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Natural killer cells regulate T cell immune responses in primary biliary cirrhosis
Author(s) -
Shimoda Shinji,
Hisamoto Satomi,
Harada Kenichi,
Iwasaka Sho,
Chong Yong,
Nakamura Minoru,
Bekki Yuki,
Yoshizumi Tomoharu,
Shirabe Ken,
Ikegami Toru,
Maehara Yoshihiko,
He XiaoSong,
Gershwin M. Eric,
Akashi Koichi
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28122
Subject(s) - cytotoxic t cell , biology , immunology , interleukin 21 , natural killer t cell , interleukin 12 , innate immune system , primary biliary cirrhosis , immune system , major histocompatibility complex , acquired immune system , mhc class i , t cell , antigen presenting cell , microbiology and biotechnology , in vitro , biochemistry
The hallmark of primary biliary cirrhosis (PBC) is the presence of autoreactive T‐ and B‐cell responses that target biliary epithelial cells (BECs). Biliary cell cytotoxicity is dependent upon initiation of innate immune responses followed by chronic adaptive, as well as bystander, mechanisms. Critical to these mechanisms are interactions between natural killer (NK) cells and BECs. We have taken advantage of the ability to isolate relatively pure viable preparations of liver‐derived NK cells, BECs, and endothelial cells, and studied interactions between NK cells and BECs and focused on the mechanisms that activate autoreactive T cells, their dependence on interferon (IFN)‐γ, and expression of BEC major histocompatibility complex (MHC) class I and II molecules. Here we show that at a high NK/BEC ratio, NK cells are cytotoxic for autologous BECs, but are not dependent on autoantigen, yet still activate autoreactive CD4 + T cells in the presence of antigen presenting cells. In contrast, at a low NK/BEC ratio, BECs are not lysed, but IFN‐γ production is induced, which facilitates expression of MHC class I and II molecules on BEC and protects them from lysis upon subsequent exposure to autoreactive NK cells. Furthermore, IFN‐γ secreted from NK cells after exposure to autologous BECs is essential for this protective function and enables autoreactive CD4 + T cells to become cytopathic. Conclusions : NK cell‐mediated innate immune responses are likely critical at the initial stage of PBC, but also facilitate and maintain the chronic cytopathic effect of autoantigen‐specific T cells, essential for progression of disease. (H epatology 2015;62:1817‐1827)