CD8+ T cells actively penetrate into hepatocytes via CD44/p-ERM/F-actin pathway in autoimmune hepatitis

Aim Emperipolesis, the cell-in-cell structure, is one of the pathological diagnostic standard of AIH. We have already identified that CD8+ T cells participated in the emperipolesis process in liver tissue of AIH patients. In this study, we aimed to clarify the characteristics and molecular mechanisms of emperipolesis in the patients with AIH in vitro and in mice with α-GalCer-induced acute hepatitis. Methods Peripheral blood mononuclear cell (PBMC) of patients with variant chronic liver diseases and healthy controls were co-cultured with hepatic cell line to induce emperipolesis in vitro. Confocal staining was performed to illustrate the cellular types and potential mechanisms of emperipolesis in AIH. In addition, the mouse model of α-GalCer-induced acute hepatitis which mimics human AIH in several features, was used to confirm the role of CD44/p-ERM/F-actin in the emperipolesis process in vivo. Results In co-culture system with PBMC and hepatic cell line, emperipolesis was observed most common in the patients with AIH. CD8+ T cells were the major cells participated in the emperipolesis process, and penetrated into hepatocytes actively via CD44/p-ERM/F-actin pathway. As a result, most CD8+ T cells engulfed in hepatocytes undergo self-apoptosis. In α-GalCer-induced acute hepatitis model, emperipolesis was observed around the inflammatory foci, and was inhibited by Ezrin phosphorylation inhibitor NSC668394. Similarly, activated murine CD8+ T cells penetrated into primary hepatocytes via CD44/p-ERM/F-actin pathway in vitro. Conclusions CD8+ T cells penetrated into hepatocytes actively via CD44/p-ERM/F-actin signaling pathway and undergo apoptosis, may be a compensative mechanism to attenuate overwhelming immune attack in AIH. This article is protected by copyright. All rights reserved.