Journal article
Indirect stimulation of human Vγ2Vδ2 T cells through alterations in isoprenoid metabolism
The Journal of immunology (1950), Vol.187(10), pp.5099-5113
11/15/2011
DOI: 10.4049/jimmunol.1002697
PMCID: PMC3326638
PMID: 22013129
Abstract
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.
Details
- Title: Subtitle
- Indirect stimulation of human Vγ2Vδ2 T cells through alterations in isoprenoid metabolism
- Creators
- Hong Wang - 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, USAGhanashyam SarikondaKia-Joo PuanYoshimasa TanakaJu FengJosé-Luis GinerRong CaoJukka MönkkönenEric OldfieldCraig T Morita
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.187(10), pp.5099-5113
- DOI
- 10.4049/jimmunol.1002697
- PMID
- 22013129
- PMCID
- PMC3326638
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Grant note
- R01 AR045504-10 / NIAMS NIH HHS AR045504 / NIAMS NIH HHS R01 CA113874-03 / NCI NIH HHS R01 CA113874-01 / NCI NIH HHS R01 AR045504-07 / NIAMS NIH HHS R01 CA113874 / NCI NIH HHS R01 AR045504 / NIAMS NIH HHS R01 AR045504-09 / NIAMS NIH HHS R01 AR045504-11 / NIAMS NIH HHS CA113874 / NCI NIH HHS R03 AR045095-04 / NIAMS NIH HHS R01 CA113874-04 / NCI NIH HHS I01 BX000972 / BLRD VA R01 CA113874-02 / NCI NIH HHS AI074233 / NIAID NIH HHS R01 AI074233 / NIAID NIH HHS R01 AR045504-08 / NIAMS NIH HHS
- Language
- English
- Date published
- 11/15/2011
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984094563402771
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