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Nadege Goutagny,
Zhaozhao Jiang, Jane Tian,
Peggy Parroche,
Jeanne Schickli,
Brian G Monks,
Nancy Ulbrandt,
Hong Ji,
Peter A Kiener,
Anthony J Coyle,
Katherine A Fitzgerald
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ABSTRACT: Human metapneumoviruses (HMPVs) are recently identified Paramyxoviridae that contribute to respiratory tract infections in children. No effective treatments or vaccines are available. Successful defense against virus infection relies on early detection by germ line-encoded pattern recognition receptors and activation of cytokine and type I IFN genes. Recently, the RNA helicase retinoic acid-inducible gene I (RIG-I) has been shown to sense HMPV. In this study, we investigated the abilities of two prototype strains of HMPV (A1 [NL\1\00] and B1 [NL\1\99]) to activate RIG-I and induce type I IFNs. Despite the abilities of both HMPV-A1 and HMPV-B1 to infect and replicate in cell lines and primary cells, only the HMPV-A1 strain triggered RIG-I to induce IFNA/B gene transcription. The failure of the HMPV-B1 strain to elicit type I IFN production was dependent on the B1 phosphoprotein, which specifically prevented RIG-I-mediated sensing of HMPV viral 5' triphosphate RNA. In contrast to most cell types, plasmacytoid dendritic cells displayed a unique ability to sense both HMPV-A1 and HMPV-B1 and in this case sensing was via TLR7 rather than RIG-I. Collectively, these data reveal differential mechanisms of sensing for two closely related viruses, which operate in cell type-specific manners.
The Journal of Immunology 02/2010; 184(3):1168-79. · 5.79 Impact Factor
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ABSTRACT: Increasing evidence suggests that the excessive accumulation of apoptotic or necrotic cellular debris may contribute to the pathology of systemic autoimmune disease. HMGB1 is a nuclear DNA-associated protein, which can be released from dying cells thereby triggering inflammatory processes. We have previously shown that IgG2a-reactive B cell receptor (BCR) transgenic AM14 B cells proliferate in response to endogenous chromatin immune complexes (ICs), in the form of the anti-nucleosome antibody PL2-3 and cell debris, in a TLR9-dependent manner, and that these ICs contain HMGB1. Activation of AM14 B cells by these chromatin ICs was inhibited by a soluble form of the HMGB1 receptor, RAGE-Fc, suggesting HMGB1-RAGE interaction was important for this response. To further explore the role of HMGB1 in autoreactive B cell activation, we assessed the capacity of purified calf thymus HMGB1 to bind dsDNA fragments and found that HMGB1 bound both CG-rich and CG-poor DNA. However, HMGB1-DNA complexes could not activate AM14 B cells unless HMGB1 was bound by IgG2a and thereby able to engage the BCR. To ascertain the role of RAGE in autoreactive B cell responses to chromatin ICs, we intercrossed AM14 and RAGE-deficient mice. We found that spontaneous and defined DNA ICs activated RAGE+ and RAGE(- ) AM14 B cells to a comparable extent. These results suggest that HMGB1 promotes B cell responses to endogenous TLR9 ligands through a RAGE-independent mechanism.
Autoimmunity 12/2009; 43(1):103-10. · 2.47 Impact Factor
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Jane Tian,
Ana Maria Avalos,
Su-Yau Mao,
Bo Chen,
Kannaki Senthil,
Herren Wu,
Peggy Parroche,
Stacey Drabic,
Douglas Golenbock,
Cherilyn Sirois, [......],
Laurent Audoly,
Greg La Rosa,
Angelika Bierhaus,
Peter Naworth,
Ann Marshak-Rothstein,
Mary K Crow,
Katherine A Fitzgerald,
Eicke Latz,
Peter A Kiener,
Anthony J Coyle
Nature Immunology 06/2007; 8(7):780-780. · 26.01 Impact Factor
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Jane Tian,
Ana Maria Avalos,
Su-Yau Mao,
Bo Chen,
Kannaki Senthil,
Herren Wu,
Peggy Parroche,
Stacey Drabic,
Douglas Golenbock,
Cherilyn Sirois, [......],
Laurent Audoly,
Greg La Rosa,
Angelika Bierhaus,
Peter Naworth,
Ann Marshak-Rothstein,
Mary K Crow,
Katherine A Fitzgerald,
Eicke Latz,
Peter A Kiener,
Anthony J Coyle
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ABSTRACT: Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.
