The Experts below are selected from a list of 153 Experts worldwide ranked by ideXlab platform
Rachel R. Caspi - One of the best experts on this subject based on the ideXlab platform.
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NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ–IL-27 axis
Journal of Experimental Medicine, 2015Co-Authors: Wai Po Chong, Nicholas J. Van Panhuys, Jun Chen, Phyllis B. Silver, Yingyos Jittayasothorn, Mary J. Mattapallil, Ronald N. Germain, Rachel R. CaspiAbstract:IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ−/− mice repleted with IFN-γ +/+ NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits Autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC–dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10–producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits Tissue-Specific Autoimmunity through an innate IFN-γ–IL-27 axis.
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Reciprocal interaction between NK cells and DCs regulates the Th17 response by controlling the innate IFN-γ/IL-27 axis (BA13P.124)
Journal of Immunology, 2014Co-Authors: Wai Po Chong, Jun Chen, Phyllis B. Silver, Rachel R. CaspiAbstract:IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis and arthritis. We previously showed that it is innate IFN-γ that is protective, whereas adaptive IFN-γ is pathogenic. Here we demonstrate by immunological and imaging methods, using IFN-γ-deficient mice repleted with IFN-γ-sufficient NK cells, that innate production of IFN-γ from NK cells is necessary and sufficient to limit Autoimmunity and to reduce the number of IL-17A and GM-CSF producing effector T cells in the eye. Mechanistic studies demonstrated that, following immunization for uveitis, DC recruited IFN-γ-producing NK cells to the draining lymph node (DLN) and interacted with them in a CXCR3-dependent fashion. During the interaction, IFN-γ from NK cells induced DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a positive feedback loop. The NK-DC-dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced Tr1-like cells, which upon adoptive transfer ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits Tissue-Specific Autoimmunity through an innate IFN-γ/IL-27 axis.
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46: Reciprocal interaction between NK and DC regulates the autopathogenic Th17 response by controlling the innate IFN-γ/IL-27 axis
Cytokine, 2013Co-Authors: Wai Po Chong, Jun Chen, Phyllis B. Silver, Mary J. Mattapallil, Reiko Horai, Ru Zhou, Rachel R. CaspiAbstract:In mouse models of experimental Tissue-Specific Autoimmunity, IFN-γ deficiency causes exacerbated disease with elevated Th17 responses. This protective effect of IFN-γ is at odds with the ability of Tissue-Specific IFN-γ-producing Th1 cells to elicit these very same diseases. Experimental autoimmune uveitis (EAU), is a model for human uveitis. Using IFN-γ deficient (GKO) mice depleted of endogenous NK cells and repleted with IFN-γ-sufficient wild type (WT) NK cells, we demonstrate that NK cells serve as a major source of the ‘protective’ IFN-γ, by turning on an innate IFN-γ/IL-27 feedback loop that controls generation of the adaptive autopathogenic response. After immunization for EAU, both NK cells and DC were recruited to the draining lymph nodes. NK recruitment was dependent on DC and required expression of the chemokine receptor CXCR3 by the NK cells. Repletion of GKO recipients with WT, but not with GKO, NK cells enhanced production of IL-27 from DC in draining lymph nodes of the recipients, inhibited their adaptive IL-17 and GM-CSF responses, and reduced their EAU scores. In vivo neutralization of IL-27 abolished the protective effect. Mechanistic studies in vitro revealed that mature DC induced NK cells to produce IFN-γ that caused DC to produce IL-27, which in turn stimulated NK cells to produce more IFN-γ, suggesting the presence of a positive feedback loop. IL-27 also promoted generation of IL-10-producing Tr1-like cells from IL-27Rα-positive precursors. Our results suggest that the magnitude of the Th17 response, and consequently the severity of autoimmune disease, is controlled by the interaction between NK cells and DC through the IFN-γ/IL-27 axis. These data help to reconcile the long-standing controversy concerning the protective vs. pathogenic role of IFN-g in Autoimmunity.
Alexander Y. Rudensky - One of the best experts on this subject based on the ideXlab platform.
