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      JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

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          Abstract

          Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.

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          Most cited references134

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          IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells.

          An efficient Th1-driven adaptive immune response requires activation of the T cell receptor and secretion of the T cell stimulatory cytokine IL-12 by activated antigen-presenting cells. IL-12 triggers Th1 polarization of naive CD4(+) T cells and secretion of IFN-gamma. We describe a new heterodimeric cytokine termed IL-27 that consists of EBI3, an IL-12p40-related protein, and p28, a newly discovered IL-12p35-related polypeptide. IL-27 is an early product of activated antigen-presenting cells and drives rapid clonal expansion of naive but not memory CD4(+) T cells. It also strongly synergizes with IL-12 to trigger IFN-gamma production of naive CD4(+) T cells. IL-27 mediates its biologic effects through the orphan cytokine receptor WSX-1/TCCR.
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            Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity.

            The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.
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              Innate lymphoid cells--how did we miss them?

              Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage that have emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the various ILC lineages that have been identified to date and summarize their functions in protective immunity to infection and their pathological roles in allergic and autoimmune diseases.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                12 November 2019
                2019
                : 10
                : 2590
                Affiliations
                [1] 1Department for Biomedical Sciences, Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna , Vienna, Austria
                [2] 2St. Anna Children's Cancer Research Institute (CCRI) , Vienna, Austria
                Author notes

                Edited by: Ewa Sitnicka, Lund University, Sweden

                Reviewed by: Roland Jacobs, Hannover Medical School, Germany; Laurel L. Lenz, University of Colorado Denver School of Medicine, United States

                *Correspondence: Dagmar Gotthardt dagmar.gotthardt@ 123456vetmeduni.ac.at

                This article was submitted to NK and Innate Lymphoid Cell Biology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.02590
                6861185
                31781102
                7da4c940-3ae6-40c8-89e6-895d7a2b652d
                Copyright © 2019 Gotthardt, Trifinopoulos, Sexl and Putz.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 August 2019
                : 18 October 2019
                Page count
                Figures: 3, Tables: 0, Equations: 0, References: 208, Pages: 16, Words: 14237
                Categories
                Immunology
                Review

                Immunology
                nk cell,ilc1,development,maturation,cytokine,jak,stat,socs
                Immunology
                nk cell, ilc1, development, maturation, cytokine, jak, stat, socs

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