Neutralization of transforming growth factor beta 1 augments hepatitis C virus-specific cytotoxic T lymphocyte induction in vitro.
In hepatitis C virus (HCV) infection, TGF-beta 1 is upregulated in the liver and may be involved in the pathogenesis of chronic liver disease. TGF-beta 1 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-beta 1 in HCV-specific cytotoxic T lymphocyte (CTL) induction and enhance their killer activity by TGF-beta 1 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-beta 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-beta 1 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-beta 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-beta 1 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-beta 1 mRNA expression in T cells and its production. These results demonstrated that endogenous TGF-beta 1 is an autocrine suppressor in CTL induction in vitro. Therefore, the blockade of endogenous TGF-beta 1 could enhance the killing potential of anti-HCV CTL.
Kanto
T
T
First Department of Medicine, Osaka University Medical School, Suita, Japan.
Takehara
T
T
Katayama
K
K
Ito
A
A
Mochizuki
K
K
Kuzushita
N
N
Tatsumi
T
T
Sasaki
Y
Y
Kasahara
A
A
Hayashi
N
N
Hori
M
M
D000328:Adult; D000917:Antibody Formation; D000918:Antibody Specificity; D004305:Dose-Response Relationship, Drug; D005260:Female; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000097:blood / Q000276:immunology / Q000473:pathology; D018937:Hepatitis C Antibodies / Q000187:drug effects / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology*
D018937:Hepatitis C Antibodies; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10