bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen Load Governs the Differential Priming of CD8 T Cells in Response to the Bacille Calmette Guérin Vaccine or Mycobacterium tuberculosis Infection
Authors: Ryan Anthony A. , Nambiar Jonathan K. , Wozniak Teresa M. , Roediger Ben , Shklovskaya Elena , Britton Warwick J. , Fazekas de St. Groth Barbara , Triccas James A. 
Published: May 2009

Abstract
One reason proposed for the failure of Mycobacterium bovis bacille Calmette Guérin (BCG) vaccination to adequately control the spread of tuberculosis is a limited ability of the vaccine to induce effective CD8 T cell responses. However, the relative capacity of the BCG vaccine and virulent Mycobacterium tuberculosis to induce activation of CD8 T cells, and the factors that govern the initial priming of these cells after mycobacterial infection, are poorly characterized. Using a TCR transgenic CD8 T cell transfer model, we demonstrate significant activation of Ag-specific CD8 T cells by BCG, but responses were delayed and of reduced magnitude compared with those following infection with M. tuberculosis. The degree of CD8 T cell activation was critically dependent on the level of antigenic stimulation, as modifying the infectious dose to achieve comparable numbers of BCG or M. tuberculosis in draining lymph nodes led to the same pattern of CD8 T cell responses to both strains. Factors specific to M. tuberculosis infection did not influence the priming of CD8 T cells, as codelivery of M. tuberculosis with BCG did not alter the magnitude of BCG-induced T cell activation. Following transfer to RAG-1−/− recipients, BCG and M. tuberculosis-induced CD8 T cells conferred equivalent levels of protection against M. tuberculosis infection. These findings demonstrate that BCG is able to prime functional CD8 T cells, and suggest that effective delivery of Ag to sites of T cell activation by vaccines may be a key requirement for optimal CD8 T cell responses to control mycobacterial infection.
IL-15 Renders Conventional Lymphocytes Resistant to Suppressive Functions of Regulatory T Cells through Activation of the Phosphatidylinositol 3-Kinase Pathway
Authors: Ahmed Mélika Ben , Belhadj Hmida Nadia , Moes Nicolette , Buyse Sophie , Abdeladhim Maha , Louzir Hechmi , Cerf-Bensussan Nadine 
Published: May 2009

Abstract
IL-15 drives chronic inflammation in several human diseases. We have recently shown that IL-15 inhibits the immunosuppressive effects of TGF-β through blockage of the Smad3-signaling pathway. Data pointing to reciprocal interactions between TGF-β and CD4+ regulatory T cells led us to investigate the impact of IL-15 on the de novo generation and function of regulatory T cells in humans. Our data indicate that IL-15 does not counteract, but rather promotes the effect of TGF-β on the de novo generation of regulatory T cells (Treg). Thus, in the presence of TGF-β, IL-15 enhanced the acquisition of regulatory functions by CD4+CD25− T cells stimulated by anti-CD3 and anti-CD28 Abs. In contrast, IL-15 impaired the functions of Tregs by acting on effector CD4 and CD8 T cells. Accordingly, in the presence of IL-15, proliferation and IFN-γ production by peripheral CD4 and CD8 T cells could not be efficiently inhibited by Tregs. IL-15-induced resistance of effector T cells to Tregs resulted from activation of the PI3K signaling pathway but did not involve the rescue of effector T cells from apoptosis. Altogether, these data point to the ambiguous role of IL-15 in the control of Treg functions. This dual role may be instrumental to mount rapid but transient proinflammatory immune responses against pathogens but may become deleterious in situations associated with protracted IL-15 over-expression.
Chemokine Receptor CCR7 Contributes to a Rapid and Efficient Clearance of Lytic Murine γ-Herpes Virus 68 from the Lung, Whereas Bronchus-Associated Lymphoid Tissue Harbors Virus during Latency
Authors: Kocks Jessica R. , Adler Heiko , Danzer Heike , Hoffmann Katharina , Jonigk Danny , Lehmann Ulrich , Förster Reinhold 
Published: May 2009

