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

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.

• Authors: Jianqiang Li, Marco J Herold, Brigitte Kimmel, Ingrid Müller, Bladimiro Rincon-Orozco, Volker Kunzmann, Thomas Herrmann
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 12 Pg. 8118-24 (Jun 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19494338 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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