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M Colonna - One of the best experts on this subject based on the ideXlab platform.
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innate Lymphoid Cell sensing of tissue vitality
Current Opinion in Immunology, 2019Co-Authors: A D Barrow, M ColonnaAbstract:Innate Lymphoid Cells (ILCs) constitute a heterogeneous population of cytokine-secreting Cells that colonize different tissues and are heavily reliant on cytokines and other secreted factors for their development, maintenance and effector functions. Most ILCs are tissue resident and differentiate in non-Lymphoid peripheral tissues. As tissue-resident sentinels, ILCs must rapidly identify pathogens or malignancy in an effort to return the tissue to homeostasis. Here we review the mechanisms that ILCs employ to sense cytokines and other potent immunoregulatory factors that promote their development in different tissues as well as the ability to distinguish pathogenic versus healthy tissue microenvironments and highlight the importance of these pathways for human disease.
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Jak3 deficiency blocks innate Lymphoid Cell development
Mucosal Immunology, 2018Co-Authors: M L Robinette, M Cella, J B Telliez, T K Ulland, A D Barrow, K Capuder, S Gilfillan, L-l Lin, L D Notarangelo, M ColonnaAbstract:Loss-of-function mutations in the tyrosine kinase JAK3 cause autosomal recessive severe combined immunodeficiency (SCID). Defects in this form of SCID are restricted to the immune system, which led to the development of immunosuppressive JAK inhibitors. We find that the B6.Cg- Nr1d1 ^ tm1Ven /LazJ mouse line purchased from Jackson Laboratories harbors a spontaneous mutation in Jak3 , generating a SCID phenotype and an inability to generate antigen-independent professional cytokine-producing innate Lymphoid Cells (ILCs). Mechanistically, Jak3 deficiency blocks ILC differentiation in the bone marrow at the ILC precursor and the pre-NK Cell progenitor. We further demonstrate that the pan-JAK inhibitor tofacitinib and the specific JAK3 inhibitor PF-06651600 impair the ability of human intraepithelial ILC1 (iILC1) to produce IFN-γ, without affecting ILC3 production of IL-22. Both inhibitors impaired the proliferation of iILC1 and ILC3 and differentiation of human ILC in vitro . Tofacitinib is currently approved for the treatment of moderate-to-severely active rheumatoid arthritis. Both tofacitinib and PF-06651600 are currently in clinical trials for several other immune-mediated conditions. Our data suggest that therapeutic inhibition of JAK may also impact ILCs and, to some extent, underlie clinical efficacy.
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innate Lymphoid Cell function in the context of adaptive immunity
Nature Immunology, 2016Co-Authors: Jennifer K Bando, M ColonnaAbstract:Innate Lymphoid Cells (ILCs) are a family of innate immune Cells that have diverse functions during homeostasis and disease. Subsets of ILCs have phenotypes that mirror those of polarized helper T Cell subsets in their expression of core transcription factors and effector cytokines. Given the similarities between these two classes of lymphocytes, it is important to understand which functions of ILCs are specialized and which are redundant with those of T Cells. Here we discuss genetic mouse models that have been used to delineate the contributions of ILCs versus those of T Cells and review the current understanding of the specialized in vivo functions of ILCs.
Tomasz I Michalak - One of the best experts on this subject based on the ideXlab platform.
