Yoram 
Published: April 2014

Abstract
CTLs act as the effector arm of the cell-mediated immune system to kill undesirable cells. Two processes regulate these effector cells to prevent self reactivity: a thymic selection process that eliminates autoreactive clones and a multistage activation or priming process that endows them with a license to kill cognate target cells. Hitherto no subsequent regulatory restrictions have been ascribed for properly primed and activated CTLs that are licensed to kill. In this study we show that CTLs possess a novel postpriming regulatory mechanism(s) that influences the outcome of their encounter with cognate target cells. This mechanism gauges the degree of Ag density, whereupon reaching a certain threshold significant changes occur that induce anergy in the effector T cells. The biological consequences of this Ag-induced postpriming control includes alterations in the expression of cell surface molecules that control immunological synapse activity and cytokine profiles and induce retarded cell proliferation. Most profound is genome-wide microarray analysis that demonstrates changes in the expression of genes related to membrane potential, TCR signal transduction, energy metabolism, and cell cycle control. Thus, a discernible and unique gene expression signature for anergy as a response to high Ag density has been observed. Consequently, activated T cells possess properties of a self-referential sensory organ. These studies identify a new postpriming control mechanism of CTL with anergenic-like properties. This mechanism extends our understanding of the control of immune function and regulation such as peripheral tolerance, viral infections, antitumor immune responses, hypersensitivity, and autoimmunity.
The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide
Authors: Laragione Teresina , Yarlett Nuriza C. , Brenner Max , Mello Adriana , Sherry Barbara , Miller Edmund J. , Metz Christine N. , Gulko Pércio S. 
Published: April 2014

Abstract
Neutrophils are required for the development of arthritis, and their migration into the synovial tissue coincides with the onset of clinical disease. Synovial neutrophil numbers also correlate with rheumatoid arthritis disease activity and severity. We hypothesized that certain arthritis severity genes regulate disease via the regulation of neutrophil migration into the joint. This hypothesis was tested in the synovial-like air pouch model injected with carrageenan using arthritis-susceptible DA and arthritis-resistant F344 rats. DA had nearly 3-fold higher numbers of exudate neutrophils compared with F344 (p &lt; 0.001). Five DA.F344(QTL) strains congenic for severity loci and protected from autoimmune arthritis were studied. Only DA.F344(Cia4) (chromosome 7) and DA.F344(Cia6) (chromosome 8) congenics had significantly lower exudate neutrophil counts compared with DA. TNF-α levels were 2.5-fold higher in DA exudates as compared with F344 exudates, and that difference was accounted for by the Cia4 locus. Exudate levels of NO, a known inhibitor of neutrophil chemotaxis, were higher in F344, compared with DA, and that difference was accounted for by Cia6. This is the first time that non-MHC autoimmune arthritis loci are found to regulate three central components of the innate immune response implicated in disease pathogenesis, namely neutrophil migration into an inflammatory site, as well as exudate levels of TNF-α and NO. These observations underscore the importance of identifying the Cia4 and Cia6 genes, and suggest that they should generate useful novel targets for development of new therapies.
Genetic Dissection of Spontaneous Autoimmunity Driven by 129-Derived Chromosome 1 Loci When Expressed on C57BL/6 Mice
Authors: Carlucci Francesco , Cortes-Hernandez Josefina , Fossati-Jimack Liliane , Bygrave Anne E. , Walport Mark J. , Vyse Timothy J. , Cook H. Terence , Botto Marina 
Published: April 2014

Abstract
Extensive evidence indicates that genetic predisposition is a central element in susceptibility to systemic lupus erythematosus both in humans and animals. We have previously shown that a congenic line carrying a 129-derived chromosome 1 interval on the C57BL/6 background developed humoral autoimmunity. To further dissect the contribution to autoimmunity of this 129 interval, we have created six subcongenic strains carrying fractions of the original 129 region and analyzed their serological and cellular phenotypes. At 1 year of age the congenic strain carrying a 129 interval between the microsatellites D1Mit15 (87.9 cM) and D1Mit115 (99.7 cM) (B6.129chr1b) had high levels of autoantibodies, while all the other congenic lines were not significantly different from the C57BL/6 controls. The B6.129chr1b strain displayed only mild proliferative glomerulonephritis despite high levels of IgG and C3 deposited in the kidneys. FACS analysis of the spleens revealed that the B6.129chr1b mice had a marked increase in the percentage of activated T cells associated with a significant reduction in the proportion of CD4+CD25high regulatory T cells. Moreover, this analysis showed a significantly reduced percentage of marginal zone B cells that preceded autoantibody production. Interestingly the 129chr1b-expressing bone marrow-derived macrophages displayed an impaired uptake of apoptotic cells in vitro. Collectively, our data indicate that the 129chr1b segment when recombined on the C57BL/6 genomic background is sufficient to induce loss of tolerance to nuclear Ags. These findings have important implication for the interpretation of the autoimmune phenotype associated with gene-targeted models.
RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs
Authors: Park Jong-Hwan , Kim Yun-Gi , McDonald Christine , Kanneganti Thirumala-Devi , Hasegawa Mizuho , Body-Malapel Mathilde , Inohara Naohiro , Núñez Gabriel 
Published: April 2014

