bluuebunny/crossref_metadata_2025_split huggingface dataset:
Memory Phenotype of CD8+ T Cells in MHC Class Ia-Deficient Mice
Authors: Kurepa Zoran , Su Jie , Forman James 
Published: April 2014

Abstract
B6.Kb−Db− mice are devoid of class Ia but express normal levels of class Ib molecules. They have low levels of CD8 T cells in both the thymus as well as peripheral T cell compartments. Although the percentage of splenic CD8αα T cells is increased in these animals, ∼90% of CD8 T cells are CD8αβ. In contrast to B6 animals, most of the CD8 T cells from these mice have a memory phenotype (CD44highCD122high CD62Llow) including both CD8αβ and CD8αα subsets. In the thymus of B6.Kb−Db− animals, there is a decrease in the percentage of SP CD8 T cells, although most are CD44low, similar to that seen in B6 mice. The spleens from day 1-old B6 and B6.Kb−Db− mice have a relatively high proportion of CD44highCD62Llow CD8 T cells. However, by day 28 most CD8 T cells in B6 mice have a naive phenotype while in B6.Kb−Db− mice the memory phenotype remains. Unlike CD44high cells that are found in B6 animals, most CD44high cells from B6.Kb−Db− mice do not secrete IFN-γ rapidly upon activation. The paucity of CD8 T cells in B6.Kb−Db− mice might be due in part to their inability to undergo homeostatic expansion. Consistent with this, we found that CD8 T cells from these animals expand poorly in X-irradiated syngeneic hosts compared with B6 CD8 T cells that respond to class Ia Ags. We examined homeostatic expansion of B6 CD8 T cells in single as well as double class Ia knockout mice and were able to estimate the fraction of cells reactive against class Ia vs class Ib molecules.
Genetic Dissection of Vα14Jα18 Natural T Cell Number and Function in Autoimmune-Prone Mice
Authors: Matsuki Naoto , Stanic Aleksandar K. , Embers Monica E. , Van Kaer Luc , Morel Laurence , Joyce Sebastian 
Published: April 2014

AbstractNonobese diabetic (NOD) mice, a model for type I diabetes (TID), have reduced numbers of invariant Vα14Jα18 TCR α-chain-positive natural T (iNKT) cells that do not release IL-4 in response to in vivo activation through their Ag receptor. The deficit in iNKT cell number and function is implicated in immune dysregulation and the etiology of TID. Therefore, we reasoned that the genetic determinant(s) that controls iNKT cell number and function might lie within Idd (insulin-dependent diabetes susceptibility locus) regions, which are known to contain TID resistance or susceptibility genes. A systematic analysis of iNKT cell number and function in Idd congenic mice revealed that neither iNKT cell number nor their inability to rapidly secrete IL-4 in response to acute in vivo activation by Ag underlies the mechanism of protection from diabetes in Idd congenic mice. Moreover, the regulation of iNKT cell number and function appears to be under the control of several genes. The most notable of these map to the Idd4, Idd5, Idd9.1, and Idd13 regions of the mouse genome. Together these findings provide a clue to the genetic mechanism(s) underlying iNKT cell deficiency in NOD mice.
IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity
Authors: Kopp Tamara , Lenz Petra , Bello-Fernandez Concha , Kastelein Robert A. , Kupper Thomas S. , Stingl Georg 
Published: April 2014

Abstract
p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic (TG) mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2q) transplanted across a MHC class I and class II barrier onto BALB/c (H-2d) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2q) (mean survival time: 10.7 days, p &lt; 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses.
Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-2
Authors: Wrenshall Lucile E. , Platt Jeffrey L. , Stevens Elliot T. , Wight Thomas N. , Miller John D. 
Published: April 2014

Abstract
IL-2, a cytokine produced by T cells, is a key regulator of immune responses and T cell homeostasis. Controlling the availability of IL-2 is consequently of significant import to the immune system. Like other cytokines, IL-2 is thought to function as a soluble agonist, transiently present when secreted in response to appropriate stimuli. In this study, we show that the most salient properties of IL-2, propagation and control of T cell responses, are mediated in vivo by bound and not free cytokine and specifically by heparan sulfate-bound IL-2. These findings necessitate a new look at how IL-2 regulates immune responses and support the notion that the microenvironment plays a determining role in modulating the character of immune responses.
Isolated Lymphoid Follicle Formation Is Inducible and Dependent Upon Lymphotoxin-Sufficient B Lymphocytes, Lymphotoxin β Receptor, and TNF Receptor I Function
Authors: Lorenz Robin G. , Chaplin David D. , McDonald Keely G. , McDonough Jacquelyn S. , Newberry Rodney D. 
Published: April 2014

