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      The TNF-Family Cytokine TL1A Promotes Allergic Immunopathology through Group 2 Innate Lymphoid Cells

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          Abstract

          The TNF-family cytokine TL1A (TNFSF15) costimulates T cells and promotes diverse T-cell dependent models of autoimmune disease through its receptor DR3. TL1A polymorphisms also confer susceptibility to inflammatory bowel disease. Here we find that allergic pathology driven by constitutive TL1A expression depends on IL-13, but not T, NKT, mast cells or commensal intestinal flora. Group 2 innate lymphoid cells (ILC2) express surface DR3 and produce IL-13 and other type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion and function in the setting of T cell dependent and independent models of allergic disease. By contrast, DR3 deficient ILC2 can still differentiate, expand and produce IL-13 when stimulated by IL-25 or IL-33, and mediate expulsion of intestinal helminths. These data identify costimulation of ILC2 as a novel function of TL1A important for allergic lung disease, and suggest that TL1A may be a therapeutic target in these settings.

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          Most cited references 35

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          Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161.

          Innate lymphoid cells (ILCs) are emerging as a family of effectors and regulators of innate immunity and tissue remodeling. Interleukin 22 (IL-22)- and IL-17-producing ILCs, which depend on the transcription factor RORγt, express CD127 (IL-7 receptor α-chain) and the natural killer cell marker CD161. Here we describe another lineage-negative CD127(+)CD161(+) ILC population found in humans that expressed the chemoattractant receptor CRTH2. These cells responded in vitro to IL-2 plus IL-25 and IL-33 by producing IL-13. CRTH2(+) ILCs were present in fetal and adult lung and gut. In fetal gut, these cells expressed IL-13 but not IL-17 or IL-22. There was enrichment for CRTH2(+) ILCs in nasal polyps of chronic rhinosinusitis, a typical type 2 inflammatory disease. Our data identify a unique type of human ILC that provides an innate source of T helper type 2 (T(H)2) cytokines.
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            Identification of an interleukin (IL)-25–dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion

            Type 2 immunity, which involves coordinated regulation of innate and adaptive immune responses, can protect against helminth parasite infection, but may lead to allergy and asthma after inappropriate activation. We demonstrate that il25−/− mice display inefficient Nippostrongylus brasiliensis expulsion and delayed cytokine production by T helper 2 cells. We further establish a key role for interleukin (IL)-25 in regulating a novel population of IL-4–, IL-5–, IL-13–producing non–B/non–T (NBNT), c-kit+, FcɛR1− cells during helminth infection. A deficit in this population in il25−/− mice correlates with inefficient N. brasiliensis expulsion. In contrast, administration of recombinant IL-25 in vivo induces the appearance of NBNT, c-kit+, FcɛR1− cells and leads to rapid worm expulsion that is T and B cell independent, but type 2 cytokine dependent. We demonstrate that these IL-25–regulated cells appear rapidly in the draining lymph nodes, implicating them as a source of type 2 cytokines during initiation of worm expulsion.
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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

                Journal
                101299742
                35518
                Mucosal Immunol
                Mucosal Immunol
                Mucosal immunology
                1933-0219
                1935-3456
                7 February 2014
                25 December 2013
                July 2014
                01 January 2015
                : 7
                : 4
                : 958-968
                Affiliations
                [1 ]Immunoregulation Section, Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA
                [2 ]Immunopathogenesis Section, Laboratory of Parasitic Diseases, NIAID, NIH
                [3 ]Laboratory of Molecular Biology, Cambridge, UK
                [4 ]Lymphocyte Cell Biology Section, NIAMS
                [5 ]Genetic Disease Research Branch, NHGRI, NIH
                [6 ]Laboratory of Immunology, NIAID, NIH
                Author notes
                [# ]Contact Information: Richard M. Siegel, M.D, Ph.D. Bldg 10 Rm 13C103A, NIH Bethesda MD, 20892, rsiegel@ 123456nih.gov 301-496-3761
                Article
                NIHMS544349
                10.1038/mi.2013.114
                4165592
                24368564
                3df53e51-c5b3-4e28-a0a4-f449ce338c64
                Categories
                Article

                Immunology

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