Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35

• Published in: The Journal of clinical investigation Vol. 129; no. 8; pp. 3201 - 3213
• Main Authors: Koda, Yuzo, Nakamoto, Nobuhiro, Chu, Po-Sung, Ugamura, Aya, Mikami, Yohei, Teratani, Toshiaki, Tsujikawa, Hanako, Shiba, Shunsuke, Taniki, Nobuhito, Sujino, Tomohisa, Miyamoto, Kentaro, Suzuki, Takahiro, Yamaguchi, Akihiro, Morikawa, Rei, Sato, Katsuaki, Sakamoto, Michiie, Yoshimoto, Takayuki, Kanai, Takanori
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2019
• Subjects: Adolescent; Adult; Aged; Animals; Apoptosis; Autoimmune diseases; Biomedical research; CD25 antigen; CD4 antigen; Cytokines; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; Disease; Female; Hepatitis; Humans; Inflammation; Interleukin 1; Interleukin-12 Subunit p35 - genetics; Interleukin-12 Subunit p35 - immunology; Interleukins - genetics; Interleukins - immunology; Liver; Liver diseases; Liver Failure, Acute - genetics; Liver Failure, Acute - immunology; Liver Failure, Acute - pathology; Liver Failure, Acute - prevention & control; Liver transplantation; Lymphocytes; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Mice; Mice, Knockout; Middle Aged; Minor Histocompatibility Antigens - genetics; Minor Histocompatibility Antigens - immunology; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; Pathogenesis; Receptors, Cytokine - genetics; Receptors, Cytokine - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; TLR7 protein; TLR9 protein; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - immunology; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Toll-like receptors; Viral infections; Hepatitis; Dendritic cells; Hepatology; Immunotherapy
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci125863

Acute liver failure (ALF) is a life-threatening condition, and liver transplantation is the only therapeutic option. Although immune dysregulation is central to its pathogenesis, the precise mechanism remains unclear. Here, we show that the number of peripheral and hepatic plasmacytoid DCs (pDCs) decrease during acute liver injury in both humans and mice. Selective depletion of pDCs in Siglechdtr/+ mice exacerbated concanavalin A-induced acute liver injury. In contrast, adoptively transferred BM-derived pDCs preferentially accumulated in the inflamed liver and protected against liver injury. This protective effect was independent of TLR7 and TLR9 signaling, since a similar effect occurred following transfer of MyD88-deficient pDCs. Alternatively, we found an unexpected immunosuppressive role of pDCs in an IL-35-dependent manner. Both Il12a and Ebi3, heterodimeric components of IL-35, were highly expressed in transferred pDCs and CD4+CD25+ Tregs. However, the protective effect of pDC transfer was completely lost in mice depleted of Tregs by anti-CD25 antibody. Moreover, pDCs derived from IL-35-deficient mice had less of a protective effect both in vivo and in vitro even in the presence of Tregs. These results highlight a unique aspect of pDCs in association with Tregs, serving as a guide for immunotherapeutic options in ALF.