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in vitro and in vivo infectivity and pathogenicity of the Lymphoid Cell derived woodchuck hepatitis virus
Journal of Virology, 2001Co-Authors: Tomasz I MichalakAbstract:Woodchuck hepatitis virus (WHV) and human hepatitis B virus are closely related, highly hepatotropic mammalian DNA viruses that also replicate in the lymphatic system. The infectivity and pathogenicity of hepadnaviruses propagating in Lymphoid Cells are under debate. In this study, hepato- and lymphotropism of WHV produced by naturally infected Lymphoid Cells was examined in specifically established woodchuck hepatocyte and Lymphoid Cell cultures and coculture systems, and virus pathogenicity was tested in susceptible animals. Applying PCR-based assays discriminating between the total pool of WHV genomes and covalently closed circular DNA (cccDNA), combined with enzymatic elimination of extraCellular viral sequences potentially associated with the Cell surface, our study documents that virus replicating in woodchuck Lymphoid Cells is infectious to homologous hepatocytes and Lymphoid Cells in vitro. The productive replication of WHV from Lymphoid Cells in cultured hepatocytes was evidenced by the appearance of virus-specific DNA, cccDNA, and antigens, transmissibility of the virus through multiple passages in hepatocyte cultures, and the ability of the passaged virus to infect virus-naive animals. The data also revealed that WHV from Lymphoid Cells can initiate classical acute viral hepatitis in susceptible animals, albeit small quantities (∼10 3 virions) caused immunovirologically undetectable (occult) WHV infection that engaged the lymphatic system but not the liver. Our results provide direct in vitro and in vivo evidence that Lymphoid Cells in the infected host support propagation of infectious hepadnavirus that has the potential to induce hepatitis. They also emphasize a principal role of the lymphatic system in the maintenance and dissemination of hepadnavirus infection, particularly when infection is induced by low virus doses.
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in vitro and in vivo infectivity and pathogenicity of the Lymphoid Cell derived woodchuck hepatitis virus
Journal of Virology, 2001Co-Authors: Yuanyee Lew, Tomasz I MichalakAbstract:Woodchuck hepatitis virus (WHV) and human hepatitis B virus are closely related, highly hepatotropic mammalian DNA viruses that also replicate in the lymphatic system. The infectivity and pathogenicity of hepadnaviruses propagating in Lymphoid Cells are under debate. In this study, hepato- and lymphotropism of WHV produced by naturally infected Lymphoid Cells was examined in specifically established woodchuck hepatocyte and Lymphoid Cell cultures and coculture systems, and virus pathogenicity was tested in susceptible animals. Applying PCR-based assays discriminating between the total pool of WHV genomes and covalently closed circular DNA (cccDNA), combined with enzymatic elimination of extraCellular viral sequences potentially associated with the Cell surface, our study documents that virus replicating in woodchuck Lymphoid Cells is infectious to homologous hepatocytes and Lymphoid Cells in vitro. The productive replication of WHV from Lymphoid Cells in cultured hepatocytes was evidenced by the appearance of virus-specific DNA, cccDNA, and antigens, transmissibility of the virus through multiple passages in hepatocyte cultures, and the ability of the passaged virus to infect virus-naive animals. The data also revealed that WHV from Lymphoid Cells can initiate classical acute viral hepatitis in susceptible animals, albeit small quantities (approximately 10(3) virions) caused immunovirologically undetectable (occult) WHV infection that engaged the lymphatic system but not the liver. Our results provide direct in vitro and in vivo evidence that Lymphoid Cells in the infected host support propagation of infectious hepadnavirus that has the potential to induce hepatitis. They also emphasize a principal role of the lymphatic system in the maintenance and dissemination of hepadnavirus infection, particularly when infection is induced by low virus doses.
James Di Santo - One of the best experts on this subject based on the ideXlab platform.
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An Id2RFP-Reporter Mouse Redefines Innate Lymphoid Cell Precursor Potentials
Immunity, 2019Co-Authors: Dylan Cherrier, Sylvestre Chea, Christian A. J. Vosshenrich, Nicolas Serafini, Maxime Petit, Pentao Liu, Rachel Golub, James Di SantoAbstract:Innate Lymphoid Cell (ILC) development proposes that ILC precursors (ILCPs) segregate along natural killer (NK) Cell versus helper Cell (ILC1, ILC2, ILC3) pathways, the latter depending on expression of Id2, Zbtb16, and Gata3. We have developed an Id2-reporter strain expressing red fluorescent protein (RFP) in the context of normal Id2 expression to re-examine ILCP phenotype and function. We show that bone-marrow ILCPs were heterogeneous and harbored extensive NK-Cell potential in vivo and in vitro. By multiplexing Id2RFP with Zbtb16CreGFP and Bcl11btdTomato strains, we made a single-Cell dissection of the ILCP compartment. In contrast with the current model, we have demonstrated that Id2+Zbtb16+ ILCPs included multi-potent ILCPs that retained NK-Cell potential. Late-stage ILC2P and ILC3P compartments could be defined by differential Zbtb16 and Bcl11b expression. We suggest a revised model for ILC differentiation that redefines the Cell-fate potential of helper-ILC-restricted Zbtb16+ ILCPs.
