title: NKG2D regulates production of soluble TRAIL by ex vivo expanded human γδ T cells.
abstract: Soluble TRAIL (sTRAIL) can be produced by myeloid-derived cells to kill cancer cells. Whether this mechanism is used by T cells, and if so, how sTRAIL production is regulated, remains unclear. Our previous studies showed that ex vivo expanded human γδ T cells express TRAIL and NK receptor group 2 (R2), member D (NKG2D), and possess potent anticancer activities both in vitro and in vivo. Here, we investigated in greater detail the mechanisms by which γδ T cells utilize TRAIL and NKG2D to kill lung cancer cells. We demonstrate that human lung cancer cells express TRAIL R2 and NKG2D ligands. Blocking TRAIL or NKG2D during γδ T-cell-lung cancer cell co-cultures significantly reduced γδ T-cell-mediated cytotoxicity. Cross-linking NKG2D with anti-NKG2D antibody to mimic ligand binding promoted γδ T cells to produce sTRAIL, which induced apoptosis in lung cancer cells through TRAIL R2. Either neutralizing sTRAIL or blocking lung cancer cell TRAIL R2 significantly reduced γδ T-cell-mediated cytotoxicity to lung cancer cells. This study demonstrates that γδ T cells can mediate anticancer immunity via NKG2D-regulated production of sTRAIL.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada.
authors.forename: Pouneh
authors.initials: P
authors.lastname: Dokouhaki
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Schuh
authors.forename: Betty
authors.initials: B
authors.lastname: Joe
authors.forename: Christopher A D
authors.initials: CA
authors.lastname: Allen
authors.forename: Sandy D
authors.initials: SD
authors.lastname: Der
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007152:Immunologic Capping / Q000187:drug effects; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
chemical_list: D000906:Antibodies; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human
keywords: Lung cancer; NKG2D; TRAIL; Tumor immunology; γδ T cells