AbstractThe gastrointestinal mucosa contains a complex network of lymphoid compartments that have evolved to efficiently protect the host from invading pathogens. Recently, an additional lymphoid structure resembling Peyer’s patches (PP) in composition and architecture has been identified in the murine small intestine, the isolated lymphoid follicle (ILF). In this study we examine the nature and factors required for ILF formation. We observed a spectrum of structures fitting the previous descriptions of ILFs, ranging from clusters of B220+ cells (which we have termed immature ILFs) to well-organized lymphoid nodules (which we have termed mature ILFs). Here we demonstrate that that similar to PP formation, ILF formation requires lymphotoxin (LT)- and LTβ receptor-dependent events. However unlike PP formation, the LT- and LTβ receptor-dependent events required for ILF formation can occur in adulthood and require LT-sufficient B lymphocytes. We demonstrate that mature ILF formation occurs in response to lumenal stimuli, including normal bacterial flora, and requires TNF receptor I function. These findings suggest that ILFs are organized intestinal lymphoid structures whose formation can be induced and whose mass can be expanded in response to mucosal challenges.
IL-12 Administration Accelerates Autoimmune Diabetes in Both Wild-Type and IFN-γ-Deficient Nonobese Diabetic Mice, Revealing Pathogenic and Protective Effects of IL-12-Induced IFN-γ
Authors: Trembleau Sylvie , Penna Giuseppe , Gregori Silvia , Giarratana Nadia , Adorini Luciano 
Published: April 2014

Abstract
IL-12 administration to nonobese diabetic (NOD) mice induces IFN-γ-secreting type 1 T cells and high circulating IFN-γ levels and accelerates insulin-dependent diabetes mellitus (IDDM). Here we show that IL-12-induced IFN-γ production is dispensable for diabetes acceleration, because exogenous IL-12 could enhance IDDM development in IFN-γ-deficient as well as in IFN-γ-sufficient NOD mice. Both in IFN-γ+/− and IFN-γ−/− NOD mice, IL-12 administration generates a massive and destructive insulitis characterized by T cells, macrophages, and CD11c+ dendritic cells, and increases the number of pancreatic CD4+ cells secreting IL-2 and TNF-α. Surprisingly, IL-12-induced IFN-γ hinders pancreatic B cell infiltration and inhibits the capacity of APCs to activate T cells. Although pancreatic CD4+ T cells from IL-12-treated IFN-γ−/− mice fail to up-regulate the P-selectin ligand, suggesting that their entry into the pancreas may be impaired, T cell expansion is favored in these mice compared with IL-12-treated IFN-γ+/− mice because IL-12 administration in the absence of IFN-γ leads to enhanced cell proliferation and reduced T cell apoptosis. NO, an effector molecule in β cell destruction, is produced ex vivo in high quantity by pancreas-infiltrating cells through a mechanism involving IL-12-induced IFN-γ. Conversely, in IL-12-treated IFN-γ-deficient mice, other pathways of β cell death appear to be increased, as indicated by the up-regulated expression of Fas ligand on Th1 cells in the absence of IFN-γ. These data demonstrate that IFN-γ has a dual role, pathogenic and protective, in IDDM development, and its deletion allows IL-12 to establish alternative pathways leading to diabetes acceleration.
Selective Induction of Dendritic Cells Using Granulocyte Macrophage-Colony Stimulating Factor, But Not fms-Like Tyrosine Kinase Receptor 3-Ligand, Activates Thyroglobulin-Specific CD4+/CD25+ T Cells and Suppresses Experimental Autoimmune Thyroiditis
Authors: Vasu Chenthamarakshan , Dogan Rukiye-Nazan E. , Holterman Mark J. , Prabhakar Bellur S. 
Published: April 2014