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Innate Lymphoid Cell Development: A T Cell Perspective
Immunity, 2018Co-Authors: Dylan Cherrier, Nicolas Serafini, James Di SantoAbstract:Innate Lymphoid Cells (ILCs) and natural killer (NK) Cells have garnered considerable interest due to their unique functional properties in immune defense and tissue homeostasis. Our current understanding of how these Cells develop has been greatly facilitated by knowledge of T Cell biology. Models of T Cell differentiation provided the basis for a conceptual classification of these innate effectors and inspired a scheme of their activation and regulation. In this review, we discuss NK Cell and ILC development from a "T Cell standpoint" in an attempt to extend the analogy between adaptive T Cells and their innate ILC and NK Cell counterparts.
Steven D Scoville - One of the best experts on this subject based on the ideXlab platform.
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cd56 expression marks human group 2 innate Lymphoid Cell divergence from a shared nk Cell and group 3 innate Lymphoid Cell developmental pathway
Immunity, 2018Co-Authors: Luxi Chen, Youssef Youssef, Cameron Robinson, Gabrielle Ernst, Mary Y Carson, Karen A Young, Steven D Scoville, Xiaoli Zhang, Regine Harris, Palak SekhriAbstract:Summary According to the established model of murine innate Lymphoid Cell (ILC) development, helper ILCs develop separately from natural killer (NK) Cells. However, it is unclear how helper ILCs and NK Cells develop in humans. Here we elucidated key steps of NK Cell, ILC2, and ILC3 development within human tonsils using ex vivo molecular and functional profiling and lineage differentiation assays. We demonstrated that while tonsillar NK Cells, ILC2s, and ILC3s originated from a common CD34−CD117+ ILC precursor pool, final steps of ILC2 development deviated independently and became mutually exclusive from those of NK Cells and ILC3s, whose developmental pathways overlapped. Moreover, we identified a CD34−CD117+ ILC precursor population that expressed CD56 and gave rise to NK Cells and ILC3s but not to ILC2s. These data support a model of human ILC development distinct from the mouse, whereby human NK Cells and ILC3s share a common developmental pathway separate from ILC2s.
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a progenitor Cell expressing transcription factor rorγt generates all human innate Lymphoid Cell subsets
Immunity, 2016Co-Authors: Steven D Scoville, Luxi Chen, Xiaoli Zhang, Bethany L Mundybosse, Michael H Zhang, Li Chen, Karen Keller, Tiffany Hughes, Stephanie Cheng, Stephen M BerginAbstract:The current model of murine innate Lymphoid Cell (ILC) development holds that mouse ILCs are derived downstream of the common Lymphoid progenitor through lineage-restricted progenitors. However, corresponding lineage-restricted progenitors in humans have yet to be discovered. Here we identified a progenitor population in human secondary Lymphoid tissues (SLTs) that expressed the transcription factor RORγt and was unique in its ability to generate all known ILC subsets, including natural killer (NK) Cells, but not other leukocyte populations. In contrast to murine fate-mapping data, which indicate that only ILC3s express Rorγt, these human progenitor Cells as well as human peripheral blood NK Cells and all mature ILC populations expressed RORγt. Thus, all human ILCs can be generated through an RORγt(+) developmental pathway from a common progenitor in SLTs. These findings help establish the developmental signals and pathways involved in human ILC development.
