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      IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection

      , PhD 1 , , MD 1 , 2 , , PhD 3 , , PhD 1 , 4 , 5

      Mucosal immunology

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          Abstract

          Influenza infection primarily targets the upper respiratory system, leading to a severe destruction of the epithelial cell layer. The role of immune cells in the regeneration of tracheal and bronchial epithelial cells is not well defined. Here, we investigated the production of pro-constructive cytokine, Interleukin-22 (IL-22), in the bronchoalveolar lavage (BAL), trachea, lung tissue, and spleen during influenza infection. We found that conventional NK cells (NCR1 +NK1.1 +CD127 RORγt ) were the predominant IL-22-producers in the BAL, trachea and lung tissues. Tracheal epithelial cells constitutively expressed high levels of IL-22R and underwent active proliferation in response to IL-22 in the wild type (WT) mice. Infection of IL-22 −/− mice with influenza virus resulted in a severe impairment in the regeneration of tracheal epithelial cells. In addition, IL-22 −/− mice continued to lose body weight even after 10 days post infection (DPI 10) without any recovery. Tracheal epithelial cell proliferation was significantly reduced in IL-22 −/− mice during influenza infection. Adoptive transfer of IL-22 sufficient but not IL-22 deficient NK cells into IL-22 −/− mice restored the tracheal/bronchial epithelial cell regeneration and conferred protection against inflammation. Our findings strongly suggest that conventional NK cells have evolved to both kill virus-infected cells and also to provide vital cytokines for tissue regeneration.

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          Most cited references 43

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          Basal cells as stem cells of the mouse trachea and human airway epithelium.

          The pseudostratified epithelium of the mouse trachea and human airways contains a population of basal cells expressing Trp-63 (p63) and cytokeratins 5 (Krt5) and Krt14. Using a KRT5-CreER(T2) transgenic mouse line for lineage tracing, we show that basal cells generate differentiated cells during postnatal growth and in the adult during both steady state and epithelial repair. We have fractionated mouse basal cells by FACS and identified 627 genes preferentially expressed in a basal subpopulation vs. non-BCs. Analysis reveals potential mechanisms regulating basal cells and allows comparison with other epithelial stem cells. To study basal cell behaviors, we describe a simple in vitro clonal sphere-forming assay in which mouse basal cells self-renew and generate luminal cells, including differentiated ciliated cells, in the absence of stroma. The transcriptional profile identified 2 cell-surface markers, ITGA6 and NGFR, which can be used in combination to purify human lung basal cells by FACS. Like those from the mouse trachea, human airway basal cells both self-renew and generate luminal daughters in the sphere-forming assay.
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            Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.

            Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-alpha, but not IFN-gamma, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-alpha. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders.
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              Human and avian influenza viruses target different cell types in cultures of human airway epithelium.

              The recent human infections caused by H5N1, H9N2, and H7N7 avian influenza viruses highlighted the continuous threat of new pathogenic influenza viruses emerging from a natural reservoir in birds. It is generally believed that replication of avian influenza viruses in humans is restricted by a poor fit of these viruses to cellular receptors and extracellular inhibitors in the human respiratory tract. However, detailed mechanisms of this restriction remain obscure. Here, using cultures of differentiated human airway epithelial cells, we demonstrated that influenza viruses enter the airway epithelium through specific target cells and that there were striking differences in this respect between human and avian viruses. During the course of a single-cycle infection, human viruses preferentially infected nonciliated cells, whereas avian viruses as well as the egg-adapted human virus variant with an avian virus-like receptor specificity mainly infected ciliated cells. This pattern correlated with the predominant localization of receptors for human viruses (2-6-linked sialic acids) on nonciliated cells and of receptors for avian viruses (2-3-linked sialic acids) on ciliated cells. These findings suggest that although avian influenza viruses can infect human airway epithelium, their replication may be limited by a nonoptimal cellular tropism. Our data throw light on the mechanisms of generation of pandemic viruses from their avian progenitors and open avenues for cell level-oriented studies on the replication and pathogenicity of influenza virus in humans.
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                Author and article information

                Journal
                101299742
                35518
                Mucosal Immunol
                Mucosal Immunol
                Mucosal immunology
                1933-0219
                1935-3456
                13 November 2013
                27 June 2012
                January 2013
                20 November 2013
                : 6
                : 1
                Affiliations
                [1 ]Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, 8727 Watertown Plank Road, Milwaukee, WI 53226
                [2 ]Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226
                [3 ]Genentech Inc, South San Francisco, CA 94080, USA
                [4 ]Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226
                [5 ]Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53226
                Author notes
                [¥ ]To whom correspondence should be addressed ( Subra.malar@ 123456bcw.edu )
                Article
                NIHMS383229
                10.1038/mi.2012.49
                3835350
                22739232
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI064828 || AI
                Categories
                Article

                Immunology

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