Drug-induced expansion and differentiation of V gamma 9V delta 2 T cells in vivo: The role of exogenous IL-2

Human V gamma 9V delta 2 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 V gamma 9V delta 2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations. of V gamma 9V delta 2 T cell activities may be clinically beneficial. The functional characteristics of V gamma 9V delta 2 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 gamma delta (but not alpha beta) T cells expressed the CD69 activation marker, indicating that V gamma 9V delta 2 T lymphocytes are more responsive to low-dose IL-2 than aJ3 T cells. Up to 100-fold increases in the numbers of peripheral blood V gamma 9V delta 2 T cells were observed in animals receiving the gamma delta stimulatory drug plus IL-2. Moreover, the expanded V gamma 9V delta 2 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.