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Extrathymically generated regulatory T cells control mucosal T_H2 inflammation
Nature, 2012Co-Authors: Steven Z. Josefowicz, Rachel E. Niec, Piper Treuting, Takatoshi Chinen, Ye Zheng, Dale T. Umetsu, Alexander Y. RudenskyAbstract:Selective impairment of peripheral regulatory T-cell differentiation is found to result in spontaneous allergic T_H2-type inflammation in the intestine and lungs, demonstrating the functional heterogeneity of regulatory T cells generated in the thymus and extrathymically in controlling immune mediated inflammation and disease. A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation^ 1 . Regulatory T (T_reg) cells prevent systemic and Tissue-Specific Autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tT_reg cells) and in the periphery (induced (i)T_reg cells), and their dual origin implies a division of labour between tT_reg and iT_reg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iT_reg cells in mice did not lead to unprovoked multi-organ Autoimmunity, exacerbation of induced Tissue-Specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (T_H1) and T_H17 cells. However, mice deficient in iT_reg cells spontaneously developed pronounced T_H2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic inflammation and asthma. Furthermore, iT_reg-cell deficiency altered gut microbial communities. These results suggest that whereas T_reg cells generated in the thymus appear sufficient for control of systemic and Tissue-Specific Autoimmunity, extrathymic differentiation of T_reg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces. Regulatory T (T_reg) cells generated in the periphery are shown to have a distinct non-redundant function compared with T_reg cells that differentiate in the thymus. Selective impairment of peripheral T_reg differentiation results in spontaneous allergic T_H2 type inflammation in the intestine and lungs. This study in mice delineates the functional heterogeneity of T_reg cells in controlling systemic mucosal inflammation and disease.
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Extrathymically generated regulatory T cells control mucosal T H 2 inflammation
Nature, 2012Co-Authors: Steven Z. Josefowicz, Rachel E. Niec, Piper Treuting, Takatoshi Chinen, Ye Zheng, Dale T. Umetsu, Alexander Y. RudenskyAbstract:A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation 1 . Regulatory T (Treg) cells prevent systemic and tissuespecific Autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tTreg cells) and in the periphery (induced (i)Treg cells), and their dual origin implies a division of labour between tTreg and iTreg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iTreg cells in mice did not lead to unprovoked multiorgan Autoimmunity, exacerbation of induced Tissue-Specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (TH1) and TH17 cells. However, mice deficient in iTreg cells spontaneously developed pronounced TH2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic inflammation and asthma. Furthermore, iTreg-cell deficiency altered gut microbial communities. These results suggest that whereas Treg cells generated in the thymus appear sufficient for control of systemic and Tissue-Specific Autoimmunity, extrathymic differentiation of Treg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces. Exquisitely balanced control mechanisms operating at mucosal sites are able to accommodate potent immune defences and the need to prevent tissue damage resulting from inflammatory responses caused by commensal microorganisms, food and environmental antigens, allergens, and noxious substances 1 .
Wai Po Chong - One of the best experts on this subject based on the ideXlab platform.
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NK-DC crosstalk controls the autopathogenic Th17 response through an innate IFN-γ–IL-27 axis
Journal of Experimental Medicine, 2015Co-Authors: Wai Po Chong, Nicholas J. Van Panhuys, Jun Chen, Phyllis B. Silver, Yingyos Jittayasothorn, Mary J. Mattapallil, Ronald N. Germain, Rachel R. CaspiAbstract:IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ−/− mice repleted with IFN-γ +/+ NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits Autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC–dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10–producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits Tissue-Specific Autoimmunity through an innate IFN-γ–IL-27 axis.
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Reciprocal interaction between NK cells and DCs regulates the Th17 response by controlling the innate IFN-γ/IL-27 axis (BA13P.124)
Journal of Immunology, 2014Co-Authors: Wai Po Chong, Jun Chen, Phyllis B. Silver, Rachel R. CaspiAbstract:IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis and arthritis. We previously showed that it is innate IFN-γ that is protective, whereas adaptive IFN-γ is pathogenic. Here we demonstrate by immunological and imaging methods, using IFN-γ-deficient mice repleted with IFN-γ-sufficient NK cells, that innate production of IFN-γ from NK cells is necessary and sufficient to limit Autoimmunity and to reduce the number of IL-17A and GM-CSF producing effector T cells in the eye. Mechanistic studies demonstrated that, following immunization for uveitis, DC recruited IFN-γ-producing NK cells to the draining lymph node (DLN) and interacted with them in a CXCR3-dependent fashion. During the interaction, IFN-γ from NK cells induced DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a positive feedback loop. The NK-DC-dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced Tr1-like cells, which upon adoptive transfer ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits Tissue-Specific Autoimmunity through an innate IFN-γ/IL-27 axis.
