Cytotoxic T-lymphocytes recognizing P-glycoprotein in murine multidrug-resistant leukemias.
A multidrug-resistant murine lymphoid leukemia P388/ADR overexpresses P-glycoprotein (P-gp), an active transporter that pumps cytotoxic drugs out of cells and a product of mdr1 gene. Cytotoxic T lymphocytes (CTL) that showed cytotoxicity against P388/ADR were generated from mixed lymphocyte tumor cell culture. CTL do not kill drugsensitive parental P388 (P388/parent) that does not express P-gp. Monoclonal antibody against P-gp inhibited cytotoxic activity. Similar results were obtained in another multidrug-resistant cell line P388/VP-16. Cytotoxic activity was mediated by Thy1+ CD4- CD8+ T-cells. When P388/ADR was treated with murine IL-4, expression of P-gp was downregulated. Monoclonal antibody against interleukin-4 (IL-4) abrogated the IL-4-induced suppression of P-gp. Cytolytic activity of CTL against IL-4-treated P388/ADR was dose dependently inhibited. These results suggest that P-gp is immunogenic and can be a target of CTL in this murine leukemia model.
Azuma
E
E
Department of Pediatrics and Clinical Immunology, Mie University School of Medicine, Japan.
Masuda
S
S
Qi
J
J
Kumamoto
T
T
Hirayama
M
M
Nagai
M
M
Hiratake
S
S
Umemoto
M
M
Komada
Y
Y
Sakurai
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D003602:Cytotoxicity, Immunologic; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D007111:Immunity, Cellular; D015847:Interleukin-4 / Q000494:pharmacology; D007942:Leukemia, Experimental / Q000276:immunology*; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015847:Interleukin-4