Abstract
Murine γ-herpes virus 68 is a natural rodent pathogen closely related to the human γ-herpes viruses Kaposi’s sarcoma-associated herpes virus and EBV. By intranasally infecting wild-type and CCR7-deficient mice, we investigated whether CCR7 is necessary for viral clearance from the lung and the establishment of latency. We found during the lytic phase of infection that inflammation in lungs of CCR7−/− mice was more severe and viral load significantly higher compared with wild-type littermates. In addition, activation of T cells was delayed and clearance of the inflammation was retarded in mutant lungs, demonstrating that CCR7 is necessary for a rapid and efficient immune response. However, for the establishment of splenomegaly and latency, the presence of CCR7 was dispensable. Finally, by microdissecting BALT, we could demonstrate that these ectopic lymphoid structures are a place in the lung where virus resides during latency.
CD2 Distinguishes Two Subsets of Human Plasmacytoid Dendritic Cells with Distinct Phenotype and Functions
Authors: Matsui Toshimichi , Connolly John E. , Michnevitz Mark , Chaussabel Damien , Yu Chun-I , Glaser Casey , Tindle Sasha , Pypaert Marc , Freitas Heidi , Piqueras Bernard , Banchereau Jacques , Palucka A. Karolina 
Published: May 2009

Abstract
Plasmacytoid dendritic cells (pDCs) are key regulators of antiviral immunity. They rapidly secrete IFN-α and cross-present viral Ags, thereby launching adaptive immunity. In this study, we show that activated human pDCs inhibit replication of cancer cells and kill them in a contact-dependent fashion. Expression of CD2 distinguishes two pDC subsets with distinct phenotype and function. Both subsets secrete IFN-α and express granzyme B and TRAIL. CD2high pDCs uniquely express lysozyme and can be found in tonsils and in tumors. Both subsets launch recall T cell responses. However, CD2high pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.
Identification of an IFN-γ-Producing Neutrophil Early in the Response to Listeria monocytogenes
Authors: Yin Jiyi , Ferguson Thomas A. 
Published: May 2009

Abstract
IFN-γ plays a critical role during the immune response to infection with Listeria monocytogenes. Early in the innate response NK cells are thought to be a primary source of IFN-γ; however, protection can be mediated by the presence of significant numbers of primed IFN-γ-secreting CD8+ T cells. In this report, we examined the early response to Listeria and found that 18 h after infection spleens contain CD11b+, Gr-1high, or Ly6G+ cells that produce significant IFN-γ. Morphological analysis of sorted Gr-1highIFN-γ+ and Gr-1lowIFN-γ+ or Ly6G+IFN-γ+ cells confirmed that these cells were neutrophils. The importance of IFN-γ production by these cells was further tested using adoptive transfer studies. Transfer of purified neutrophils from Ifng+/+ mice led to increased bacterial clearance in Ifng−/− mice. Transfer of Ifng−/− neutrophils provided no such protection. We conclude that neutrophils are an early source of IFN-γ during Listeria infection and are important in providing immune protection.
Pollen-Derived E1-Phytoprostanes Signal via PPAR-γ and NF-κB-Dependent Mechanisms
Authors: Gilles Stefanie , Mariani Valentina , Bryce Martina , Mueller Martin J. , Ring Johannes , Jakob Thilo , Pastore Saveria , Behrendt Heidrun , Traidl-Hoffmann Claudia 
Published: May 2009

Abstract
In a humid milieu such as mucosal surfaces, pollen grains do not only release allergens but also proinflammatory and immunomodulatory lipids, termed pollen-associated lipid mediators. Among these, the E1-phytoprostanes (PPE1) were identified to modulate dendritic cell (DC) function: PPE1 inhibit the DC’s capacity to produce IL-12 and enhance DC mediated TH2 polarization of naive T cells. The mechanism(s) by which PPE1 act on DC remained elusive. We thus analyzed candidate signaling elements and their role in PPE1-mediated regulation of DC function. Aqueous birch pollen extracts induced a marked cAMP response in DC that could be blocked partially by EP2 and EP4 antagonists. In contrast, PPE1 hardly induced cAMP and the inhibitory effect on IL-12 production was mostly independent of EP2 and EP4. Instead, PPE1 inhibited the LPS-induced production of IL-12 p70 by a mechanism involving the nuclear receptor PPAR-γ. Finally, PPE1 efficiently blocked NF-κB signaling in DCs by inhibiting IκB-α degradation, translocation of p65 to the nucleus, and binding to its target DNA elements. We conclude that pollen-derived PPE1 modulate DC function via PPAR-γ dependent pathways that lead to inhibition of NFκB activation and result in reduced DC IL-12 production and consecutive TH2 polarization.
TLR2 Deficiency Leads to Increased Th17 Infiltrates in Experimental Brain Abscesses
Authors: Nichols Jessica R. , Aldrich Amy L. , Mariani Monica M. , Vidlak Debbie , Esen Nilufer , Kielian Tammy 
Published: May 2009