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the transcription factor ahr prevents the differentiation of a stage 3 innate Lymphoid Cell subset to natural killer Cells
Cell Reports, 2014Co-Authors: Tiffany Hughes, Steven D Scoville, Karen Keller, Edward L Briercheck, Aharon G Freud, Rossana Trotta, Susan Mcclory, Youcai Deng, Jordan P Cole, Nicholas HarrisonAbstract:Accumulating evidence indicates that human natural killer (NK) Cells develop in secondary Lymphoid tissue (SLT) through a so-called "stage 3" developmental intermediate minimally characterized by a CD34(-)CD117(+)CD94(-) immunophenotype that lacks mature NK Cell function. This stage 3 population is heterogeneous, potentially composed of functionally distinct innate Lymphoid Cell (ILC) types that include interleukin-1 receptor (IL-1R1)-positive, IL-22-producing ILC3s. Whether human ILC3s are developmentally related to NK Cells is a subject of ongoing investigation. Here, we show that antagonism of the aryl hydrocarbon receptor (AHR) or silencing of AHR gene expression promotes the differentiation of tonsillar IL-22-producing IL-1R1(hi) human ILC3s to CD56(bright)CD94(+) interferon (IFN)-γ-producing cytolytic mature NK Cells expressing eomesodermin (EOMES) and T-Box Protein 21 (TBX21 or TBET). Hence, we demonstrate the lineage plasticity of human ILCs by identifying AHR as a transcription factor that prevents IL-1R1(hi) ILC3s from differentiating into NK Cells.
Nicolas Serafini - One of the best experts on this subject based on the ideXlab platform.
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An Id2RFP-Reporter Mouse Redefines Innate Lymphoid Cell Precursor Potentials
Immunity, 2019Co-Authors: Dylan Cherrier, Sylvestre Chea, Christian A. J. Vosshenrich, Nicolas Serafini, Maxime Petit, Pentao Liu, Rachel Golub, James Di SantoAbstract:Innate Lymphoid Cell (ILC) development proposes that ILC precursors (ILCPs) segregate along natural killer (NK) Cell versus helper Cell (ILC1, ILC2, ILC3) pathways, the latter depending on expression of Id2, Zbtb16, and Gata3. We have developed an Id2-reporter strain expressing red fluorescent protein (RFP) in the context of normal Id2 expression to re-examine ILCP phenotype and function. We show that bone-marrow ILCPs were heterogeneous and harbored extensive NK-Cell potential in vivo and in vitro. By multiplexing Id2RFP with Zbtb16CreGFP and Bcl11btdTomato strains, we made a single-Cell dissection of the ILCP compartment. In contrast with the current model, we have demonstrated that Id2+Zbtb16+ ILCPs included multi-potent ILCPs that retained NK-Cell potential. Late-stage ILC2P and ILC3P compartments could be defined by differential Zbtb16 and Bcl11b expression. We suggest a revised model for ILC differentiation that redefines the Cell-fate potential of helper-ILC-restricted Zbtb16+ ILCPs.
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Innate Lymphoid Cell Development: A T Cell Perspective
Immunity, 2018Co-Authors: Dylan Cherrier, Nicolas Serafini, James Di SantoAbstract:Innate Lymphoid Cells (ILCs) and natural killer (NK) Cells have garnered considerable interest due to their unique functional properties in immune defense and tissue homeostasis. Our current understanding of how these Cells develop has been greatly facilitated by knowledge of T Cell biology. Models of T Cell differentiation provided the basis for a conceptual classification of these innate effectors and inspired a scheme of their activation and regulation. In this review, we discuss NK Cell and ILC development from a "T Cell standpoint" in an attempt to extend the analogy between adaptive T Cells and their innate ILC and NK Cell counterparts.
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Transcriptional regulation of innate Lymphoid Cell fate.
Nature Reviews Immunology, 2015Co-Authors: Nicolas Serafini, Christian A. J. Vosshenrich, James P Di SantoAbstract:Innate Lymphoid Cells (ILCs) are a recently described family of Lymphoid effector Cells that have important roles in immune defence, inflammation and tissue remodelling. It has been proposed that ILCs represent 'innate' homologues of differentiated effector T Cells, and they have been categorized into three groups — namely, ILC1s, ILC2s and ILC3s — on the basis of their expression of cytokines and transcription factors that are typically associated with T helper 1 (T(H)1)-, T(H)2- and T(H)17-type immune responses, respectively. Indeed, remarkable similarity is seen between the specific transcription factors required for the development and diversification of different ILC groups and those that drive effector T Cell differentiation. The recent identification of dedicated ILC precursors has provided a view of the mechanisms that control this first essential stage of ILC development. Here, we discuss the transcriptional mechanisms that regulate ILC development and diversification into distinct effector subsets with key roles in immunity and tissue homeostasis. We further caution against the current distinction between 'helper' versus 'killer' subsets in the evolving area of ILC nomenclature.
