IL-15-producing splenic B cells play pathogenic roles in the development of autoimmune hepatitis
Sota Fujimori,
Po-Sung Chu,
Toshiaki Teratani,
Yosuke Harada,
Takahiro Suzuki,
Takeru Amiya,
Nobuhito Taniki,
Ryosuke Kasuga,
Yohei Mikami,
Yuzo Koda,
Masataka Ichikawa,
Takaya Tabuchi,
Rei Morikawa,
Karin Yamataka,
Fumie Noguchi,
Hanako Tsujikawa,
Yutaka Kurebayashi,
Michiie Sakamoto,
Takanori Kanai,
Nobuhiro Nakamoto
Affiliations
Sota Fujimori
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
Po-Sung Chu
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Toshiaki Teratani
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Yosuke Harada
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Takahiro Suzuki
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Takeru Amiya
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
Nobuhito Taniki
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Ryosuke Kasuga
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Yohei Mikami
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Yuzo Koda
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan
Masataka Ichikawa
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Takaya Tabuchi
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Rei Morikawa
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Karin Yamataka
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Fumie Noguchi
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
Hanako Tsujikawa
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Yutaka Kurebayashi
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Michiie Sakamoto
Department of Pathology, Keio University School of Medicine, Tokyo, Japan
Takanori Kanai
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Japan Agency for Medical Research and Development, AMED, Tokyo, Japan; Corresponding authors. Address: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan.
Nobuhiro Nakamoto
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan; Corresponding authors. Address: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 1608582, Japan.
Background & Aims: B-cell depletion therapy with an anti-CD20 is an effective treatment strategy for patients with refractory autoimmune hepatitis (AIH). However, the mechanisms underlying B-cell action are unclear. Methods: Herein, we used the adeno-associated virus IL-12 model, in which hepatic IL-12 expression triggers liver injuries characteristic of AIH. We also analysed the clinical samples of patients with AIH. Results: B-cell depletion using anti-CD20 or splenectomy was found to improve liver functions and decrease the cytotoxic CD8+ T-cell (cytotoxic T lymphocyte [CTL]) count in the liver. This improvement was reversed by the adoptive transfer of splenic B cells derived from AAV IL-12-treated mice to splenectomised mice as it caused the hepatic CTL count to increase. RNA-sequencing analysis identified IL-15 as a key factor in pathogenic B cells, which promotes CTL expansion and subsequent migration to the liver via the CXCL9/CXCR3 axis. Indeed, IL-15 neutralisation ameliorated hepatitis by suppressing splenic and hepatic CTLs in vivo. The close distribution of B220+ B cells and CD8+ T cells in the spleen of AIH mice suggested mutual interactions. Mechanistically, IFNγ and CD40L/CD40 signalling were indispensable for the expression of IL-15 in B cells, and in vitro co-culture experiments revealed that splenic CD40L+CD8+ T cells promoted IL-15 production in B cells, which led to CTL expansion. In patients with AIH, high serum IL-15 concentration and IL-15+ B-cell counts, positively correlating with serum alanine aminotransferase levels, support translation and potential therapeutic targeting in human AIH. Conclusions: This investigation elucidated the roles of IL-15-producing splenic B cells that occur in concert with pathogenic CD8+ T cells during the development of AIH. Impact and Implications: IL-15-producing B cells were shown to exacerbate experimental AIH via cytotoxic T lymphocyte expansion. CD40L+CD8+ T cells promoted IL-15 expression in B cells, indicating the mutual interaction of both cells. High serum IL-15 concentrations, IL-15+ B-cell counts, and CD40L+IL-15Rα+CD8+ T-cell counts were confirmed in the blood of patients with AIH.
