Reduced expression of the mevalonate pathway enzyme farnesyl pyrophosphate synthase unveils recognition of tumor cells by Vgamma9Vdelta2 T cells.
Human Vgamma9Vdelta2 T cells are characterized by a unique specificity for certain tumors (e.g., Daudi), cells presenting so-called phosphoantigens such as isopentenyl pyrophosphate (IPP), or cells treated with aminobisphosphonates. We now report conversion of hematopoietic and nonhematopoietic tumor cell lines into Vgamma9Vdelta2 T cell activators by means of short hairpin RNA-mediated knockdown of expression of the IPP-consuming enzyme, farnesyl pyrophosphate synthase (FPPS). FPPS knockdown cells activated Vgamma9Vdelta2 T cells, as measured by increased levels of CD69 and CD107a, killing of FPPS knockdown cells, and induction of IFN-gamma secretion. The IPP-synthesis-inhibiting drug mevastatin reduced Vgamma9Vdelta2 T cell activation by FPPS knockdown cells but not activation by the phosphoantigen bromohydrin pyrophosphate. In conclusion, our data support the concept of Vgamma9Vdelta2 T cells as sensors of a dysregulated isoprenoid metabolism and suggest therapeutic down-modulation of FPPS expression as an additional tool to target tumor cells to Vgamma9Vdelta2 T cell-mediated immunosurveillance.
Li
Jianqiang
J
Institut für Virologie und Immunbiologie, Julius-Maximilians Universität Würzburg, Würzburg, Germany.
Herold
Marco J
MJ
Kimmel
Brigitte
B
Müller
Ingrid
I
Rincon-Orozco
Bladimiro
B
Kunzmann
Volker
V
Herrmann
Thomas
T
D002460:Cell Line; D004122:Dimethylallyltranstransferase / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006410:Hematopoiesis; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008798:Mevalonic Acid / Q000494:pharmacology*; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*
D016692:Receptors, Antigen, T-Cell, gamma-delta; D004122:Dimethylallyltranstransferase; D008798:Mevalonic Acid