P1-025  Mast cells play a key role in host defense against lethal herpes simplex virus infection through TNF-α and IL-6 production induced by keratinocyte-derived alarmin IL-33

The essential contribution of mast cells (MCs) to bacterial host defense has been well established; however, little is known about their role in viral infections in vivo. Here, we found that intradermal injection with HSV-2 into MC deficient KitW/W-v mice lead to increased clinical severity and mortality with elevated virus titers in HSV-infected skins. Ex vivo HSV-specific tetramer staining assay demonstrated that MC deficiency did not affect the frequency of HSV-specific CTLs in draining lymph nodes. Moreover, the high mortality in KitW/W-v mice was completely reversed by intradermal reconstitution with BMMCs from wild-type, but not TNF−/− or IL-6−/−, mice. HSV did not directly induce TNF-α or IL-6 production by BMMCs, whereas supernatants from HSV-infected keratinocytes induced production of these cytokines by BMMCs without degranulation. Furthermore, IL-33 expression was induced in HSV-infected keratinocytes and blocking the IL-33 receptor, T1/ST2 on BMMCs significantly reduced TNF-α and IL-6 production by BMMCs. These results indicate MC involvement in host defense at HSV-infected sites through TNF-α and IL-6 production, which is induced by keratinocyte-derived IL-33.