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      MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4 + T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion

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          Summary

          Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.

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          Highlights

          • Genetic ablation of ILC2s impairs type-2 immunity
          • MHCII-expressing ILC2s potentiate Th2 responses
          • IL-2 from T cells promotes ILC2 proliferation and expression of type-2 cytokines
          • MHCII and IL-13 expression by ILC2s is important for N. brasiliensis expulsion

          Abstract

          Type-2 innate lymphoid cells proliferate and release interleukin-13 during protective immunity to helminth infection and detrimentally during allergy and asthma. McKenzie and colleagues establish that these activities are potentiated through an MHC class II-mediated dialogue with T cells.

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          Most cited references 49

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          Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity

          Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity – responsible for protective immune responses to helminth parasites1,2 and the underlying cause of the pathogenesis of allergic asthma3,4 – consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)-4, IL-5 and IL-13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively elucidated. Here, through the use of novel Il13eGFP reporter mice, we present the identification and functional characterisation of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type 2-inducing cytokines IL-25 and IL-33, and represent the predominant early source of IL-13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL-25 and IL-33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wildtype, but not IL-13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity.
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            Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.

            Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines. Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue 'FALC' (fat-associated lymphoid cluster). FALC Lin(-)c-Kit(+)Sca-1(+) cells are distinct from lymphoid progenitors and lymphoid tissue inducer cells. These cells proliferate in response to IL2 and produce large amounts of T(H)2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody production and self-renewal of B1 cells. Indeed, FALC Lin(-)c-Kit(+)Sca-1(+) cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection. After helminth infection and in response to IL33, FALC Lin(-)c-Kit(+)Sca-1(+) cells produce large amounts of IL13, which leads to goblet cell hyperplasia-a critical step for helminth expulsion. In mice devoid of FALC Lin(-)c-Kit(+)Sca-1(+) cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin(-)c-Kit(+)Sca-1(+) cells are T(H)2-type innate lymphocytes, and we propose that these cells be called 'natural helper cells'.
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              Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements.

              We describe the generation of ovalbumin (OVA)-specific, MHC class II-restricted alpha beta T cell receptor (TCR) transgenic mice. Initial attempts at generating these transgenic mice utilized heterologous regulatory elements to drive the expression of cDNA genes encoding the separate alpha- and beta-chains of the TCR. Unexpectedly, T cells bearing the transgenic alpha beta TCR failed to emerge from the thymus in these mice, although the transgenes did modify endogenous TCR expression. However, subsequent modification of the approach which enabled expression of the TCR beta-chain under the control of its natural regulatory elements generated mice whose peripheral T cells expressed the transgenic TCR and were capable of antigen-dependent proliferation. These results show that successful generation of MHC class II-restricted, OVA-specific alpha beta TCR transgenic mice was dependent upon combining cDNA- and genomic DNA-based constructs for expression of the respective alpha- and beta-chains of the TCR.
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                Author and article information

                Contributors
                Journal
                Immunity
                Immunity
                Immunity
                Cell Press
                1074-7613
                1097-4180
                21 August 2014
                21 August 2014
                : 41
                : 2
                : 283-295
                Affiliations
                [1 ]MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK
                [2 ]MRC Human Immunology Unit, NIHR Biomedical Research Centre, University of Oxford, John Radcliffe Hospital, OX3 9DS, UK
                [3 ]Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
                [4 ]National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland
                [5 ]Institute of Molecular Medicine, Trinity College Dublin, Dublin 2, Ireland
                [6 ]Institute of Infection, Immunity and Inflammation, GRBC, University Place, Glasgow, G12 8TA, UK
                Author notes
                []Corresponding author anm@ 123456mrc-lmb.cam.ac.uk
                [7]

                Co-first author

                [8]

                Present address: MedImmune, Milstein Building, Granta Park, Cambridge, CB1 6GH, UK

                Article
                S1074-7613(14)00243-X
                10.1016/j.immuni.2014.06.016
                4148706
                25088770
                © 2014 The Authors
                Categories
                Article

                Immunology

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