IL-21-mediated potentiation of antitumor cytolytic and proinflammatory responses of human V gamma 9V delta 2 T cells for adoptive immunotherapy.

Abstract

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.

• Authors: Aurélie Thedrez, Christelle Harly, Alexis Morice, Samuel Salot, Marc Bonneville, Emmanuel Scotet
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 6 Pg. 3423-31 (Mar 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19265120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Inflammation Mediators
• Interleukin-2
• Interleukins
• Phosphoproteins
• Receptors, Antigen, T-Cell, gamma-delta
• Recombinant Proteins
• interleukin-21

Topics

• Adenocarcinoma (immunology, pathology, prevention & control)
• Adjuvants, Immunologic (physiology)
• Adult
• Burkitt Lymphoma (immunology, pathology, prevention & control)
• Cell Differentiation (immunology)
• Cell Line, Tumor
• Cell Polarity (immunology)
• Cell Proliferation
• Cytotoxicity, Immunologic
• Humans
• Immunotherapy, Adoptive (methods)
• Inflammation Mediators (physiology)
• Interleukin-2 (physiology)
• Interleukins (physiology)
• Kidney Neoplasms (immunology, pathology, prevention & control)
• Lymphocyte Activation
• Phosphoproteins (physiology)
• Receptors, Antigen, T-Cell, gamma-delta (biosynthesis, physiology)
• Recombinant Proteins (pharmacology)
• Th1 Cells (immunology, pathology, transplantation)