Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: the role of exogenous IL-2.
Human Vgamma9Vdelta2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vgamma9Vdelta2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vgamma9Vdelta2 T cell activities may be clinically beneficial. The functional characteristics of Vgamma9Vdelta2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 x 10(5) U/animal) IL-2 induces a large pool of CD27+ and CD27- effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only gammadelta (but not alphabeta) T cells expressed the CD69 activation marker, indicating that Vgamma9Vdelta2 T lymphocytes are more responsive to low-dose IL-2 than alphabeta T cells. Up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells were observed in animals receiving the gammadelta stimulatory drug plus IL-2. Moreover, the expanded Vgamma9Vdelta2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-gamma. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.
Casetti
Rita
R
National Institute for Infectious Diseases, Lazzaro Spallanzani, Istituto di Ricerca e Cura a Carattere Scientifico, Rome, Italy.
Perretta
Gemma
G
Taglioni
Alessandra
A
Mattei
Maurizio
M
Colizzi
Vittorio
V
Dieli
Francesco
F
D'Offizi
Gianpiero
G
Malkovsky
Miroslav
M
Poccia
Fabrizio
F
D019794:2,3-Diphosphoglycerate / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D016516:CD4-CD8 Ratio; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D011756:Diphosphates / Q000008:administration & dosage / Q000276:immunology; D004164:Diphosphonates / Q000008:administration & dosage / Q000276:immunology; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000276:immunology; D045782:Hemiterpenes / Q000008:administration & dosage / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000502:physiology*; D008252:Macaca fascicularis; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000276:immunology; D000077268:Pamidronate; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000941:Antigens; D011756:Diphosphates; D004164:Diphosphonates; D004852:Epoxy Compounds; D045782:Hemiterpenes; D007376:Interleukin-2; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C429553:bromohydrin pyrophosphate; D019794:2,3-Diphosphoglycerate; C077385:3-methyl-3,4-epoxybutyl diphosphate; C004809:isopentenyl pyrophosphate; D007371:Interferon-gamma; D000077268:Pamidronate