Abstract
RICK is a kinase that has been implicated in Nod1 and Nod2 signaling. In addition, RICK has been proposed to mediate TLR signaling in that its absence confers reduced responses to certain bacterial products such as LPS. We show here that macrophages and mice lacking RICK are defective in their responses to Nod1 and Nod2 agonists but exhibit unimpaired responses to synthetic and highly purified TLR agonists. Furthermore, production of chemokines induced by the bacterial dipeptide γ-d-glutamyl-meso-diaminopimelic acid was intact in MyD88 deficient mice but abolished in RICK-null mice. Stimulation of macrophages with muramyl dipeptide, the Nod2 activator, enhanced immune responses induced by LPS, IFN-γ, and heat-killed Listeria in wild-type but not in RICK- or Nod2-deficient macrophages. Finally, we show that the absence of RICK or double deficiency of Nod1 and Nod2 was associated with reduced cytokine production in Listeria-infected macrophages. These results demonstrate that RICK functions in innate immunity by mediating Nod1 and Nod2 signaling but not TLR-mediated immune responses.
Mucosal Luminal Manipulation of T Cell Geography Switches on Protective Efficacy by Otherwise Ineffective Parenteral Genetic Immunization
Authors: Santosuosso Michael , McCormick Sarah , Roediger Elizabeth , Zhang Xizhong , Zganiacz Anna , Lichty Brian D. , Xing Zhou 
Published: April 2014

Abstract
Genetic immunization holds great promise for future vaccination against mucosal infectious diseases. However, parenteral genetic immunization is ineffective in control of mucosal intracellular infections, and the underlying mechanisms have remained unclear. By using a model of parenteral i.m. genetic immunization and pulmonary tuberculosis (TB), we have investigated the mechanisms that determine the failure and success of parenteral genetic immunization. We found that lack of protection from pulmonary Mycobacterium tuberculosis (M.tb) challenge by i.m. immunization with a recombinant adenovirus-vectored tuberculosis vaccine was linked to the absence of M.tb Ag-specific T cells within the airway lumen before M.tb challenge despite potent T cell activation in the systemic compartments. Furthermore, pulmonary mycobacterial challenge failed to recruit CD8 T cells into the airway lumen of i.m. immunized mice. Such defect in T cell recruitment, intra-airway CTL, and immune protection was restored by creating acute inflammation in the airway with inflammatory agonists such as virus. However, the Ag-specific T cells recruited as such were not retained in the airway lumen, resulting in a loss of protection. In comparison, airway exposure to low doses of soluble M.tb Ags not only recruited but retained Ag-specific CD8 T cells in the airway lumen over time that provided robust protection against M.tb challenge. Thus, our study reveals that mucosal protection by parenteral immunization is critically determined by T cell geography, i.e., whether Ag-specific T cells are within or outside of the mucosal lumen and presents a feasible solution to empower parenteral immunization strategies against mucosal infectious diseases.
Expression of the p60 Autolysin Enhances NK Cell Activation and Is Required forListeria monocytogenesExpansion in IFN-γ-Responsive Mice
Authors: Humann Jessica , Bjordahl Ryan , Andreasen Karl , Lenz Laurel L. 
Published: April 2014

AbstractBoth peptidoglycan and muropeptides potently modulate inflammatory and innate immune responses. The secreted Listeria monocytogenes p60 autolysin digests peptidoglycan and promotes bacterial infection in vivo. Here, we report that p60 contributes to bacterial subversion of NK cell activation and innate IFN-γ production. L. monocytogenes deficient for p60 (Δp60) competed well for expansion in mice doubly deficient for IFNAR1 and IFN-γR1 or singly deficient for IFN-γR1, but not in wild-type, IFNAR1−/−, or TLR2−/− mice. The restored competitiveness of p60-deficient bacteria suggested a specific role for p60 in bacterial subversion of IFN-γ-mediated immune responses, since in vivo expansion of three other mutant L. monocytogenes strains (ΔActA, ΔNamA, and ΔPlcB) was not complemented in IFN-γR1−/− mice. Bacterial expression of p60 was not required to induce socs1, socs3, and il10 expression in infected mouse bone marrow macrophages but did correlate with enhanced production of IL-6, IL-12p70, and most strikingly IFN-γ. The primary source of p60-dependent innate IFN-γ was NK cells, whereas bacterial p60 expression did not significantly alter innate IFN-γ production by T cells. The mechanism for p60-dependent NK cell stimulation was also indirect, given that treatment with purified p60 protein failed to directly activate NK cells for IFN-γ production. These data suggest that p60 may act on infected cells to indirectly enhance NK cell activation and increase innate IFN-γ production, which presumably promotes early bacterial expansion through its immunoregulatory effects on bystander cells. Thus, the simultaneous induction of IFN-γ production and factors that inhibit IFN-γ signaling may be a common strategy for misdirection of early antibacterial immunity.
TLR9 Signaling in B Cells Determines Class Switch Recombination to IgG2a
Authors: Jegerlehner Andrea , Maurer Patrik , Bessa Juliana , Hinton Heather J. , Kopf Manfred , Bachmann Martin F. 
Published: April 2014