Abstract
TLR2 plays a pivotal role in recognizing Staphylococcus aureus, a common etiologic agent of CNS parenchymal infections, such as brain abscess. We previously reported that brain abscesses of TLR2 knockout (KO) mice exhibited elevated IL-17 levels, suggesting the presence of an alternative pathway available to respond to S. aureus infection that may involve Th17 cells. Both CD4+ and CD8+ T cell infiltrates were elevated in brain abscesses of TLR2 KO mice at days 3, 7, and 14 postinfection compared with wild-type animals. Intracellular cytokine staining revealed a significant increase in the frequency of IL-17-producing Th17 cells in TLR2 KO mice with relatively few IFN-γ-positive cells. γδ T cells were also a source of IL-17 in brain abscesses. Microglia, astrocytes, and macrophages were shown to express both IL-17RA and IL-17RC. Despite receptor expression, IL-17 was relatively ineffective at eliciting glial activation, whereas the cytokine augmented the ability of TNF-α to induce CXCL2 and CCL2 expression by macrophages. Based on the ability of IL-17 to elicit the release of chemokines and other proinflammatory mediators, we propose that the exaggerated IL-17 response that occurs in TLR2 KO mice functions in a compensatory manner to control brain abscess pathogenesis, with cells other than glia as targets for IL-17 action. This is supported by our findings in which innate immune infiltrates were not significantly different between TLR2 KO and wild-type mice in conjunction with the lack of prolonged alterations in the synthesis of other proinflammatory molecules during the course of infection.
TLR Activation Induces TNF-α Production from Adult Neural Stem/Progenitor Cells
Authors: Covacu Ruxandra , Arvidsson Lisa , Andersson Åsa , Khademi Mohsen , Erlandsson-Harris Helena , Harris Robert A. , Svensson Mikael A. , Olsson Tomas , Brundin Lou 
Published: May 2009

Abstract
Adult neural stem cells (NSCs) are believed to facilitate CNS repair and tissue regeneration. However, it is not yet clear how these cells are influenced when the cellular environment is modified during neurotrauma or neuroinflammatory conditions. In this study, we determine how different proinflammatory cytokines modulate the expression of TLR2 and TLR4 in NSCs and how these cells respond to TLR2 and TLR4 agonists. Primary cultures of neural stem/progenitor cells isolated from the subventricular zone of brains from adult Dark Agouti rats were exposed to 1) supernatants from activated macrophages; 2) proinflammatory cytokines IFN-γ, TNF-α, or both; and 3) agonists for TLR2 and TLR4. Both TLR2 and TLR4 were expressed during basal conditions and their mRNA levels were further increased following cytokine exposure. TLR4 was up-regulated by IFN-γ and this effect was reversed by TNF-α. TLR2 expression was increased by supernatants from activated macrophages and by TNF-α, which synergized with IFN-γ. TLR agonists induced the expression of TNF-α mRNA. Importantly, TNF-α could be translated into protein and released into the supernatants where it was quantified by cytokine ELISA. In conclusion, we demonstrate that NSCs constitutively express TLR2 and TLR4 and that their expression is increased as a consequence of exposure to proinflammatory mediators. Additionally, activation of these receptors can induce production of proinflammatory cytokines. These findings suggest that NSCs may be primed to participate in cytokine production during neuroinflammatory or traumatic conditions.
The Chicken Leukocyte Receptor Complex Encodes a Family of Different Affinity FcY Receptors
Authors: Viertlboeck Birgit C. , Schweinsberg Sonja , Schmitt Ramona , Herberg Friedrich W. , Göbel Thomas W. 
Published: May 2009

Abstract
Chicken Ig-like receptors (CHIR) form a large family in the leukocyte receptor complex on microchromosome 31 with inhibitory, activating, and bifunctional receptors. Recently, we characterized CHIR-AB1 as a high-affinity, primordial FcY receptor. Given that the CHIR family represents a multigene family, it is plausible that more than a single receptor binds to IgY. Therefore, after comparing CHIR-AB1-like sequences in databases, we cloned CHIR-AB1 homologues from two individual chickens representing the lines M11 and R11 with primers binding to highly conserved regions. In both lines this approach yielded 18 different CHIR-AB amino acid versions, with one sequence out of each line that was identical with the previously characterized B19 CHIR-AB1 Ig domain and two additional R11-M11 identical sequence pairs. All M11-derived CHIR-AB homologues were then expressed as soluble human Ig fusion proteins. Following standardization of the fusion protein concentration with an ELISA, the IgY, IgM, and IgA binding activities were determined by ELISA. Six fusion proteins recognized IgY, whereas none bound to IgM and IgA. The affinities of selected fusion proteins were determined using surface plasmon resonance yielding an equilibrium binding constant between 25 nM for high binders and 260 nM for low binders. Sequence comparisons and subsequent mutational analysis of selected residues identified five amino acids that are potentially involved in IgY binding. These results imply that multiple FcY receptors of variable affinity are encoded by the CHIR locus and that different chicken lines may express both unique as well as highly conserved FcY receptors.
Dominant Human CD8 T Cell Clonotypes Persist Simultaneously as Memory and Effector Cells in Memory Phase
Authors: Touvrey Cédric , Derré Laurent , Devevre Estelle , Corthesy Patricia , Romero Pedro , Rufer Nathalie , Speiser Daniel E. 
Published: May 2009

