CpG and Interleukin-15 Synergize to Enhance IFN-γ Production by Activated CD8(+) T Cells

Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8(+) T cells. Paradoxically, we previously reported that IL-15 could enhance CD8(+) T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8(+) T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN-γ by CD8(+) T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN-γ production. The effect of CpG and IL-15 was also evident with CD8(+) T cells recovered from mice infected with the parasite Trypanosoma cruzi (T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8(+) T cells and CD4(+)CD25(+) regulatory T cells. Although IFN-γ was not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8(+) T cells required expression of the IFN-γ-inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8(+) T-cell responses to infectious agents and tumors.