bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ly6Clow Monocytes Differentiate into Dendritic Cells and Cross-Tolerize T Cells through PDL-1
Authors: Peng YuFeng , Latchman Yvette , Elkon Keith B. 
Published: February 2009

Abstract
Monocyte-derived dendritic cells are active participants during the immune response against infection, but whether they play a role in maintaining self-tolerance under steady-state conditions is not known. Here we investigated the differentiation of monocytes, their ability to ingest apoptotic cells, and their potential functionality in vivo. We observed that Ly6C (Gr-1)low mature monocytes up-regulate their MHC II level in the spleen, express high levels of PDL-1 (programmed death ligand 1), and are more efficient than Ly6Chigh immature monocytes in the ingestion of apoptotic cells in vivo. Sorted circulating Ly6Clow monocytes were able to cross-present both apoptotic cell-associated OVA and soluble OVA protein. Monocytes containing apoptotic cells can further differentiate into CD11c+CD8α−MHC II+ splenic dendritic cells that maintained high expression of PDL-1. Since wild-type but not PDL-1-deficient peripheral blood monocytes containing apoptotic cell-associated OVA suppressed the response to OVA immunization, PDL-1 expression was required for monocyte-mediated T cell tolerance. These observations demonstrate that Ly6Clow mature monocytes can promote tolerance to self Ag contained in apoptotic cells through a PDL-1-dependent mechanism.
Membrane Estrogen Receptor Regulates Experimental Autoimmune Encephalomyelitis through Up-regulation of Programmed Death 1
Authors: Wang Chunhe , Dehghani Babak , Li Yuexin , Kaler Laurie J. , Proctor Thomas , Vandenbark Arthur A. , Offner Halina 
Published: February 2009

AbstractAlthough estrogens exert a pronounced protective effect on multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), their therapeutic application has been limited by undesirable side effects thought to be mediated primarily through estradiol binding to intracellular estrogen receptor α. In this study, we found that signaling through the putative membrane estrogen receptor, G protein-coupled receptor 30 (GPR30), was sufficient to mediate protection against EAE, which was significantly impaired in GPR30 gene-deficient mice. Treatment with G-1, an agonist that selectively activates GPR30 without engagement of the intracellular estrogen receptors, retained the ability of estradiol to protect against clinical and histological EAE without estradiol-associated side effects, deviated cytokine profiles, and enhanced suppressive activity of CD4+Foxp3+ T regulatory cells through a GPR30- and programmed death 1-dependent mechanism. This study is the first to evaluate the protective effect of GPR30 activation on EAE, and provides a strong foundation for the clinical application of GPR30 agonists such as G-1 in multiple sclerosis.
NK Cell Enhancement of Antigen Presentation by B Lymphocytes
Authors: Jennings Paula , Yuan Dorothy 
Published: February 2009

Abstract
Ag presentation to CD4 T cells can be mediated by a number of cell types depending on the anatomical site in which Ag is first encountered. For blood borne Ags, cells localized in situ in the spleen should be major players. There is now much evidence that B cell Ag presentation may be particularly important in the priming of memory T cells. The majority of NK cells are also localized the spleen. Inasmuch as we have previously shown that NK cells can modulate various aspects of B cell differentiation, we entertained the possibility that NK cells can also influence Ag presentation by B cells. By specific depletion of NK cells before immunization, we show herein that NK cells play an important role in modulating the ability of B cells to process and present Ag to T cells. These effects are particularly important in the generation of memory T cells. The findings are further substantiated by in vitro experiments showing that the enhancement does not require IFN-γ but is mediated by direct cell-cell interaction. These results show, for the first time, that the rapid activation of a component of the innate response can even exert effects on the Ag-specific memory response.
STAT6 Deletion Converts the Th2 Inflammatory Pathology Afflicting LatY136F
Mice into a Lymphoproliferative Disorder Involving Th1 and CD8 Effector T Cells
Authors: Archambaud Cristel , Sansoni Amandine , Mingueneau Michael , Devilard Elisabeth , Delsol Georges , Malissen Bernard , Malissen Marie 
Published: February 2009