Nature Immunology 06/2007; 8(5):487-96. · 26.01 Impact Factor
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ABSTRACT: Rip2 (Rick, Cardiak, CCK2, and CARD3) is a serine/threonine kinase containing a caspase recruitment domain (CARD) at the C terminus. Previous reports have shown that Rip2 is involved in multiple receptor signaling pathways that are important for innate and adaptive immune responses. However, it is not known whether Rip2 kinase activity is required for its function. Here we confirm that Rip2 participates in lipopolysaccharide (LPS)/Toll-like receptor (TLR4) signaling and demonstrate that its kinase activity is not required. Upon LPS stimulation, Rip2 was transiently recruited to the TLR4 receptor complex and associated with key TLR signaling mediators IRAK1 and TRAF6. Furthermore, Rip2 kinase activity was induced by LPS treatment. These data indicate that Rip2 is directly involved in the LPS/TLR4 signaling. Whereas macrophages from Rip2-deficient mice showed impaired NF-kappaB and p38 mitogen-activated protein kinase activation and reduced cytokine production in response to LPS stimulation, LPS signaling was intact in macrophages from mice that express Rip2 kinase-dead mutant. These results demonstrate that Rip2-mediated LPS signaling is independent of its kinase activity. Our findings strongly suggest that Rip2 functions as an adaptor molecule in transducing signals from immune receptors.
Journal of Biological Chemistry 05/2005; 280(16):16278-83. · 4.77 Impact Factor
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ABSTRACT: Signal transduction from proinflammatory stimuli leading to NF-kappa B-dependent gene expression is mediated by the I kappa B kinase 2 (IKK2/IKK beta). Therefore, IKK2 has become an important drug target for treatment of inflammatory conditions. T cells, whose activation depends to a large extent on the activity of NF-kappa B transcription factors, play important roles in inflammation and autoimmunity. Ablation of IKK2 specifically in T cells in CD4cre/Ikk2(FL) mice allows their survival and activation by polyclonal stimuli in vitro, suggesting that IKK2 is dispensable for T cell activation. We report in this study that IKK2-deficient T cells expand efficiently in response to superantigen administration in vivo, but are completely deficient in recall responses, most likely due to inefficient priming. IKK2-deficient T cells provide suboptimal B cell help and fail to support germinal center reactions. Finally, IKK2 is essential for homeostatic expansion of naive T cells, reflected by the inability of IKK2-deficient T cells to induce colitis in lymphopenic hosts.
The Journal of Immunology 09/2004; 173(3):1612-9. · 5.79 Impact Factor
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ABSTRACT: Natural killer-like (NK) T, regulatory T (TR), and memory type T cells display surface phenotypes reminiscent of activated T cells. Previously, we reported that the generation of TR cells and, to a lesser extent, of memory type T cells, depends on IkappaB kinase 2. Here, we show that T cell-specific ablation of IkappaB kinase 2, in addition, completely precludes NKT cell development. T cell antigen receptor (TCR)-induced signals to activate NF-kappaB are essential for mature T cell activation, leading us to hypothesize that this pathway could play an important role in the generation of the antigen-driven T cell subsets comprising TR, memory type T, and NKT cells. TCR-mediated NF-kappaB activation critically depends on Bcl10 and PKCtheta. By using mice deficient for these proteins, we demonstrate that the generation of TR and, to a lesser extent, of memory type T cells, depends on Bcl10 and PKCtheta, and therefore, most likely on NF-kappaB activation initiated by TCR engagement. NKT cells, on the other hand, require PKCtheta for thymic development, whereas absence of Bcl10 leads primarily to the reduction of peripheral NKT cell numbers.
Proceedings of the National Academy of Sciences 04/2004; 101(13):4566-71. · 9.68 Impact Factor
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Ype P de Jong,
Svend T Rietdijk,
William A Faubion,
Ana C Abadia-Molina,
Kareem Clarke,
Emiko Mizoguchi, Jane Tian,
Tracy Delaney,
Stephen Manning,
Jose-Carlos Gutierrez-Ramos,
Atul K Bhan,
Anthony J Coyle,
Cox Terhorst
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ABSTRACT: Several autoimmune disease models depend on an imbalance in the activation of aggressor T(h)1 and CD4(+)CD25(+) regulatory T (T(reg)) cells. Here we compare the requirement for signals through the co-stimulatory molecules CD28 and inducible co-stimulator (ICOS) in chronic murine colitis, a model for inflammatory bowel disease. We used a colitis model in which disease-causing CD45RB(hi) T cells alone or in combination with CD4(+)CD25(+) T cells from either CD28-deficient or wild-type donors were transferred into T cell-deficient animals, half of which were treated with ICOS-blocking reagents. Blocking ICOS on the surface of CD28-deficient T(h)1 cells abrogated development of colitis, whereas blocking CD28 or ICOS alone had little to no effect on disease induction. In contrast to T(h)1 cells, regulatory T cell functioning depended mostly on CD28 signaling with only a minor contribution for ICOS. We conclude that CD28 and ICOS collaborate to development of murine colitis by aggressor T(h)1 cells, and that CD28 is required for T(reg) cells, which should caution against the use of CD28-blocking reagents in inflammatory bowel disease.
