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Profound Enhancement of the IL-12/IL-18 Pathway of IFN- Secretion in Human CD8⁺ Memory T Cell Subsets via IL-15¹

Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298

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 -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- production. Importantly, IL-15 and IL-7 lowered the threshold concentrations of IL-12 and IL-18 required for induction of IFN- 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-, 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- 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-, down-regulation of CD62L expression correlated well with increased IL-12-IL-18-induced IFN-. Purified central memory T cells stimulated with IL-15 and IL-7 down-regulated CD62L and acquired potent IL-12-IL-18-induced IFN- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds provided by Virginia Commonwealth University and Department of Microbiology and Immunology, as well as a grant from the Thomas F. and Kate Miller Jeffress Memorial Trust.

² Address correspondence and reprint requests to Dr. Ronald B. Smeltz, Department of Microbiology and Immunology, Medical College of Virginia, Virginia Commonwealth University, P.O. Box 980678, Richmond, VA 23298. E-mail address: rbsmeltz{at}vcu.edu

³ Abbreviations used in this paper: T_CM, central memory T cell; T_EM, effector memory T cell; T_EMRA, CD45RA⁺ T effector memory; _c, common -chain; CD62L, CD62 ligand.