Natural killer cells regulate T cell immune responses in primary biliary cirrhosis

Shinji Shimoda, Satomi Hisamoto, Kenichi Harada, Sho Iwasaka, Yong Chong, Minoru Nakamura, Yuki Bekki, Tomoharu Yoshizumi, Ken Shirabe, Toru Ikegami, Yoshihiko Maehara, Xiao Song He, M. Eric Gershwin, Koichi Akashi

研究成果: ジャーナルへの寄稿記事

31 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)1817-1827
ページ数11
ジャーナルHepatology
62
発行部数6
DOI
出版物ステータス出版済み - 12 1 2015

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Biliary Liver Cirrhosis
Natural Killer Cells
Epithelial Cells
T-Lymphocytes
Interferons
Autoantigens
Major Histocompatibility Complex
Innate Immunity
Antigen-Presenting Cells
Cell Communication
Disease Progression
B-Lymphocytes
Endothelial Cells

All Science Journal Classification (ASJC) codes

  • Hepatology

これを引用

Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. / Shimoda, Shinji; Hisamoto, Satomi; Harada, Kenichi; Iwasaka, Sho; Chong, Yong; Nakamura, Minoru; Bekki, Yuki; Yoshizumi, Tomoharu; Shirabe, Ken; Ikegami, Toru; Maehara, Yoshihiko; He, Xiao Song; Gershwin, M. Eric; Akashi, Koichi.

:: Hepatology, 巻 62, 番号 6, 01.12.2015, p. 1817-1827.

研究成果: ジャーナルへの寄稿記事

Shimoda, S, Hisamoto, S, Harada, K, Iwasaka, S, Chong, Y, Nakamura, M, Bekki, Y, Yoshizumi, T, Shirabe, K, Ikegami, T, Maehara, Y, He, XS, Gershwin, ME & Akashi, K 2015, 'Natural killer cells regulate T cell immune responses in primary biliary cirrhosis', Hepatology, 巻. 62, 番号 6, pp. 1817-1827. https://doi.org/10.1002/hep.28122
Shimoda, Shinji ; Hisamoto, Satomi ; Harada, Kenichi ; Iwasaka, Sho ; Chong, Yong ; Nakamura, Minoru ; Bekki, Yuki ; Yoshizumi, Tomoharu ; Shirabe, Ken ; Ikegami, Toru ; Maehara, Yoshihiko ; He, Xiao Song ; Gershwin, M. Eric ; Akashi, Koichi. / Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. :: Hepatology. 2015 ; 巻 62, 番号 6. pp. 1817-1827.
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abstract = "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.",
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AU - Shimoda, Shinji

AU - Hisamoto, Satomi

AU - Harada, Kenichi

AU - Iwasaka, Sho

AU - Chong, Yong

AU - Nakamura, Minoru

AU - Bekki, Yuki

AU - Yoshizumi, Tomoharu

AU - Shirabe, Ken

AU - Ikegami, Toru

AU - Maehara, Yoshihiko

AU - He, Xiao Song

AU - Gershwin, M. Eric

AU - Akashi, Koichi

PY - 2015/12/1

Y1 - 2015/12/1

N2 - 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.

AB - 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.

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