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Neutralization of Transforming Growth Factor β1 Augments Hepatitis C Virus-Specific Cytotoxic T Lymphocyte Induction in Vitro

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Abstract

In hepatitis C virus (HCV) infection, TGF-β1 is upregulated in the liver and may be involved in the pathogenesis of chronic liver disease. TGF-β1 is also produced by activated T cells and acts as a potent immunosuppressor. The aim of this study was to investigate the roles of TGF-β1 in HCV-specific cytotoxic T lymphocyte (CTL) induction and enhance their killer activity by TGF-β1 modulation. We generated anti-HCV CTL from peripheral blood mononuclear cells from HLA-A2 patients under stimulation with the HCV-core peptide having the HLA-A2.1 binding motif. The lytic activities of CTL or precursor frequency (CTLpf) generated with or without anti-TGF-p antibody were compared. To optimize the IL-2 dose for CTL induction, low (50 U/ml) and high (500 U/ml) doses were tested and the lytic activities were compared. TGF-β1 amounts in the supernatants were assessed by enzyme-linked immunosorbent assay and by their growth inhibitory effect on mink lung epithelial cells. CTL activity was enhanced by anti-TGF-β antibody in a dose-dependent manner but CTLpf did not significantly change. A high dose of IL-2 reduced the activity to 45% of that observed with a low dose, whereas TGF-β1 increased as the dose of IL-2 increased. Exogenous IL-10 reversed the inhibitory effect of a high dose of IL-2 on the killing activity by reducing TGF-β1 mRNA expression in T cells and its production. These results demonstrated that endogenous TGF-β1 is an autocrine suppressor in CTL induction in vitro. Therefore, the blockade of endogenous TGF-β1 could enhance the killing potential of anti-HCV CTL.

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Authors and Affiliations

  1. First Department of Medicine, Osaka University Medical School, 2-2 Yamada-oka, Suita, 565, Japan

    Tatsuya Kanto, Tetsuo Takehara, Kazuhiro Katayama, Akihiko Ito, Kiyoshi Mochizuki, Noriyoshi Kuzushita, Tomohide Tatsumi, Yutaka Sasaki, Akinori Kasahara, Norio Hayashi & Masatsugu Hori

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  1. Tatsuya Kanto
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  2. Tetsuo Takehara
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  3. Kazuhiro Katayama
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  4. Akihiko Ito
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  5. Kiyoshi Mochizuki
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  6. Noriyoshi Kuzushita
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  7. Tomohide Tatsumi
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  11. Masatsugu Hori
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Kanto, T., Takehara, T., Katayama, K. et al. Neutralization of Transforming Growth Factor β1 Augments Hepatitis C Virus-Specific Cytotoxic T Lymphocyte Induction in Vitro . J Clin Immunol 17, 462–471 (1997). https://doi.org/10.1023/A:1027367626317

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