Abstract
Mutant mice in which tyrosine 136 of linker for activation of T cells (LAT) was replaced with a phenylalanine (LatY136F mice) develop a lymphoproliferative disorder involving polyclonal CD4 effector T cells that produce massive amounts of IL-4 and trigger severe Th2 inflammation. Naive CD4 T cells can themselves produce IL-4 and thereby initiate a self-reinforcing positive regulatory loop that involves the STAT6 transcription factor and leads to Th2 polarization. We determined the functional outcome that results when LatY136F T cells differentiate in the absence of such STAT6-dependent regulatory loop. The lack of STAT6 had no effect on the timing and magnitude of the lymphoproliferative disorder. However, in LatY136F mice deprived of STAT6, the expanding CD4 T cell population was dominated by Th1 effector cells that triggered B cell proliferation, elevated IgG2a and IgG2b levels as well as the production of autoantibodies. In contrast to LatY136F mice that showed no CD8 T cell expansion, the CD8 T cells present in LatY136F mice deprived of STAT6 massively expanded and acquired effector potential. Therefore, the lack of STAT6 is sufficient to convert the Th2 lymphoproliferative disorder that characterizes LatY136F mice into a lymphoproliferative disorder that is dominated by Th1 and CD8 effector T cells. The possibility to dispose of a pair of mice that differs by a single gene and develops in the absence of deliberate immunization large numbers of Th cells with almost reciprocal polarization should facilitate the identification of genes involved in the control of normal and pathological Th cell differentiation.
End-Organ Damage in a Mouse Model of Fulminant Liver Inflammation Requires CD4+ T Cell Production of IFN-γ but Is Independent of Fas
Authors: Robinson Richard T. , Wang Jing , Cripps James G. , Milks Michael W. , English Kathryn A. , Pearson Todd A. , Gorham James D. 
Published: February 2009

Abstract
Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-γ-producing T cells. The BALB/c-Tgfb1−/− mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-γ-producing CD4+ and CD8+ T cells. Liver damage depends on the presence of an intact Ifng gene. We determined the relevant cellular source(s) of IFN-γ. In Tgfb1−/− liver, CD4+ T cells were more numerous than CD8+ T cells and NK cells, and produced more IFN-γ. Depletion of CD4+ T cells eliminated both the elevation in plasma IFN-γ and aspartate aminotransferase, whereas depletion of CD8+ T cells did not. Rag1−/−Tgfb1−/− mice exhibited neither IFN-γ elevation nor tissue damage, indicating that NK cells are not sufficient. IFN-γ was required for strong overexpression of class II genes but not for CD4+ T cell activation, oligoclonal expansion, or accumulation in the liver. The T cell inhibitory molecule PD-L1 was strongly expressed in Tgfb1−/− livers, ruling out a lack of PD-L1 expression as an explanation for aberrant liver T cell activation. Finally, whereas Tgfb1−/− CD4+ T cells overexpressed Fas ligand, hepatocellular damage was observed in Faslpr/lprTgfb1−/− mice, indicating that liver pathology is Fas independent. We conclude that liver damage in this model of fulminant autoimmune hepatitis is driven by CD4+ T cell production of IFN-γ, is independent of both CD8+ T cells and the Fas ligand/Fas pathway, and is not explained by a lack of PD-L1 expression.
Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Microbial Killing
Authors: Mylonas Katie J. , Nair Meera G. , Prieto-Lafuente Lidia , Paape Daniel , Allen Judith E. 
Published: February 2009

Abstract
The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-γ) is microbial destruction. Alternatively activated macrophages (activated by Th2 cytokines, such as IL-4 and IL-13) play important roles in allergy and responses to helminth infection. We utilize a murine model of filarial infection, in which adult nematodes are surgically implanted into the peritoneal cavity of mice, as an in vivo source of alternatively activated macrophages. At 3 wk postinfection, the peritoneal exudate cell population is dominated by macrophages, termed nematode-elicited macrophages (NeMφ), that display IL-4-dependent features such as the expression of arginase 1, RELM-α (resistin-like molecule α), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeMφ to proinflammatory Th1-activating signals was investigated to determine whether a switch between alternative and classical activation could occur in macrophages differentiated in an in vivo infection setting. Despite the long-term exposure to Th2 cytokines and antiinflammatory signals in vivo, we found that NeMφ were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-γ. This was reflected by a switch in the enzymatic pathway for arginine metabolism from arginase to inducible NO synthase and the reduced expression of RELM-α and Ym1. Furthermore, this enabled NeMφ to become antimicrobial, as LPS/IFN-γ-treated NeMφ produced NO that mediated killing of Leishmania mexicana. However, the adaptation to antimicrobial function did not extend to key regulatory pathways, such as IL-12 production, which remained unaltered.
Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Proinflammatory Cytokine Production in Peritoneal Macrophages
Authors: Mogi Chihiro , Tobo Masayuki , Tomura Hideaki , Murata Naoya , He Xiao-dong , Sato Koichi , Kimura Takao , Ishizuka Tamotsu , Sasaki Takehiko , Sato Takashi , Kihara Yasuyuki , Ishii Satoshi , Harada Akihiro , Okajima Fumikazu 
Published: February 2009

