PI3K/mTOR-dependent IL-22 production modulates polyfunctional T cell responses in viral hepatitis.

Abstract

IL-22 is an important cytokine in modulating the consequences of inflammation in lesions, including the liver. However, the role of IL-22 in Lymphocytic Choriomeningitis Virus (LCMV)-induced viral hepatitis remains obscure. Here, we report that LCMV-induced IL-23 release promoted IL-22 production. And gdT cells and double negative T cells (DNT, CD3+ CD4− CD8− γδTCR− NK1.1−) were the main sources of IL-22 and IL-17 productions following LCMV infection in the liver. Interestingly, we also found that IL-23-stimulated IL-17 production in γδ T cells, and DNT cells were totally dependent on RORγt and PI3K/mTOR, but independent in AhR activities. Although IL-22 production in these two lymphocyte subsets depended on PI3K/mTOR, unlike IL-17 production, IL-22 production required additional signals from RORγt and AhR. Furthermore, IL-22 appeared to act as an important mediator in T cell responses in LCMV-induced viral hepatitis, despite the fact that the IL-22 receptor is restricted to being expressed on non-hematopoitic cells. IL-22−/− mice increased the recruitment of activated T cells to the liver and enhanced polyfunctional cytokine productions in effector CD4+ and CD8+ T cells in LCMV-induced acute or persistent viral hepatitis. Thus, our data revealed a novel connection between IL-23-PI3K/mTOR signaling pathway and the regulation of IL-22/IL-17 productions in the liver, and showed a novel role of IL-22 in modulating the plurifunctionality of anti-viral T cell responses during acute and persistent LCMV infection.