We set out to test the hypothesis that
interleukin-22 (IL-22), a
cytokine crucial for epithelial cell homeostasis and recovery from tissue injury, would be protective during influenza virus
infection. Recent studies have identified phenotypically and functionally unique intestinal NK cells capable of producing the
cytokine IL-22. Unlike gut NK cells that produce
IL-22, the surface phenotypes of lung NK cells were similar to those of spleen NK cells and were characteristically mature. With
mitogen stimulation, both single and double IL-22- and
gamma interferon (IFN-gamma)-producing lung NK cells were detected. However, only the IL-22(+) IFN-gamma(-) lung NK subset was observed after stimulation with
IL-23.
IL-23 receptor (IL-23R) blocking dramatically inhibited
IL-22 production, but not IFN-gamma production. Furthermore, we found that NK1.1(+) or CD27(-) lung NK cells were the primary sources of
IL-22. After influenza virus
infection, lung NK cells were quickly activated to produce both IFN-gamma and
IL-22 and had increased cytotoxic potential. The level of
IL-22 in the lung tissue declined shortly after
infection, gradually returning to the baseline after virus clearance, although the
IL-22 gene expression was maintained. Furthermore, depletion of NK cells with or without influenza virus
infection reduced the
protein level of
IL-22 in the lung. Anti-IL-22 neutralization in vivo did not dramatically affect
weight loss and survival after virus clearance. Unexpectedly, anti-IL-22-treated mice had reduced virus titers. Our data suggest that during primary respiratory
viral infection,
IL-22 seems to a play a marginal role for protection, indicating a differential requirement of this
cytokine for bacterial and
viral infections.