AbstractExtracellular acidification inhibited LPS-induced TNF-α protein production, which was associated with an inhibition of TNF-α mRNA expression, in mouse peritoneal macrophages. The LPS-induced cytokine production was also inhibited by Gs protein-coupled receptor agonists prostaglandin E1 and isoproterenol. Among OGR1 family proton-sensing GTP-binding regulatory protein-coupled receptors, TDAG8, OGR1, and G2A are expressed in the cells. The inhibitory action by acidic pH on TNF-α production was significantly attenuated in macrophages from TDAG8Tp/Tp mice but not in those from OGR1geo/geo mice. Moreover, small interfering RNA specific to TDAG8, but not to G2A, clearly attenuated the acidification-induced inhibition of TNF-α production. On the other hand, the down-regulation or deficiency of TDAG8 hardly affected prostaglandin E1- or isoproterenol-induced actions. LPS-induced IL-6 production was also inhibited by extracellular acidification in a manner that was sensitive to TDAG8 expression. The acidic pH-induced inhibitory action on the cytokine production was significantly reversed either by a small interfering RNA specific to Gs proteins or by a protein kinase A (PKA)-specific inhibitor H89. Indeed, a PKA-specific cAMP derivative inhibited LPS-induced cytokine production. Moreover, acidification induced cAMP accumulation in a TDAG8-specific way. We conclude that TDAG8, at least partly, mediates the extracellular acidification-induced inhibition of proinflammatory cytokine production through the Gs protein/cAMP/PKA signaling pathway in mouse macrophages.
Vaccinia Virus-Based Multivalent H5N1 Avian Influenza Vaccines Adjuvanted with IL-15 Confer Sterile Cross-Clade Protection in Mice
Authors: Poon Leo L. M. , Leung Y. H. Connie , Nicholls John M. , Perera Pin-Yu , Lichy Jack H. , Yamamoto Masafumi , Waldmann Thomas A. , Peiris J. S. Malik , Perera Liyanage P. 
Published: February 2009

Abstract
The potential for a global influenza pandemic remains significant with epidemiologic and ecologic indicators revealing the entrenchment of the highly pathogenic avian influenza A H5N1 in both wild bird populations and domestic poultry flocks in Asia and in many African and European countries. Indisputably, the single most effective public health intervention in mitigating the devastation such a pandemic could unleash is the availability of a safe and effective vaccine that can be rapidly deployed for pre-exposure vaccination of millions of people. We have developed two vaccinia-based influenza vaccines that are molecularly adjuvanted with the immune stimulatory cytokine IL-15. The pentavalent Wyeth/IL-15/5Flu vaccine expresses the hemagglutinin, neuraminidase, and nucleoprotein derived from the H5N1 influenza virus A/Vietnam/1203/2004 and the matrix proteins M1 and M2 from the H5N1 A/CK/Indonesia/PA/2003 virus on the backbone of a currently licensed smallpox vaccine. The bivalent MVA/IL-15/HA/NA vaccine expresses only the H5 hemagglutinin and N1 neuraminidase on the modified vaccinia virus Ankara (MVA) backbone. Both vaccines induced cross-neutralizing Abs and robust cellular immune responses in vaccinated mice and conferred sterile cross-clade protection when challenged with the H5N1 virus of a different clade. In addition to having potential as a universal influenza vaccine, in the event of an impending pandemic the Wyeth/IL-15/5Flu is also readily amenable to bulk production to cover the global population. For those individuals for whom the use of the Wyeth vaccine is contraindicated, our MVA/IL-15/HA/NA offers a substitute or a prevaccine to be used in a mass vaccination campaign similar to the smallpox eradication campaigns of few decades ago.
Amplification of Autoimmune Response through Induction of Dendritic Cell Maturation in Inflamed Tissues
Authors: Melli Kristin , Friedman Rachel S. , Martin Ashley E. , Finger Erik B. , Miao Gang , Szot Gregory L. , Krummel Matthew F. , Tang Qizhi 
Published: February 2009

