Profound Enhancement of the IL-12/IL-18 Pathway of IFN-γ Secretion in Human CD8+ Memory T Cell Subsets via IL-15

Abstract

Human memory CD8+ T cell subsets, termed central memory and effector memory T cells, can be identified by expression of CD45RA, CD62 ligand (CD62L), and CCR7. Accordingly, functional differences have been described for each subset, reflecting unique roles in immunological memory. The common γ-chain cytokines IL-15 and IL-7 have been shown to induce proliferation and differentiation of human CD8+ T cell subsets, as well as increased effector functions (i.e., cytokines, cytotoxicity). In this study, we observed that addition of IL-15 or IL-7 to cultures of human CD8+ T cells profoundly enhanced the IL-12-IL-18 pathway of IFN-γ production. Importantly, IL-15 and IL-7 lowered the threshold concentrations of IL-12 and IL-18 required for induction of IFN-γ by 100-fold. Comparison of IL-15 and IL-7 demonstrated that IL-15 was superior in its ability to enhance IL-12-IL-18-induced IFN-γ, without evidence of a synergistic effect between IL-15 and IL-7. We also observed that IL-15- and IL-7-mediated enhancement of IL-12-IL-18-induced IFN-γ production was a functional property of effector memory CD8+ T cells. Despite a lack of association between cell division and acquisition of IL-12-IL-18-induced IFN-γ, down-regulation of CD62L expression correlated well with increased IL-12-IL-18-induced IFN-γ. Purified central memory T cells stimulated with IL-15 and IL-7 down-regulated CD62L and acquired potent IL-12-IL-18-induced IFN-γ similar to effector memory T cells. Thus, in addition to its known role in development of T cell memory, IL-15 may amplify memory CD8+ T cell effector functions by increasing sensitivity to proinflammatory cytokine stimulation.