Abstract
The adaptive immune system plays a critical role in protection at the time of secondary infection. It does so through the rapid and robust reactivation of memory T cells which are maintained long-term, in a phenotypically heterogeneous state, following their primary encounter with Ag. Although most HLA-A*0201/influenza matrix protein58–66-specific CD8 T cells from healthy donors display characteristics typical of memory T cells, through our extensive phenotypic analysis we have further shown that up to 20% of these cells express neither the IL-7 receptor CD127 nor the costimulatory molecule CD28. In contrast to the majority of CD28pos cells, granzyme B and perforin were frequently expressed by the CD28neg cells, suggesting that they are effector cells. Indeed, these cells were able to kill target cells, in an Ag-specific manner, directly ex vivo. Thus, our findings demonstrate the remarkable long-term persistence in healthy humans of not only influenza-specific memory cells, but also of effector T cells. We further observed that granzyme B expression in influenza-specific CD8 T cells paralleled levels in the total CD8 T cell population, suggestive of Ag-nonspecific bystander activation. Sequencing of TCR α- and β-chains showed that the TCR repertoire specific for this epitope was dominated by one, or a few, T cell clonotype per healthy donor. Moreover, our sequencing analysis revealed, for the first time in humans, that identical clonotypes can coexist as both memory and effector T cells, thereby supporting the principle of multipotent clonotypic differentiation.
The CD4+ T Cell-Mediated IFN-γ Response to Helicobacter Infection Is Essential for Clearance and Determines Gastric Cancer Risk
Authors: Sayi Ayca , Kohler Esther , Hitzler Iris , Arnold Isabelle , Schwendener Reto , Rehrauer Hubert , Müller Anne 
Published: May 2009

Abstract
Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in the majority of individuals. We report here that the C57BL/6 mouse model of experimental infection with the closely related Helicobacter felis recapitulates this wide range in host susceptibility. Although the majority of infected animals develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia, and intestinal metaplasia, a subset of mice is completely protected from preneoplasia. Protection is associated with a failure to mount an IFN-γ response to the infection and with a concomitant high Helicobacter burden. Using a vaccine model as well as primary infection and adoptive transfer models, we demonstrate that IFN-γ, secreted predominantly by CD4+CD25− effector TH cells, is essential for Helicobacter clearance, but at the same time mediates the formation of preneoplastic lesions. We further provide evidence that IFN-γ triggers a common transcriptional program in murine gastric epithelial cells in vitro and in vivo and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-γ in Helicobacter pathogenesis that could be the basis for the differential susceptibility to H. pylori-induced gastric pathology in the human population.
Coronin-1 Is Associated with Neutrophil Survival and Is Cleaved during Apoptosis: Potential Implication in Neutrophils from Cystic Fibrosis Patients
Authors: Moriceau Sandra , Kantari Chahrazade , Mocek Julie , Davezac Noélie , Gabillet Julie , Guerrera Ida Chiara , Brouillard Frank , Tondelier Danielle , Sermet-Gaudelus Isabelle , Danel Claire , Lenoir Gérard , Daniel Soizic , Edelman Aleksander , Witko-Sarsat Véronique 
Published: May 2009

