Drug-Induced Expansion and Differentiation of Vγ9Vδ2 T Cells In Vivo: The Role of Exogenous IL-2

Abstract

Human Vγ9Vδ2 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 Vγ9Vδ2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vγ9Vδ2 T cell activities may be clinically beneficial. The functional characteristics of Vγ9Vδ2 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 γδ (but not αβ) T cells expressed the CD69 activation marker, indicating that Vγ9Vδ2 T lymphocytes are more responsive to low-dose IL-2 than αβ T cells. Up to 100-fold increases in the numbers of peripheral blood Vγ9Vδ2 T cells were observed in animals receiving the γδ stimulatory drug plus IL-2. Moreover, the expanded Vγ9Vδ2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-γ. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.

Antigen-specific Vγ2Vδ2 T effector cells confer homeostatic protection against pneumonic plaque lesions

“…We have recently demonstrated that HMBPP is associated with antigen-presenting cells and specifically recognized by V␥2V␦2 T cell receptor (TCR) (14). We have also shown that single-dose HMBPP treatment plus IL-2 can induce remarkable expansion of V␥2V␦2 T cells in the blood and prolonged accumulation of V␥2V␦2 T cells in lungs in nonhuman primates (15)(16)(17). V␥2V␦2 T cells accumulating in lungs can re-recognize HMBPP and mount effector function of production of antimicrobial cytokines, IFN-␥, and perforin/granzyme B (17,18).…”

Select Plant Tannins Induce IL-2Rα Up-Regulation and Augment Cell Division in γδ T Cells

“…A concern with the prophylactic use of any immunomodulatory compound is the induction of chronic inflammation. Current phosphoantigen-based drugs lead to overt cytokine release in humans (64,65) including the proinflammatory cytokines TNF-␣ and IFN-␥, which would contribute to systemic inflammation in the patient. In a concurrent study, we found that the tannin preparation we tested up-regulated CD11b on ␥␦ T cells, but importantly, did not alter transcript levels for TNF-␣.…”

Phosphoantigens Overcome Human TCRVγ9+ γδ Cell Immunosuppression by TGF-β: Relevance for Cancer Immunotherapy

“…1B, 1C). Furthermore, increasing dose of PAg also augments the rate of proliferating TCRVg9 + gd cells (13,20,21,49) and increasing concentrations of BrHPP rescued the proliferating gd cells from TGF-b inhibition (Fig. 1D, 1E).…”

“…TCRVg9 + gd lymphocytes usually represent ∼1% of the circulating mononuclear cells, so their expansion is critically required to bring a significant contribution to cancer immunotherapies. By underlining the negative incidence of TGF-b may have on therapeutic protocols involving in vivo gd cell expansions, this study also provides a rationale for gd cell-based protocols composed of either in vitro expansions (49) or in vivo activation by high-dose PAg supplemented with exogenous IL-2 (12,20,21,25,66,67). In addition, the proliferative response of PAg/IL-2-stimulated gd lymphocytes is essentiallyif not exclusively-mediated by cells from the N and CM compartments of TCRVg9 + lymphocytes (4,8), suggesting that TGF-b might target more selectively these maturation stages.…”

“…These drugs have led several groups to demonstrate antitumor functions of human gd T lymphocytes in different in vivo contexts. Studies in nonhuman primates (20,21) and in cancer patients (7,(22)(23)(24)(25)(26)(27) have illustrated the potential of activated TCRVg9 + T lymphocytes against leukemia, lymphoma, and carcinoma (reviewed in Refs. [28][29][30][31].…”