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46: Reciprocal interaction between NK and DC regulates the autopathogenic Th17 response by controlling the innate IFN-γ/IL-27 axis
Cytokine, 2013Co-Authors: Wai Po Chong, Jun Chen, Phyllis B. Silver, Mary J. Mattapallil, Reiko Horai, Ru Zhou, Rachel R. CaspiAbstract:In mouse models of experimental Tissue-Specific Autoimmunity, IFN-γ deficiency causes exacerbated disease with elevated Th17 responses. This protective effect of IFN-γ is at odds with the ability of Tissue-Specific IFN-γ-producing Th1 cells to elicit these very same diseases. Experimental autoimmune uveitis (EAU), is a model for human uveitis. Using IFN-γ deficient (GKO) mice depleted of endogenous NK cells and repleted with IFN-γ-sufficient wild type (WT) NK cells, we demonstrate that NK cells serve as a major source of the ‘protective’ IFN-γ, by turning on an innate IFN-γ/IL-27 feedback loop that controls generation of the adaptive autopathogenic response. After immunization for EAU, both NK cells and DC were recruited to the draining lymph nodes. NK recruitment was dependent on DC and required expression of the chemokine receptor CXCR3 by the NK cells. Repletion of GKO recipients with WT, but not with GKO, NK cells enhanced production of IL-27 from DC in draining lymph nodes of the recipients, inhibited their adaptive IL-17 and GM-CSF responses, and reduced their EAU scores. In vivo neutralization of IL-27 abolished the protective effect. Mechanistic studies in vitro revealed that mature DC induced NK cells to produce IFN-γ that caused DC to produce IL-27, which in turn stimulated NK cells to produce more IFN-γ, suggesting the presence of a positive feedback loop. IL-27 also promoted generation of IL-10-producing Tr1-like cells from IL-27Rα-positive precursors. Our results suggest that the magnitude of the Th17 response, and consequently the severity of autoimmune disease, is controlled by the interaction between NK cells and DC through the IFN-γ/IL-27 axis. These data help to reconcile the long-standing controversy concerning the protective vs. pathogenic role of IFN-g in Autoimmunity.
Steven Z. Josefowicz - One of the best experts on this subject based on the ideXlab platform.
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Extrathymically generated regulatory T cells control mucosal T_H2 inflammation
Nature, 2012Co-Authors: Steven Z. Josefowicz, Rachel E. Niec, Piper Treuting, Takatoshi Chinen, Ye Zheng, Dale T. Umetsu, Alexander Y. RudenskyAbstract:Selective impairment of peripheral regulatory T-cell differentiation is found to result in spontaneous allergic T_H2-type inflammation in the intestine and lungs, demonstrating the functional heterogeneity of regulatory T cells generated in the thymus and extrathymically in controlling immune mediated inflammation and disease. A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation^ 1 . Regulatory T (T_reg) cells prevent systemic and Tissue-Specific Autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tT_reg cells) and in the periphery (induced (i)T_reg cells), and their dual origin implies a division of labour between tT_reg and iT_reg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iT_reg cells in mice did not lead to unprovoked multi-organ Autoimmunity, exacerbation of induced Tissue-Specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (T_H1) and T_H17 cells. However, mice deficient in iT_reg cells spontaneously developed pronounced T_H2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic inflammation and asthma. Furthermore, iT_reg-cell deficiency altered gut microbial communities. These results suggest that whereas T_reg cells generated in the thymus appear sufficient for control of systemic and Tissue-Specific Autoimmunity, extrathymic differentiation of T_reg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces. Regulatory T (T_reg) cells generated in the periphery are shown to have a distinct non-redundant function compared with T_reg cells that differentiate in the thymus. Selective impairment of peripheral T_reg differentiation results in spontaneous allergic T_H2 type inflammation in the intestine and lungs. This study in mice delineates the functional heterogeneity of T_reg cells in controlling systemic mucosal inflammation and disease.
