Indirect Stimulation of Human V 2V 2 T Cells through Alterations in Isoprenoid Metabolism

Division of Immunology, Department of Internal Medicine, Interdisciplinary Graduate Program in Immunology, University of Iowa Carver College of Medicine, Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2011; 187(10):5099-113. DOI: 10.4049/jimmunol.1002697
Source: PubMed


Human Vγ2Vδ2 T cells monitor isoprenoid metabolism by recognizing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate in the 2-C-methyl-d-erythritol-4-phosphate pathway used by microbes, and isopentenyl pyrophosphate (IPP), an intermediate in the mevalonate pathway used by humans. Aminobisphosphonates and alkylamines indirectly stimulate Vγ2Vδ2 cells by inhibiting farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, thereby increasing IPP/triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester that directly stimulate. In this study, we further characterize stimulation by these compounds and define pathways used by new classes of compounds. Consistent with FDPS inhibition, stimulation of Vγ2Vδ2 cells by aminobisphosphonates and alkylamines was much more sensitive to statin inhibition than stimulation by prenyl pyrophosphates; however, the continuous presence of aminobisphosphonates was toxic for T cells and blocked their proliferation. Aminobisphosphonate stimulation was rapid and prolonged, independent of known Ag-presenting molecules, and resistant to fixation. New classes of stimulatory compounds-mevalonate, the alcohol of HMBPP, and alkenyl phosphonates-likely stimulate differently. Mevalonate, a rate-limiting metabolite, appears to enter cells to increase IPP levels, whereas the alcohol of HMBPP and alkenyl phosphonates are directly recognized. The critical chemical feature of bisphosphonates is the amino moiety, because its loss switched aminobisphosphonates to direct Ags. Transfection of APCs with small interfering RNA downregulating FDPS rendered them stimulatory for Vγ2Vδ2 cells and increased cellular IPP. Small interfering RNAs for isopentenyl diphosphate isomerase functioned similarly. Our results show that a variety of manipulations affecting isoprenoid metabolism lead to stimulation of Vγ2Vδ2 T cells and that pulsing aminobisphosphonates would be more effective for the ex vivo expansion of Vγ2Vδ2 T cells for adoptive cancer immunotherapy.

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Available from: Jukka Mönkkönen
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    • "IPP is also a natural antigen that directly stimulates γδ T cells caring the Vγ2Vδ2 T cell receptors and is strongly implicated in the human innate immune response against tumors (Morita et al., 2007). Short hairpin RNA-mediated knockdown of hFPPS in hematopoietic and non-hematopoietic tumor cell lines has been shown to activate Vγ2Vδ2 T cells and induce IFN-γ secretion (Figure 1) (Li et al., 2009; Wang et al., 2011). Immunostimulation and increased Vγ9Vδ2 T cell-mediated cytotoxicity has been observed in animal models of human breast cancer after treatment with N-BPs, suggesting an adjuvant role for N-BPs in cancer chemotherapy (Benzaïd et al., 2012). "
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