Reduced expression of the mevalonate pathway enzyme farnesyl pyrophosphate synthase unveils recognition of tumor cells by Vgamma9Vdelta2 T cells

J Immunol. 2009 Jun 15;182(12):8118-24. doi: 10.4049/jimmunol.0900101.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dimethylallyltranstransferase / genetics
  • Dimethylallyltranstransferase / metabolism*
  • Gene Expression Regulation
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Hematopoiesis
  • Humans
  • Lymphocyte Activation / immunology
  • Mevalonic Acid / pharmacology*
  • Neoplasms / enzymology*
  • Neoplasms / immunology*
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*

Substances

  • Receptors, Antigen, T-Cell, gamma-delta
  • Dimethylallyltranstransferase
  • Mevalonic Acid