Effector CD8+ T cell-derived interleukin-10 enhances acute liver immunopathology

• DOI: 10.1016/j.jhep.2017.04.020
• Publication Date: 2017-05-06T02:01:40Z
• Authors: Jessica Fioravanti; Pietro Di Lucia; Diletta Magini; Federica Moalli; Carolina Boni; Alexandre Pierre ...; Valeria Fumagalli; Donato Inverso; Andrea Vecchi; Amleto Fiocchi; Stefan Wieland; Robert Purcell; Carlo Ferrari; Francis V. Chisari; Luca G. Guidotti; Matteo Iannacone
• Keywords: 0301 basic medicine; 570; Hepatitis B virus; Mice, Inbred BALB C; Pan troglodytes; 610; Apoptosis; Hepatitis B viru; CD8-Positive T-Lymphocytes; CD8+T cells; Hepatitis B virus; IL-10; Liver immunopathology; Hepatology; Interleukin-10; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Liver; Liver Immunopathology; IL-10; Acute Disease; Animals; Humans; Interleukin-2; CD8+ T cell; Research Article

Besides secreting pro-inflammatory cytokines, chemokines and effector molecules, effector CD8+ T cells that arise upon acute infection with certain viruses have been shown to produce the regulatory cytokine interleukin (IL)-10 and, therefore, contain immunopathology. Whether the same occurs during acute hepatitis B virus (HBV) infection and role that IL-10 might play in liver disease is currently unknown.Mouse models of acute HBV pathogenesis, as well as chimpanzees and patients acutely infected with HBV, were used to analyse the role of CD8+ T cell-derived IL-10 in liver immunopathology.Mouse HBV-specific effector CD8+ T cells produce significant amounts of IL-10 upon in vivo antigen encounter. This is corroborated by longitudinal data in a chimpanzee acutely infected with HBV, where serum IL-10 was readily detectable and correlated with intrahepatic CD8+ T cell infiltration and liver disease severity. Unexpectedly, mouse and human CD8+ T cell-derived IL-10 was found to act in an autocrine/paracrine fashion to enhance IL-2 responsiveness, thus preventing antigen-induced HBV-specific effector CD8+ T cell apoptosis. Accordingly, the use of mouse models of HBV pathogenesis revealed that the IL-10 produced by effector CD8+ T cells promoted their own intrahepatic survival and, thus supported, rather than suppressed liver immunopathology.Effector CD8+ T cell-derived IL-10 enhances acute liver immunopathology. Altogether, these results extend our understanding of the cell- and tissue-specific role that IL-10 exerts in immune regulation. Lay summary: Interleukin-10 is mostly regarded as an immunosuppressive cytokine. We show here that HBV-specific CD8+ T cells produce IL-10 upon antigen recognition and that this cytokine enhances CD8+ T cell survival. As such, IL-10 paradoxically promotes rather than suppresses liver disease.