Natural killer cells regulate T cell immune responses in primary biliary cirrhosis.
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.
Department of Medicine and Biosystemic Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Fukuoka, Japan.
Shinji
S
Shimoda
Department of Medicine and Biosystemic Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Fukuoka, Japan.
Satomi
S
Hisamoto
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Kenichi
K
Harada
Department of Medicine and Biosystemic Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Fukuoka, Japan.
Sho
S
Iwasaka
Department of Medicine and Biosystemic Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Fukuoka, Japan.
Yong
Y
Chong
Clinical Research Center in National Hospital Organization (NHO) Nagasaki Medical Center and Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan.
Minoru
M
Nakamura
Department of Surgery and Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan.
Yuki
Y
Bekki
Department of Surgery and Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan.
Tomoharu
T
Yoshizumi
Department of Surgery and Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan.
Ken
K
Shirabe
Department of Surgery and Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan.
Toru
T
Ikegami
Department of Surgery and Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Japan.
Yoshihiko
Y
Maehara
Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, CA.
Xiao-Song
XS
He
Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California at Davis, Davis, CA.
M Eric
ME
Gershwin
Department of Medicine and Biosystemic Science Graduate School of Medical Sciences, Kyushu University Fukuoka, Fukuoka, Japan.
Koichi
K
Akashi
D006801:Humans; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000502:physiology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*