title: CD40 ligation converts TGF-beta-secreting tolerogenic CD4-8- dendritic cells into IL-12-secreting immunogenic ones.
abstract: CD40L, the ligand for CD40 on dendritic cells (DCs), plays an important role in maturation and activation of DCs leading to induction of immune responses. Our previous studies showed that the mouse splenic CD4(-)8(-) DCs are tolerogenic and capable of stimulating suppressive type 1 CD4(+) regulatory T (Tr1) cell responses via TGF-beta secretion. In this study, we investigated whether CD40 ligation is able to convert tolerogenic CD4(-)8(-) DCs into immunogenic ones by in vitro treatment of DCs with anti-CD40 antibody. Our data showed that in vitro CD40 ligation with anti-CD40 antibody converted TGF-beta-secreting tolerogenic CD4(-)8(-) DCs into IL-12-secreting immunogenic ones capable of stimulating type 1 CD4(+) helper T (Th1) and CD8(+) cytotoxic T lymphocyte (CTL) responses leading to induction of antitumor immunity. In addition, in vivo CD40 ligation by intratumoral injection of adenoviral vector AdVCD40L expressing CD40 ligand also induced tumor growth inhibition and regression of established P815 tumors with infiltration of tolerogenic CD4(-)8(-) DCs. Therefore, our data provide new information for and may thus have useful impacts in CD40 ligation-based immunotherapy of cancer.
authors.affiliation: Cancer Research Unit, Saskatchewan Cancer Agency and Departments of Oncology and Immunology, Pathology, University of Saskatchewan, 20 Campus Drive, Saskatoon, Saskatchewan S7N 0W0, Canada.
authors.forename: Xueshu
authors.initials: X
authors.lastname: Zhang
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kedl
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000276:immunology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance; D018664:Interleukin-12 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D015704:CD4 Antigens; D019013:CD40 Antigens; D016827:CD8 Antigens; D016212:Transforming Growth Factor beta; D023201:CD40 Ligand; D018664:Interleukin-12