Specific requirements for Vgamma9Vdelta2 T cell stimulation by a natural adenylated phosphoantigen.
Human Vgamma9Vdelta2 T lymphocytes recognize phosphorylated alkyl Ags. Isopentenyl pyrophosphate (IPP) was previously proposed as the main Ag responsible for Vgamma9Vdelta2 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 Vgamma9Vdelta2 T cells from PBMCs. In the absence of APCs, however, ApppI has little stimulatory activity on Vgamma9Vdelta2 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 Vgamma9Vdelta2 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 Vgamma9Vdelta2 cells.
Vantourout
Pierre
P
Département Lipoprotéines et Médiateurs Lipidiques, INSERM, Unité 563, Centre de Physiopathologie de Toulouse Purpan, Université Toulouse III Paul Sabatier, Toulouse, France.
Mookerjee-Basu
Jayati
J
Rolland
Corinne
C
Pont
Frédéric
F
Martin
Hélène
H
Davrinche
Christian
C
Martinez
Laurent O
LO
Perret
Bertrand
B
Collet
Xavier
X
Périgaud
Christian
C
Peyrottes
Suzanne
S
Champagne
Eric
E
D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004164:Diphosphonates; D045782:Hemiterpenes / Q000276:immunology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology; D009943:Organophosphorus Compounds / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D004164:Diphosphonates; D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C543712:triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester; C004809:isopentenyl pyrophosphate; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate