1. Antitumour activity mediated by CD4+ cytotoxic T lymphocytes against MHC class II-negative mouse hepatocellular carcinoma induced by dendritic cell vaccine and interleukin-12
- Author
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Gotaro Toda, Hideo Komita, Tsuneya Ohno, Yukiko Sagawa, and Sadamu Homma
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,Pore Forming Cytotoxic Proteins ,Carcinoma, Hepatocellular ,Fas Ligand Protein ,Immunology ,CD1 ,Apoptosis ,CD8-Positive T-Lymphocytes ,Cancer Vaccines ,Mice ,Interleukin 21 ,Liver Neoplasms, Experimental ,Antigens, Neoplasm ,Cell Line, Tumor ,MHC class I ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,Antigen-presenting cell ,Mice, Inbred BALB C ,MHC class II ,Membrane Glycoproteins ,biology ,Perforin ,Histocompatibility Antigens Class II ,Dendritic Cells ,Original Articles ,Flow Cytometry ,Natural killer T cell ,Interleukin-12 ,Virology ,Molecular biology ,Killer Cells, Natural ,biology.protein ,Interleukin 12 ,Female ,Spleen - Abstract
When BALA/c mice with BNL hepatocellular carcinoma (HCC) were treated with dendritic cells fused with BNL cells (DC/BNL) and recombinant murine interleukin (IL)-12, tumour development was significantly suppressed, whereas treatment with either DC/BNL or IL-12 alone did not show a tumour-suppressive effect. Antitumour activity induced by DC/BNL + IL-12 was abrogated by depletion of CD4+ T cells, but not by depletion of CD8+ T cells or natural killer cells. Splenic CD4+ T cells and CD8+ T cells from DC/BNL-treated mice showed cytotoxic activity against BNL cells after 3 days of incubation with DC/BNL, although BNL cells do not express major histocompatibility complex (MHC) class II molecules even after treatment with interferon (INF)-gamma. Furthermore, CD4+ T cells killed syngeneic-irrelevant CT26 cells and even allogeneic Hepa1-6 cells. This cytotoxicity was blocked by concanamycin A, but not by an anti-Fas ligand (FasL) monoclonal antibody, indicating that cytotoxic activity was mediated by perforin. Immunofluorescence microscopy demonstrated that abundant CD4+ T cells and MHC class II-positive macrophages, but not CD8(+) T cells, had infiltrated tumour tissue in mice treated with DC/BNL + IL-12. Flow cytometric analysis of tumour-infiltrating cells in mice treated with DC/BNL + IL-12 showed increases in CD4+ T cells and MHC class II+ CD11b+ cells but not in CD8+ T cells or MHC class I+ CD11b+ cells. Our results suggest that, in BNL-bearing mice treated with DC/BNL + IL-12, tumour macrophages activated by INF-gamma produced by IL-12-stimulated T cells might present BNL tumour antigens and activate DC/BNL-primed CD4+ cytotoxic T lymphocytes (CTLs) in a MHC class II-dependent manner, leading to perforin-mediated bystander killing of neighbouring MHC class II-negative tumour cells.
- Published
- 2005