Abstract
Although IgG2a is the most potent Ab isotype in the host response to viral and bacterial infections, the regulation of class switch recombination to IgG2a in vivo is not yet well understood. Recognition of pathogen-associated molecular patterns by dendritic cells expressing TLRs, like TLR7, recognizing ssRNA, or TLR9, recognizing DNA rich in nonmethylated CG motifs (CpG), favors induction of Th1 responses. It is generally assumed that these Th1 responses are responsible for the TLR-mediated induction of IgG2a. Using virus-like particles loaded with CpGs, we show here that TLR9 ligands can directly stimulate B cells to undergo isotype switching to IgG2a. Unexpectedly, TLR9 expression in non-B cells did not affect isotype switching in the Ab response against virus-like particles. Thus, TLR9 can regulate isotype switching to IgG2a directly by interacting with B cells rather than indirectly by inducing Th1 responses.
Heat Shock Protein 27 Regulates Neutrophil Chemotaxis and Exocytosis through Two Independent Mechanisms
Authors: Jog Neelakshi R. , Jala Venkatakrishna R. , Ward Richard A. , Rane Madhavi J. , Haribabu Bodduluri , McLeish Kenneth R. 
Published: April 2014

Abstract
The targets of the p38 MAPK pathway responsible for regulation of neutrophil chemotaxis and exocytosis are unknown. One target of this pathway is the actin-binding protein, heat shock protein 27 (Hsp27). Therefore, we tested the hypothesis that Hsp27 mediates p38 MAPK-dependent chemotaxis and exocytosis in human neutrophils through regulation of actin reorganization. Sequestration of Hsp27 by introduction of anti-Hsp27 Ab, but not an isotype Ab, inhibited fMLP-stimulated chemotaxis, increased cortical F-actin in the absence of fMLP stimulation, and inhibited fMLP-stimulated exocytosis. Pretreatment with latrunculin A prevented actin reorganization and the changes in fMLP-stimulated exocytosis induced by Hsp27 sequestration. To determine the role of Hsp27 phosphorylation, wild-type, phosphorylation-resistant, or phosphorylation-mimicking recombinant Hsp27 was introduced into neutrophils by electroporation. The phosphorylation-resistant mutant significantly reduced migration toward fMLP, whereas none of the Hsp27 proteins affected fMLP-stimulated or TNF-α-stimulated exocytosis or actin polymerization. Endogenous Hsp27 colocalized with F-actin in unstimulated and fMLP-stimulated neutrophils, whereas phosphorylated Hsp27 showed cytosolic localization in addition to colocalization with F-actin. Our results suggest that Hsp27 regulates neutrophil chemotaxis and exocytosis in an actin-dependent, phosphorylation-independent manner. Phosphorylation of Hsp27 regulates chemotaxis, but not exocytosis, independent of regulation of actin reorganization.
PU.1 Redirects Adenovirus to Lysosomes in Alveolar Macrophages, Uncoupling Internalization from Infection
Authors: Carey Brenna , Staudt Margaret K. , Bonaminio Dana , van der Loo Johannes C. M. , Trapnell Bruce C. 
Published: April 2014

Abstract
Adenovirus is endocytosed and efficiently destroyed by human and murine alveolar macrophages (AMs) and rapidly cleared from the lungs of wild-type but not GM-CSF−/− mice. We hypothesized that GM-CSF may regulate adenovirus clearance in AMs via the transcription factor PU.1 by redirecting virion trafficking from the nucleus to lysosomes. This hypothesis was tested in murine AM cell lines with altered GM-CSF and/or PU.1 expression including MH-S (GM-CSF+/+PU.1Pos), mAM (GM-CSF−/−/PU.1Neg), and mAMPU.1+ (GM-CSF−/−/PU.1Pos; PU.1-transduced mAM cells) and A549 (an epithelial-like cell line) using a human adenovirus expressing a β-galactosidase reporter. In PU.1Neg mAM and A549 cells, adenovirus efficiently escaped from endosomes, translocated to the nucleus, and expressed the viral reporter in most cells. In marked contrast, in PU.1Pos mAMPU.1+ and MH-S cells, adenovirus failed to escape from endosomes, colocalized exclusively with endosome/lysosome markers (Rab5, Rab7, and Lamp1), and rarely expressed the reporter. Retroviral expression of PU.1 in A549 cells blocked endosomal escape, nuclear translocation and reporter expression. Inhibition of endosome acidification also blocked escape, nuclear translocation, and reporter expression in PU.1Neg cells. The effect of PU.1 on viral trafficking and transduction could not be explained by an effect on endosome acidification or on differences in viral load. PU.1 reduced expression of integrin β5, a host factor important for endosomal escape of adenovirus, suggesting that PU.1 redirects adenoviral trafficking by modulating integrin signaling. These results demonstrate that PU.1 uncouples infection from internalization in AMs, providing a mechanism for AMs to avoid infection by adenovirus during clearance.