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Extrathymically generated regulatory T cells control mucosal T H 2 inflammation
Nature, 2012Co-Authors: Steven Z. Josefowicz, Rachel E. Niec, Piper Treuting, Takatoshi Chinen, Ye Zheng, Dale T. Umetsu, Alexander Y. RudenskyAbstract:A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation 1 . Regulatory T (Treg) cells prevent systemic and tissuespecific Autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tTreg cells) and in the periphery (induced (i)Treg cells), and their dual origin implies a division of labour between tTreg and iTreg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iTreg cells in mice did not lead to unprovoked multiorgan Autoimmunity, exacerbation of induced Tissue-Specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (TH1) and TH17 cells. However, mice deficient in iTreg cells spontaneously developed pronounced TH2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic inflammation and asthma. Furthermore, iTreg-cell deficiency altered gut microbial communities. These results suggest that whereas Treg cells generated in the thymus appear sufficient for control of systemic and Tissue-Specific Autoimmunity, extrathymic differentiation of Treg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces. Exquisitely balanced control mechanisms operating at mucosal sites are able to accommodate potent immune defences and the need to prevent tissue damage resulting from inflammatory responses caused by commensal microorganisms, food and environmental antigens, allergens, and noxious substances 1 .
Emil R. Unanue - One of the best experts on this subject based on the ideXlab platform.
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Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides
Nature, 2018Co-Authors: Bernd H. Zinselmeyer, Pavel N. Zakharov, Anthony N. Vomund, Laura Santambrogio, Mark S. Anderson, Cheryl F. Lichti, Ruth Taniguchi, Emil R. UnanueAbstract:A sensitive T cell tracking assay reveals immunogenic activity of specific catabolized peptide fragments of insulin and their effects on T cell activity in lymph nodes, highlighting communication between pancreatic islets and lymphoid tissue. Tissue-Specific Autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice^ 1 , 2 . A major set of pathogenic CD4 T cells specifically recognizes the 12–20 segment of the insulin B-chain (B:12–20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells^ 3 , 4 . These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13–21^ 4 . CD4 T cells that recognize B:12–20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13–21 have only a minor role in Autoimmunity^ 3 – 5 . Although presentation of B:12–20 is evident in the islets^ 3 , 6 , insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread^ 7 , 8 . Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in β-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues.
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Pancreatic islets communicate with lymphoid tissues via exocytosis of insulin peptides
Nature, 2018Co-Authors: Bernd H. Zinselmeyer, Pavel N. Zakharov, Anthony N. Vomund, Ruth T. Taniguchi, Laura Santambrogio, Mark S. Anderson, Cheryl F. Lichti, Emil R. UnanueAbstract:Tissue-Specific Autoimmunity occurs when selected antigens presented by susceptible alleles of the major histocompatibility complex are recognized by T cells. However, the reason why certain specific self-antigens dominate the response and are indispensable for triggering autoreactivity is unclear. Spontaneous presentation of insulin is essential for initiating autoimmune type 1 diabetes in non-obese diabetic mice1,2. A major set of pathogenic CD4 T cells specifically recognizes the 12–20 segment of the insulin B-chain (B:12–20), an epitope that is generated from direct presentation of insulin peptides by antigen-presenting cells3,4. These T cells do not respond to antigen-presenting cells that have taken up insulin that, after processing, leads to presentation of a different segment representing a one-residue shift, B:13–214. CD4 T cells that recognize B:12–20 escape negative selection in the thymus and cause diabetes, whereas those that recognize B:13–21 have only a minor role in Autoimmunity3–5. Although presentation of B:12–20 is evident in the islets3,6, insulin-specific germinal centres can be formed in various lymphoid tissues, suggesting that insulin presentation is widespread7,8. Here we use live imaging to document the distribution of insulin recognition by CD4 T cells throughout various lymph nodes. Furthermore, we identify catabolized insulin peptide fragments containing defined pathogenic epitopes in β-cell granules from mice and humans. Upon glucose challenge, these fragments are released into the circulation and are recognized by CD4 T cells, leading to an activation state that results in transcriptional reprogramming and enhanced diabetogenicity. Therefore, a tissue such as pancreatic islets, by releasing catabolized products, imposes a constant threat to self-tolerance. These findings reveal a self-recognition pathway underlying a primary autoantigen and provide a foundation for assessing antigenic targets that precipitate pathogenic outcomes by systemically sensitizing lymphoid tissues.