Abstract
Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed β cell-derived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40high intra-islet DCs up-regulated CCR7, and a small number of CD40high DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.
Promoter Knock-In Mutations Reveal a Role of Mcl-1 in Thymocyte-Positive Selection and Tissue or Cell Lineage-Specific Regulation of Mcl-1 Expression
Authors: Yang Chia-Yu , Lin Nai-Hui , Lee Jan-Mou , Huang Ching-Yu , Min Hsiang-Ju , Yen Jeffrey Jong-Young , Liao Nan-Shih , Yang-Yen Hsin-Fang 
Published: February 2009

Abstract
We previously demonstrated that IL-3 stimulates transcription of the antiapoptotic gene mcl-1 via two promoter elements designated as the SIE and CRE-2 sites. To further study the functional role of these two DNA elements, mutant mice with targeted mutations of both SIE and CRE-2 sites (SC mutants) were generated. Homozygous SC mutants manifested a markedly reduced level of Mcl-1 in thymus but not in other major organs such as spleen, liver, lung, or heart. Reduced expression of Mcl-1 in SC mutant thymus resulted in attenuated positive selection of double-positive thymocytes into both CD4 and CD8 lineages, a result likely due to reduced survival of SC mutant double-positive thymocytes that were supposed to be positively selected. In contrast, in the peripheral lymphoid organs, only CD8+ but not CD4+ T cells were significantly reduced in homozygous SC mutant mice, a result consistent with a more dramatic decrease both of Mcl-1 expression and cell viability in mutant CD8+ compared with mutant CD4+ T cells. Impaired T cell development and peripheral CD8+ lymphopenia in homozygous SC mutant mice were both cell autonomous and could be rescued by enforced expression of human Mcl-1. Together, the promoter-knock-in mouse model generated in this study not only revealed a role of Mcl-1 in thymocyte-positive selection, but also uncovered that Mcl-1 expression is regulated in a tissue or cell lineage-specific manner.
Fas Ligand Is Required for the Development of Respiratory Syncytial Virus Vaccine-Enhanced Disease
Authors: Olson Matthew R. , Varga Steven M. 
Published: February 2009

Abstract
Children immunized with a formalin-inactivated respiratory syncytial virus (RSV) vaccine experienced enhanced disease and exhibited pulmonary eosinophilia upon natural RSV infection. BALB/c mice immunized with either formalin-inactivated RSV or a recombinant vaccinia virus (vacv) expressing the RSV attachment (G) protein develop extensive pulmonary eosinophilia after RSV challenge that mimics the eosinophilic response observed in the children during the 1960s vaccine trials. Fas ligand (FasL) is a major immune effector molecule that can contribute to the clearance of respiratory viruses. However, the role of FasL in the development of RSV vaccine-enhanced disease has not been elucidated. RSV challenge of vacvG-immunized gld mice, that lack functional FasL, results in diminished systemic disease as well as pulmonary eosinophilia. The magnitude of the secondary RSV G-specific CD4 T cell response was diminished in gld mice as compared with wild-type controls. Furthermore, we show that CD4 T cells isolated after RSV challenge of vacvG-immunized gld mice exhibit enhanced expression of Annexin V and caspase 3/7 indicating that FasL is important for either the survival or the expansion of virus-specific secondary effector CD4 T cells. Taken together, these data identify a previously undefined role for FasL in the accumulation of secondary effector CD4 T cells and the development of RSV vaccine-enhanced disease.
The TLR9 Ligand CpG Promotes the Acquisition of Plasmodium falciparum-Specific Memory B Cells in Malaria-Naive Individuals
Authors: Crompton Peter D. , Mircetic Marko , Weiss Greta , Baughman Amy , Huang Chiung-Yu , Topham David J. , Treanor John J. , Sanz Iñaki , Lee F. Eun-Hyung , Durbin Anna P. , Miura Kazutoyo , Narum David L. , Ellis Ruth D. , Malkin Elissa , Mullen Gregory E. D. , Miller Louis H. , Martin Laura B. , Pierce Susan K. 
Published: February 2009