International Immunology 03/2004; 16(2):205-13. · 3.41 Impact Factor
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Alberto Sánchez-Fueyo, Jane Tian,
Dominic Picarella,
Christoph Domenig,
Xin Xiao Zheng,
Catherine A Sabatos,
Natasha Manlongat,
Orissa Bender,
Thomas Kamradt,
Vijay K Kuchroo,
José-Carlos Gutiérrez-Ramos,
Anthony J Coyle,
Terry B Strom
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ABSTRACT: Although T helper (T(H)) cell-mediated immunity is required to effectively eliminate pathogens, unrestrained T(H) activity also contributes to tissue injury in many inflammatory and autoimmune diseases. We report here that the T(H) type 1 (T(H)1)-specific Tim-3 (T cell immunoglobulin domain, mucin domain) protein functions to inhibit aggressive T(H)1-mediated auto- and alloimmune responses. Tim-3 pathway blockade accelerated diabetes in nonobese diabetic mice and prevented acquisition of transplantation tolerance induced by costimulation blockade. These effects were mediated, at least in part, by dampening of the antigen-specific immunosuppressive function of CD4(+)CD25(+) regulatory T cell populations. Our data indicate that the Tim-3 pathway provides an important mechanism to down-regulate T(H)1-dependent immune responses and to facilitate the development of immunological tolerance.
Nature Immunology 12/2003; 4(11):1093-101. · 26.01 Impact Factor
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Alberto S|[aacute]|nchez-Fueyo, Jane Tian,
Dominic Picarella,
Christoph Domenig,
Xin Xiao Zheng,
Catherine A Sabatos,
Natasha Manlongat,
Orissa Bender,
Thomas Kamradt,
Vijay K Kuchroo,
Jos|[eacute]|-Carlos Guti|[eacute]|rrez-Ramos,
Anthony J Coyle,
Terry B Strom
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ABSTRACT: Although T helper (TH) cell−mediated immunity is required to effectively eliminate pathogens, unrestrained TH activity also contributes to tissue injury in many inflammatory and autoimmune diseases. We report here that the TH type 1 (TH1)-specific Tim-3 (T cell immunoglobulin domain, mucin domain) protein functions to inhibit aggressive TH1-mediated auto- and alloimmune responses. Tim-3 pathway blockade accelerated diabetes in nonobese diabetic mice and prevented acquisition of transplantation tolerance induced by costimulation blockade. These effects were mediated, at least in part, by dampening of the antigen-specific immunosuppressive function of CD4+CD25+ regulatory T cell populations. Our data indicate that the Tim-3 pathway provides an important mechanism to down-regulate TH1-dependent immune responses and to facilitate the development of immunological tolerance.
Nature Immunology. 10/2003; 4(11):1093-1101.
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ABSTRACT: The transcription factor NF-kappaB is implicated in various aspects of T cell development and function. The IkappaB kinase (IKK) complex, consisting of two kinases, IKK1/alpha and IKK2/beta, and the NEMO/IKKgamma regulatory subunit, mediates NF-kappaB activation by most known stimuli. Adoptive transfer experiments had demonstrated that IKK1 and IKK2 are dispensable for T cell development. We show here that T lineage-specific deletion of IKK2 allows survival of naive peripheral T cells but interferes with the generation of regulatory and memory T cells. T cell-specific ablation of NEMO or replacement of IKK2 with a kinase-dead mutant prevent development of peripheral T cells altogether. Thus, IKK-induced NF-kappaB activation, mediated by either IKK1 or IKK2, is essential for the generation and survival of mature T cells, and IKK2 has an additional role in regulatory and memory T cell development.
Immunity 10/2003; 19(3):377-89. · 21.64 Impact Factor
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ABSTRACT: El copyright pertenece a The Rockefeller University Press Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predomipredominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo. Peer reviewed
