{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T01:09:44Z","timestamp":1791421784115,"version":"4.3.3"},"reference-count":82,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2011,11,1]],"date-time":"2011-11-01T00:00:00Z","timestamp":1320105600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human V\u03b32V\u03b42 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 V\u03b32V\u03b42 cells by inhibiting farnesyl diphosphate synthase (FDPS) in the mevalonate pathway, thereby increasing IPP\/triphosphoric acid 1-adenosin-5\u2032-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 V\u03b32V\u03b42 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\u2014mevalonate, the alcohol of HMBPP, and alkenyl phosphonates\u2014likely 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 V\u03b32V\u03b42 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 V\u03b32V\u03b42 T cells and that pulsing aminobisphosphonates would be more effective for the ex vivo expansion of V\u03b32V\u03b42 T cells for adoptive cancer immunotherapy.<\/jats:p>","DOI":"10.4049\/jimmunol.1002697","type":"journal-article","created":{"date-parts":[[2011,10,20]],"date-time":"2011-10-20T00:49:41Z","timestamp":1319071781000},"page":"5099-5113","source":"Crossref","is-referenced-by-count":86,"title":["Indirect Stimulation of Human V\u03b32V\u03b42 T Cells through Alterations in Isoprenoid Metabolism"],"prefix":"10.1093","volume":"187","author":[{"given":"Hong","family":"Wang","sequence":"first","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghanashyam","family":"Sarikonda","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kia-Joo","family":"Puan","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimasa","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Center for Innovation in Immunoregulative Technology and Therapeutics, Graduate School of Medicine, Kyoto University , Sakyo, Kyoto 606-8501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ju","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Chemistry, State University of New York College of Environmental Science and Forestry , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9-Luis","family":"Giner","sequence":"additional","affiliation":[{"name":"Department of Chemistry, State University of New York College of Environmental Science and Forestry , Syracuse, NY 13210"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Illinois at Urbana\u2013Champaign , Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"M\u00f6nkk\u00f6nen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland , Kuopio 70211 ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Oldfield","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Illinois at Urbana\u2013Champaign , Urbana, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig T","family":"Morita","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,11,15]]},"reference":[{"key":"2025032410463416600_r1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/j.1600-065X.2006.00479.x","article-title":"Nonpeptide antigens, presentation mechanisms, and immunological memory of human V\u03b32V\u03b42 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens","volume":"215","author":"Morita","year":"2007","journal-title":"Immunol. 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