Abstractfms-like tyrosine kinase receptor 3-ligand (Flt3-L) and GM-CSF cause expansion of different subsets of dendritic cells and skew the immune response toward predominantly Th1 and Th2 type, respectively. In the present study, we investigated their effects on experimental autoimmune thyroiditis in CBA/J mice. Relative to mouse thyroglobulin (mTg) immunized controls, mTg-immunized mice treated with Flt3-L showed more severe thyroiditis characterized by enhanced lymphocytic infiltration of the thyroid, and IFN-γ and IL-2 production. In contrast, mice treated with GM-CSF, either before or after immunization with mTg, showed suppressed T cell response to mTg and failed to develop thyroiditis. Lymphocytes from these mice, upon activation with mTg in vitro, produced higher levels of IL-4 and IL-10. Additionally, GM-CSF-treated mice showed an increase in the frequency of CD4+/CD25+ T cells, which suppressed the mTg-specific T cell response. Neutralization of IL-10, but not IL-4, or depletion of CD4+/CD25+ cells resulted in increased mTg-specific in vitro T cell proliferation suggesting that IL-10 produced by the Ag-specific CD4+/CD25+ regulatory T cells might be critical for disease suppression. These results indicate that skewing immune response toward Th2, through selective activation of dendritic cells using GM-CSF, may have therapeutic potential in Th1 dominant autoimmune diseases including Hashimoto’s thyroiditis.
Mast Cell Activation byMycobacterium tuberculosis: Mediator Release and Role of CD48
Authors: Muñoz Samira , Hernández-Pando Rogelio , Abraham Soman N. , Enciso Jose Antonio 
Published: April 2014

AbstractMast cells (MC) are abundant in the lung and other peripheral tissue, where they participate in inflammatory processes against bacterial infections. Like other effector cells of the innate immune system, MC interact directly with a wide variety of infectious agents. This interaction results in MC activation and inflammatory mediator release. We demonstrated that MC interact with Mycobacterium tuberculosis, triggering the release of several prestored reagents, such as histamine and β-hexosaminidase, and de novo synthesized cytokines, such as TNF-α and IL-6. A number of M. tuberculosis Ags, ESAT-6, MTSA-10, and MPT-63, have been implicated in MC activation and mediator release. A MC plasmalemmal protein, CD48, was implicated in interactions with mycobacteria because CD48 appeared to aggregate in the MC membrane at sites of bacterial binding and because Abs to CD48 inhibited the MC histamine response to mycobacteria. Cumulatively, these findings suggest that MC, even in the absence of opsonins, can directly recognize M. tuberculosis and its Ags and have the potential to play an active role in mediating the host’s innate response to M. tuberculosis infection.
Subversion and Utilization of the Host Cell Cyclic Adenosine 5′-Monophosphate/Protein Kinase A Pathway byBrucellaDuring Macrophage Infection
Authors: Gross Antoine , Bouaboula Monsif , Casellas Pierre , Liautard Jean-Pierre , Dornand Jacques 
Published: April 2014

AbstractBrucella spp. are intramacrophage pathogens that induce chronic infections in a wide range of mammals, including domestic animals and humans. Therefore, the macrophage response to infection has important consequences for both the survival of phagocytosed bacteria and the further development of host immunity. However, very little is known about the macrophage cell signaling pathways initiated upon infection and the virulence strategy that Brucella use to counteract these responses and secure their survival. In a previous study, we have shown that macrophages activated by SR141716A, a ligand of the cannabinoid receptor CB1, acquired the capacity to control Brucella and observed that the CB1 receptor-triggering engages the microbicidal activity of phagocytes. To analyze the perturbation of cell signaling pathway during macrophage infection by Brucella, we hypothesized that SR141716A provides cell signaling that interferes with the bacterial message leading to inhibition of macrophage functions. As CB1 receptor belongs to the family of G protein-linked receptors, we explored the cAMP signaling pathway. In this study, we show that the CB1 ligand inhibited the bacteria-induced cell signaling. Taking advantage of this result, we then demonstrated that Brucella infection elicited a rapid activation of the cAMP/protein kinase A pathway. This activation resulted in a prolonged phosphorylation of the transcription factor CREB. We finally demonstrate that the activation of the cAMP/protein kinase A pathway is crucial for the survival and establishment of Brucella within macrophages. For the first time in phagocytes, we thus characterized a primordial virulence strategy of Brucella involving the host signaling pathway, a novel point of immune intervention of this virulent pathogen.
Hepatitis C Virus Core and Nonstructural Protein 3 Proteins Induce Pro- and Anti-inflammatory Cytokines and Inhibit Dendritic Cell Differentiation
Authors: Dolganiuc Angela , Kodys Karen , Kopasz Andrea , Marshall Christopher , Do Twan , Romics Laszlo , Mandrekar Pranoti , Zapp Maria , Szabo Gyongyi 
Published: April 2014

