Innate Interleukin-17 and Interleukin-22 play important roles in viral hepatitis

Intrahepatic cell-derived IL-17 and IL-22 are important for T cell priming and hepatoprotection in viral hepatitis, respectively; however, the source and regulation of these cytokines in the liver microenvironment are not well defined. Here, we present evidence for a significant expansion of IL-17- and IL-22-producing cells in mouse liver during viral infection. We found that a subset of IL-17+ and IL-22+ cells expressed no myeloid/lymphoid lineage markers. Instead, they expressed high levels of stem-like markers, IL-7Rα and RORγt, consistent with the newly described group 3 innate lymphoid cells (ILC3s). They contributed significantly to the establishment of the early cytokine milieu in virus-infected mouse livers. Functional studies with mice deficient of IL-17 receptor, IL-17A, and IL-17F further revealed that IL-17 signaling was critical for priming T cell responses in viral hepatitis. Further studies showed that IL-17A repressed IL-17F secretion in vivo and in vitro; IL-17F+ intrahepatic cells expanded more vigorously in IL-17A knockout animals, permitting efficient antigen-presentation and T cell function. However, IL-17F neither inhibited IL-17A in vitro nor regulated its secretion in vivo. Interestingly, retinoic acid, secreted by hepatic stellate cells (HSCs), increased in the liver after viral infection. Moreover, hepatic stellate cell-derived retinoic acid promoted IL-22 production by ILC3s in the liver and protected the liver against acute viral hepatitis. Notably, hepatic IL-7 was important for ILC3-derived IL-22 production. The blockade of IL-7Rα in vivo significantly decreased IL-22 levels and exacerbated liver inflammation. Collectively, this study has demonstrated the importance of a unique intrahepatic subpopulation ILC3 and its cytokine production during the initial stages of viral infection in the liver. Moreover, the crosstalk among hepatic stellate cells and innate immune cells may play a critical role in modulating immune responses in viral hepatitis.