Abstract
Because neutrophil apoptosis plays a key role in resolving inflammation, identification of proteins regulating neutrophil survival should provide new strategies to modulate inflammation. Using a proteomic approach, coronin-1 was identified as a cytosolic protein cleaved during neutrophil apoptosis. Coronin-1 is an actin-binding protein that can associate with phagosomes and NADPH oxidase, but its involvement in apoptosis was currently unknown. In coronin-1-transfected PLB985 cells, coronin-1 overexpression did not modify the kinetics of granulocyte differentiation as assessed by CD11b labeling. Concerning apoptosis, increased coronin-1 expression in dimethylformamide-differentiated PLB985 significantly decreased gliotoxin-induced mitochondrial depolarization as compared with controls. Likewise, coronin-1 significantly decreased TRAIL-induced apoptosis with less mitochondrial depolarization, caspase-3 and caspase-9 activities, but not caspase-8 or Bid truncation suggesting that coronin-1 interfered with mitochondria-related events. To validate the prosurvival role of coronin-1 in a pathophysiological condition involving neutrophil-dominated inflammation, neutrophils from cystic fibrosis (CF) patients were studied. Circulating neutrophils from CF patients had more coronin-1 expression assessed by immunoblotting or proteomic analysis of cytosolic proteins. This was associated with a lower apoptosis rate than those from controls evidenced by delayed phosphatidylserine externalization and mitochondria depolarization. In addition, inflammatory neutrophils from CF patients lungs showed an intense coronin-1 immunolabeling. We concluded that coronin-1 could constitute a potential target in resolving inflammation.
IL-7 Promotes CXCR3 Ligand-Dependent T Cell Antitumor Reactivity in Lung Cancer
Authors: Andersson Åsa , Yang Seok-Chul , Huang Min , Zhu Li , Kar Upendra K. , Batra Raj K. , Elashoff David , Strieter Robert M. , Dubinett Steven M. , Sharma Sherven 
Published: May 2009

Abstract
We are evaluating the immune enhancing activities of cytokines for their optimum utility in augmenting cellular immune responses against lung cancer. In this study, we evaluated the mechanism of antitumor responses following IL-7 administration to mice bearing established Lewis lung cancer. IL-7 decreased tumor burden with concomitant increases in the frequency of CD4 and CD8 T lymphocyte subsets, T cell activation markers CXCR3, CD69, and CD127low, effector memory T cells, and T cell cytolytic activity against parental tumor cells. Accompanying the antitumor responses were increases in IFN-γ, CXCL9, CXCL10, and IL-12. Individual neutralization of CD4, CD8 T lymphocytes, or the CXCR3 ligands CXCL9 and CXCL10 reversed the antitumor benefit of IL-7, indicating their importance for optimal responses in vivo. Furthermore, IL-7 decreased the tumor-induced apoptosis of T cells with subsequent decrease of the proapoptotic marker Bim. We assessed the impact of IL-7 treatment on regulatory T cells that negatively impact antitumor immune responses. IL-7 decreased regulatory T Foxp3 as well as cell suppressive activity with a reciprocal increase in SMAD7. These results indicate that IL-7 induces CXCR3 ligand-dependent T cell antitumor reactivity in lung cancer.
Vav1 Is Essential for Mechanotactic Crawling and Migration of Neutrophils out of the Inflamed Microvasculature
Authors: Phillipson Mia , Heit Bryan , Parsons Sean A. , Petri Björn , Mullaly Sarah C. , Colarusso Pina , Gower R. Michael , Neely Gregory , Simon Scott I. , Kubes Paul 
Published: May 2009

Abstract
Mac-1-dependent crawling is a new step in the leukocyte recruitment cascade that follows LFA-1-dependent adhesion and precedes emigration. Neutrophil adhesion via LFA-1 has been shown to induce cytoskeletal reorganization through Vav1-dependent signaling, and the current study investigates the role of Vav1 in the leukocyte recruitment process in vivo with particular attention to the events immediately downstream of LFA-1-dependent adhesion. Intravital and spinning-disk-confocal microscopy was used to investigate intravascular crawling in relation to endothelial junctions in vivo in wild-type and Vav1−/− mice. Adherent wild-type neutrophils almost immediately began crawling perpendicular to blood flow via Mac-1 until they reached an endothelial junction where they often changed direction. This pattern of perpendicular, mechanotactic crawling was recapitulated in vitro when shear was applied. In sharp contrast, the movement of Vav1−/− neutrophils was always in the direction of flow and appeared more passive as if the cells were dragged in the direction of flow in vivo and in vitro. More than 80% of Vav1−/− neutrophils moved independent of Mac-1 and could be detached with LFA-1 Abs. An inability to release the uropod was frequently noted for Vav1−/− neutrophils, leading to greatly elongated tails. The Vav1−/− neutrophils failed to stop or follow junctions and ultimately detached, leading to fewer emigrated neutrophils. The Vav1−/− phenotype resulted in fewer neutrophils recruited in a relevant model of infectious peritonitis. Clearly, Vav1 is critical for the complex interplay between LFA-1 and Mac-1 that underlies the programmed intravascular crawling of neutrophils.