AbstractAntiviral immunity requires recognition of viral pathogens and activation of cytotoxic and Th cells by innate immune cells. In this study, we demonstrate that hepatitis C virus (HCV) core and nonstructural protein 3 (NS3), but not envelope 2 proteins (E2), activate monocytes and myeloid dendritic cells (DCs) and partially reproduce abnormalities found in chronic HCV infection. HCV core or NS3 (not E2) triggered inflammatory cytokine mRNA and TNF-α production in monocytes. Degradation of I-κBα suggested involvement of NF-κB activation. HCV core and NS3 induced production of the anti-inflammatory cytokine, IL-10. Both monocyte TNF-α and IL-10 levels were higher upon HCV core and NS3 protein stimulation in HCV-infected patients than in normals. HCV core and NS3 (not E2) inhibited differentiation and allostimulatory capacity of immature DCs similar to defects in HCV infection. This was associated with elevated IL-10 and decreased IL-2 levels during T cell proliferation. Increased IL-10 was produced by HCV patients’ DCs and by core- or NS3-treated normal DCs, while IL-12 was decreased only in HCV DCs. Addition of anti-IL-10 Ab, not IL-12, ameliorated T cell proliferation with HCV core- or NS3-treated DCs. Reduced allostimulatory capacity in HCV core- and NS3-treated immature DCs, but not in DCs of HCV patients, was reversed by LPS maturation, suggesting more complex DC defects in vivo than those mediated by core or NS3 proteins. Our results reveal that HCV core and NS3 proteins activate monocytes and inhibit DC differentiation in the absence of the intact virus and mediate some of the immunoinhibitory effects of HCV via IL-10 induction.
Dendritic Cell-Based Immunotherapy Combined with Antimony-Based Chemotherapy Cures Established Murine Visceral Leishmaniasis
Authors: Ghosh Monidipa , Pal Chiranjib , Ray Mitali , Maitra Sudipta , Mandal Labanya , Bandyopadhyay Santu 
Published: April 2014

AbstractDendritic cells (DCs) have been proposed to play a critical role as adjuvants in vaccination and immunotherapy. In this study we evaluated the combined effect of soluble Leishmania donovani Ag (SLDA)-pulsed syngeneic bone marrow-derived DC-based immunotherapy and antimony-based chemotherapy for the treatment of established murine visceral leishmaniasis. Three weekly injections of SLDA-pulsed DCs into L. donovani-infected mice reduced liver and splenic parasite burden significantly, but could not clear parasite load from these organs completely. Strikingly, the conventional antileishmanial chemotherapy (sodium antimony gluconate) along with injections of SLDA-pulsed DCs resulted in complete clearance of parasites from both these organs. Repetitive in vitro stimulation of splenocytes from uninfected or L. donovani-infected mice with SLDA-pulsed DCs led to the emergence of CD4+ T cells with characteristics of Th1 cells. Our data indicate that DC-based immunotherapy enhances the in vivo antileishmanial potential of antimony or vice versa.
Rac1 Deletion in Mouse Neutrophils Has Selective Effects on Neutrophil Functions
Authors: Glogauer Michael , Marchal Christophe C. , Zhu Fei , Worku Aelaf , Clausen Björn E. , Foerster Irmgard , Marks Peter , Downey Gregory P. , Dinauer Mary , Kwiatkowski David J. 
Published: April 2014

