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A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity

Abstract

Natural killer (NK) cells are classically viewed as lymphocytes that provide innate surveillance against virally infected cells and tumour cells through the release of cytolytic mediators and interferon (IFN)-γ. In humans, blood CD56dim NK cells specialize in the lysis of cell targets1. In the lymph nodes, CD56bright NK cells secrete IFN-γ cooperating with dendritic cells and T cells in the generation of adaptive responses1,2. Here we report the characterization of a human NK cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer’s patches, which is hard-wired to secrete interleukin (IL)-22, IL-26 and leukaemia inhibitory factor. These NK cells, which we refer to as NK-22 cells, are triggered by acute exposure to IL-23. In vitro, NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate and express a variety of mitogenic and anti-apoptotic molecules. NK-22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK-22 cells provide an innate source of IL-22 that may help constrain inflammation and protect mucosal sites.

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Figure 1: NKp44 + NK cells are prominently found within MALT.
Figure 2: A subset of tonsil NKp44 + NK cells express CCR6, respond to CCL20 in vitro and in vivo , produce CCL20 and adhere to epithelial cells.
Figure 3: Tonsil NKp44 + NK cells produce IL-22, IL-26 and LIF. IL-23 and TLR-activated monocytes trigger IL-22 secretion.
Figure 4: NK-22 cell-secreted cytokines stimulate epithelial cells to proliferate, release IL-10 and activate STAT1 and STAT3.
Figure 5: Identification of mouse NK-22 cells.

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Acknowledgements

We thank J. Hughes, B. Eades and S. Schloehmann for cell sorting; R. Clary and the nursing staff at the Children’s Hospital, Washington University School of Medicine, for providing tonsil specimens; S. Lonardi for assistance in immunohistochemistry; J. Pfeifer for providing gut specimens; A. Rapaport and S. McCartney for help in gene chip analysis; and S. Gilfillan for critically reading the manuscript. This work was supported by National Institutes of Health (NIH) grants R01AI056139-05 and R21AI067748-02 (to M.Co.) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01 DK079798 (to J.C.M.). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIH and NIDDK.

Author contributions M.Ce., A.F., K.O. and J.M.D. performed the experiments. W.V., F.F. and J.K.M.L. performed immunohistochemical analyses. J.C.M. designed experiments. M.Co. wrote the manuscript and directed the research.

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Correspondence to Marco Colonna.

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Cella, M., Fuchs, A., Vermi, W. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009). https://doi.org/10.1038/nature07537

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