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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(s) -
Homma Sadamu,
Komita Hideo,
Sagawa Yukiko,
Ohno Tsuneya,
Toda Gotaro
Publication year - 2005
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2005.02179.x
Subject(s) - cytotoxic t cell , interleukin 12 , cd8 , biology , interleukin 21 , microbiology and biotechnology , major histocompatibility complex , natural killer t cell , cd40 , mhc class i , dendritic cell , cd1 , antigen presenting cell , mhc class ii , perforin , antigen , immunology , in vitro , biochemistry
Summary 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)‐γ. 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‐γ 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.