IL-21-mediated potentiation of antitumor cytolytic and proinflammatory responses of human V gamma 9V delta 2 T cells for adoptive immunotherapy.
Vgamma9Vdelta2 T lymphocytes are a major human gammadelta T cell subset that react against a wide array of tumor cells, through recognition of phosphorylated isoprenoid pathway metabolites called phosphoantigens. Immunotherapeutic protocols targeting Vgamma9Vdelta2 T cells have yielded promising, yet limited, signs of antitumor efficacy. To improve these approaches, we analyzed the effects on gammadelta T cells of IL-21, a cytokine known to enhance proliferation and effector functions of CD8(+) T cells and NK cells. IL-21 induced limited division of phosphoantigen-stimulated Vgamma9Vdelta2 T cells, but did not modulate their sustained expansion induced by exogenous IL-2. Vgamma9Vdelta2 T cells expanded in the presence of IL-21 and IL-2 showed enhanced antitumor cytolytic responses, associated with increased expression of CD56 and several lytic molecules, and increased tumor-induced degranulation capacity. IL-21 plus IL-2-expanded Vgamma9Vdelta2 T cells expressed higher levels of inhibitory receptors (e.g., ILT2 and NKG2A) and lower levels of the costimulatory molecule NKG2D. Importantly, these changes were rapidly and reversibly induced after short-term culture with IL-21. Finally, IL-21 irreversibly enhanced the proinflammatory Th1 polarization of expanded Vgamma9Vdelta2 T cells when added at the beginning of the culture. These data suggest a new role played by IL-21 in the cytotoxic and Th1 programming of precommitted Ag-stimulated gammadelta T cells. On a more applied standpoint, IL-21 could be combined to IL-2 to enhance gammadelta T cell-mediated antitumor responses, and thus represents a promising way to optimize immunotherapies targeting this cell subset.
Thedrez
Aurélie
A
Institut National de la Santé et de la Recherche Médicale, Unité 892, Centre de Recherche en Cancérologie Nantes-Angers, Nantes, France.
Harly
Christelle
C
Morice
Alexis
A
Salot
Samuel
S
Bonneville
Marc
M
Scotet
Emmanuel
E
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000276:Adjuvants, Immunologic / Q000502:physiology*; D000328:Adult; D002051:Burkitt Lymphoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000276:immunology; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D018836:Inflammation Mediators / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation; D010750:Phosphoproteins / Q000502:physiology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D000098546:Interleukin-21
D000276:Adjuvants, Immunologic; D018836:Inflammation Mediators; D007376:Interleukin-2; D007378:Interleukins; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011994:Recombinant Proteins; D000098546:Interleukin-21