Drug-Induced Expansion and Differentiation of Vg9Vd2 T Cells In Vivo: The Role of Exogenous IL-21

Human V?9V?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?9V?2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of V?9V?2 T cell activities may be clinically beneficial. The functional characteristics of V?9V?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 × 105 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 ?? (but not ??) T cells expressed the CD69 activation marker, indicating that V?9V?2 T lymphocytes are more responsive to low-dose IL-2 than ?? T cells. Up to 100-fold increases in the numbers of peripheral blood V?9V?2 T cells were observed in animals receiving the ?? stimulatory drug plus IL-2. Moreover, the expanded V?9V?2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-?. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.