Abstract
Defects in myeloid cell function in Rac2 knockout mice underline the importance of this isoform in activation of NADPH oxidase and cell motility. However, the specific role of Rac1 in neutrophil function has been difficult to assess since deletion of Rac1 results in embryonic lethality in mice. To elucidate the specific role of Rac1 in neutrophils, we generated mice with a conditional Rac1 deficiency restricted to cells of the granulocyte/monocyte lineage. As observed in Rac2-deficient neutrophils, Rac1-deficient neutrophils demonstrated profound defects in inflammatory recruitment in vivo, migration to chemotactic stimuli, and chemoattractant-mediated actin assembly. In contrast, superoxide production is normal in Rac1-deficient neutrophils but markedly diminished in Rac2 null cells. These data demonstrate that although Rac1 and Rac2 are both required for actin-mediated functions, Rac2 is specifically required for activation of the neutrophil NADPH oxidase.
CC Chemokine Ligand 5/RANTES Chemokine Antagonists Aggravate Glomerulonephritis Despite Reduction of Glomerular Leukocyte Infiltration
Authors: Anders Hans-Joachim , Frink Michael , Linde Yvonne , Banas Bernard , Wörnle Markus , Cohen Clemens D. , Vielhauer Volker , Nelson Peter J. , Gröne Hermann-Josef , Schlöndorff Detlef 
Published: April 2014

Abstract
The chemokine CC chemokine ligand (CCL)5/RANTES as well as its respective receptor CCR5 mediate leukocyte infiltration during inflammation and are up-regulated early during the course of glomerulonephritis (GN). We tested the effects of the two CCL5/RANTES blocking analogs, Met-RANTES and amino-oxypentane-RANTES, on the course of horse apoferritin (HAF)-induced GN. HAF-injected control mice had proliferative GN with mesangial immune complex deposits of IgG and HAF. Daily i.p. injections of Met-RANTES or amino-oxypentane-RANTES markedly reduced glomerular cell proliferation and glomerular macrophage infiltration, which is usually associated with less glomerular injury and proteinuria in HAF-GN. Surprisingly, however, HAF-GN mice treated with both analogs showed worse disease with mesangiolysis, capillary obstruction, and nephrotic range albuminuria. These findings were associated with an enhancing effect of the CCL5/RANTES analogs on the macrophage activation state, characterized by a distinct morphology and increased inducible NO synthetase expression in vitro and in vivo, but a reduced uptake of apoptotic cells in vivo. The humoral response and the Th1/Th2 balance in HAF-GN and mesangial cell proliferation in vitro were not affected by the CCL5/RANTES analogs. We conclude that, despite blocking local leukocyte recruitment, chemokine analogs can aggravate some specific disease models, most likely due to interactions with systemic immune reactions, including the removal of apoptotic cells and inducible NO synthetase expression.
IL-1α, Innate Immunity, and Skin Carcinogenesis: The Effect of Constitutive Expression of IL-1α in Epidermis on Chemical Carcinogenesis
Authors: Murphy Jo-Ellen , Morales Romeo E. , Scott Jordan , Kupper Thomas S. 
Published: April 2014

Abstract
Tumor promoters such as the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) are proinflammatory agents, and their mechanism of action in epithelial carcinogenesis has been linked to the release of IL-1α and the induction of chronic inflammation in skin. To test the role of IL-1α and inflammation in models of cutaneous carcinogenesis, we used our previously described FVB/N transgenic mice overexpressing 17-kDa IL-1α in the epidermis under the keratin 14 (K14) promoter. Strikingly, the K14/IL-1α mice were completely resistant to papilloma and carcinoma formation induced by a two-stage DMBA/TPA protocol, while littermate controls developed both tumor types. K14/IL-1α mice crossed with the highly sensitive TG.AC mice, constitutively expressing mutant Ha-Ras, also failed to develop papillomas or carcinomas. When the K14/IL-1α transgene was bred onto a recombinase-activating gene-2-deficient background, the resistance persisted, indicating that innate, but not acquired, mechanisms may be involved in the resistance to the initiation/promotion model. As an alternative approach, a complete carcinogenesis protocol using repetitive application of DMBA alone was applied. Surprisingly, although the IL-1α mice still did not develop papillomas, they did develop carcinomas de novo at an accelerated rate compared with controls. We conclude that constitutive IL-1α expression rendered FVB mice completely resistant to carcinomas that required evolution from prior papillomas, but facilitated carcinomas that did not evolve from papillomas, as in the complete carcinogenesis protocol. Thus, the role of IL-1α and, by extension that of other proinflammatory factors, in epithelial carcinogenesis are more complex than previously appreciated. These mice may provide a mechanism to investigate the validity of these models of human skin tumorigenesis.