IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNγ and IL-2, but not IL-10. Enhanced secretion of IFNγ was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.

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Keywords Cytokines, Cytotoxicity, IL-15, IL-21, T lymphocyte
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Journal Cancer Immunology, Immunotherapy: other biological response modifications
Pouw, N.M.C, Treffers-Westerlaken, E, Kraan, J, Wittink, F, ten Hagen, T.L.M, Verweij, J, & Debets, J.E.M.A. (2010). Combination of IL-21 and IL-15 enhances tumour-specific cytotoxicity and cytokine production of TCR-transduced primary T cells. Cancer Immunology, Immunotherapy: other biological response modifications, 59(6), 921–931. doi:10.1007/s00262-010-0818-0