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

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.