Abstract
Despite the central role of memory B cells (MBC) in protective immune responses, little is understood about how they are acquired in naive individuals in response to Ag exposure, and how this process is influenced by concurrent activation of the innate immune system’s TLR. In this longitudinal study of malaria-naive individuals, we examined the MBC response to two candidate malaria vaccines administered with or without CpG, a TLR9 ligand. We show that the acquisition of MBC is a dynamic process in which the vaccine-specific MBC pool rapidly expands and then contracts, and that CpG enhances the kinetics, magnitude, and longevity of this response. We observed that the percentage of vaccine-specific MBC present at the time of reimmunization predicts vaccine-specific Ab levels 14 days later; and that at steady-state, there is a positive correlation between vaccine-specific MBC and Ab levels. An examination of the total circulating MBC and plasma cell pools also suggests that MBC differentiate into plasma cells through polyclonal activation, independent of Ag specificity. These results provide important insights into the human MBC response, which can inform the development of vaccines against malaria and other pathogens that disrupt immunological memory.
NF-κB1 p105 Regulates T Cell Homeostasis and Prevents Chronic Inflammation
Authors: Chang Mikyoung , Lee Andrew J. , Fitzpatrick Leo , Zhang Minying , Sun Shao-Cong 
Published: February 2009

Abstract
Transcription factor NF-κB is regulated by a family of inhibitors, IκBs, as well as the NF-κB1 and NF-κB2 precursor proteins, p105 and p100. Although the different NF-κB inhibitors can all inhibit NF-κB in vitro, their physiological functions are incompletely understood. In this study, we demonstrate that p105 plays an important role in the regulation of T cell homeostasis and prevention of chronic inflammation. Mice lacking p105, but expressing the mature NF-κB1 p50, spontaneously develop intestinal inflammation with features of human inflammatory bowel disease. This inflammatory disorder occurs under specific pathogen-free conditions and critically involves T cells. Consistently, the p105-deficient mice have reduced frequency of naive T cells and increased frequency of memory/effector T cells in the peripheral lymphoid organs. Although p105 is dispensable for the production of immunosuppressive regulatory T cells, p105 deficiency renders CD4 T cells more resistant to Treg-mediated inhibition. We further show that the loss of p105 results in hyperproduction of Th17 subset of inflammatory T cells. Together, these findings suggest a critical role for NF-κB1 p105 in the regulation of T cell homeostasis and differentiation and the control of chronic inflammation.
Reversal of Human Papillomavirus-Specific T Cell Immune Suppression through TLR Agonist Treatment of Langerhans Cells Exposed to Human Papillomavirus Type 16
Authors: Fahey Laura M. , Raff Adam B. , Da Silva Diane M. , Kast W. Martin 
Published: February 2009

Abstract
Human papillomavirus (HPV) type 16 infects the epithelial layer of cervical mucosa and is causally associated with the generation of cervical cancer. Langerhans cells (LC) are the resident APCs at the site of infection and therefore are responsible for initiating an immune response against HPV16. On the contrary, LC exposed to HPV16 do not induce a specific T cell immune response, which leads to the immune evasion of HPV16. Demonstrating that TLR7 and TLR8 are expressed on human LC, we hypothesized that imidazoquinolines would activate LC exposed to HPV16, leading to the induction of an HPV16-specific cell-mediated immune response. Surprisingly, both phenotypic and functional hallmarks of activation are not observed when LC are exposed to HPV16 virus-like particles and treated with imiquimod (TLR7 agonist). However, we found that LC are activated by 3M-002 (TLR8 agonist) and resiquimod (TLR8/7 agonist). LC exposed to HPV16 virus-like particles and subsequently treated with 3M-002 or resiquimod highly up-regulate surface activation markers, secrete proinflammatory cytokines and chemokines, induce CCL21-directed migration, and initiate an HPV16-specific CD8+ T cell response. These data strongly indicate that 3M-002 and resiquimod are promising therapeutics for treatment of HPV infections and HPV-induced cervical lesions.