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9V
2 T Cell Stimulation by a Natural Adenylated Phosphoantigen1
* Département Lipoprotéines et Médiateurs Lipidiques and
Immunologie et Pathologies Infectieuses, INSERM, Unité 563, Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul Sabatier, Toulouse, France;
Institut Claude de Préval (IFR150), Technical Platform Interactions et Profils d'Expression Protéiques, Toulouse, France; and
Unité Mixte de Recherche 5247-Centre National de la Recherche Scientifique- Université Montpellier 1-Université Montpellier 2, Equipe Nucléosides et Effecteurs Phosphorylés, Montpellier, France
Human V
9V
2 T lymphocytes recognize phosphorylated alkyl Ags. Isopentenyl pyrophosphate (IPP) was previously proposed as the main Ag responsible for V9V2 T cell activation by cancer cells. However, triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), a metabolite in which the isopentenyl moiety is linked to ATP, was reported in cells activated with aminobisphosphonates. The contribution of this compound to tumor-stimulatory activity was thus examined. ApppI induces selective expansion of V9V2 T cells from PBMCs. In the absence of APCs, however, ApppI has little stimulatory activity on V9V2 T cells, and optimal activation with ApppI requires addition of a nucleotide pyrophosphatase releasing IPP plus AMP. Thus, ApppI has no intrinsic stimulatory activity. Nevertheless, stimulation by ApppI is strengthened by the presence of APCs. Moreover, in contrast to IPP, ApppI can be efficiently pulsed on dendritic cells as well as on nonprofessional APCs. Pulsed APCs display stable and phosphatase-resistant stimulatory activity, indicative of Ag modification. HPLC analysis of tumor cell extracts indicates that latent phosphoantigenic activity is stored intracellularly in the V9V2 cell-sensitive tumor Daudi and can be activated by a nucleotide pyrophosphatase activity. The presence of ApppI in Daudi cell extracts was demonstrated by mass spectrometry. Nucleotidic Ags such as ApppI are thus a storage form of phosphoantigen which may represent a major source of phosphoantigenic activity in tumor cells. The unique properties of ApppI may be important for the design of Ags used in anticancer immunotherapeutic protocols using V9V2 cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the French Association pour la Recherche sur le Cancer (to P.V. and Contract 3711-3913-4847) and by Ligue Nationale Contre le Cancer (Contract R07002BBA). L.M. and J.M.B. are supported by INSERM (Avenir) and Fondation pour la Recherche Médicale, respectively.
2 P.V. and J.M.-B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Eric Champagne, Departement Lipoprotéines et Médiateurs Lipidiques, INSERM Unité 563, Centre Hospitalier de Toulouse Purpan, Boîte Postale 3028, F-31024, Toulouse, France. E-mail address: Eric.Champagne{at}inserm.fr
4 Abbreviations used in this paper: HDMAPP, hydroxyldimethylallyl pyrophosphate; ApppI, triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester; IPP, isopentenyl pyrophosphate; NPP, nucleotide pyrophosphatase; DC, dendritic cell; iDC, immature DC; mDC, mature DC; PPADS, pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid.
5 The online version of this article contains supplemental material.
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