The E3 Ubiquitin Ligase Adaptor Ndfip1 Regulates Th17 Differentiation by Limiting the Production of Proinflammatory Cytokines

Abstract

Ndfip1 is an adaptor for the E3 ubiquitin ligase Itch. Both Ndfip1- and Itch-deficient T cells are biased toward Th2 cytokine production. In this study, we demonstrate that lungs from Ndfip1−/− mice showed increased numbers of neutrophils and Th17 cells. This was not because Ndfip1−/− T cells are biased toward Th17 differentiation. In fact, fewer Ndfip1−/− T cells differentiated into Th17 cells in vitro due to high IL-4 production. Rather, Th17 differentiation was increased in Ndfip1−/− mice due to increased numbers of IL-6–producing eosinophils. IL-6 levels in mice that lacked both Ndfip1 and IL-4 were similar to wild-type controls, and these mice had fewer Th17 cells in their lungs. These results indicate that Th2 inflammation, such as that observed in Ndfip1−/− mice, can increase Th17 differentiation by recruiting IL-6–producing eosinophils into secondary lymphoid organs and tissues. This may explain why Th17 cells develop within an ongoing Th2 inflammatory response.