title: Immunosuppressive effects of radiation on human dendritic cells: reduced IL-12 production on activation and impairment of naive T-cell priming.
abstract: Dendritic cells (DC) are professional antigen-presenting cells (APC) of the immune system, uniquely able to prime naive T-cell responses. They are the focus of a range of novel strategies for the immunotherapy of cancer, a proportion of which include treating DC with ionising radiation to high dose. The effects of radiation on DC have not, however, been fully characterised. We therefore cultured human myeloid DC from CD14+ precursors, and studied the effects of ionising radiation on their phenotype and function. Dendritic cells were remarkably resistant against radiation-induced apoptosis, showed limited changes in surface phenotype, and mostly maintained their endocytic, phagocytic and migratory capacity. However, irradiated DC were less effective in a mixed lymphocyte reaction, and on maturation produced significantly less IL-12 than unirradiated controls, while IL-10 secretion was maintained. Furthermore, peptide-pulsed irradiated mature DC were less effective at naive T-cell priming, stimulating fewer effector cells with lower cytotoxicity against antigen-specific targets. Hence irradiation of DC in vitro, and potentially in vivo, has a significant impact on their function, and may shift the balance between T-cell activation and tolerization in DC-mediated immune responses.
authors.affiliation: Cancer Research UK Clinical Center, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: A
authors.initials: A
authors.lastname: Merrick
authors.forename: F
authors.initials: F
authors.lastname: Errington
authors.forename: K
authors.initials: K
authors.lastname: Milward
authors.forename: D
authors.initials: D
authors.lastname: O'Donnell
authors.forename: K
authors.initials: K
authors.lastname: Harrington
authors.forename: A
authors.initials: A
authors.lastname: Bateman
authors.forename: H
authors.initials: H
authors.lastname: Pandha
authors.forename: R
authors.initials: R
authors.lastname: Vile
authors.forename: E
authors.initials: E
authors.lastname: Morrison
authors.forename: P
authors.initials: P
authors.lastname: Selby
authors.forename: A
authors.initials: A
authors.lastname: Melcher
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000528:radiation effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000528:radiation effects*; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D016753:Interleukin-10; D018664:Interleukin-12