Interleukin 15 promotes antigen-independent in vitro expansion and long-term survival of antitumor cytotoxic T lymphocytes

The survival and expansion of effector cytotoxic T lymphocytes (CTLs) during an immunological response are critical for the successful elimination of life-threatening attacks by microorganisms, parasites, or malignant cells. Among the numerous factors that regulate the immune response, interleukin (IL)-2, and its close relative, IL-15 are known to function as growth and survival factors for antigenexperienced T cells. However, major differences appear to exist between these lymphokines in their capacity to act on various T-cell types such as CD4+ versus CD8+ or effector versus memory T lymphocytes. Although several studies have been done in the mouse system, less information is available regarding the function of these lymphokines in the human system. Here, we report that IL-15 or high concentrations of IL-2 induced antigen-independent expansion of effector CD8+ CTLs. Neither IL-2 nor IL-15 induced the proliferation of CD4+ T cells. In the absence of antigen, at least one of these lymphokines was required for the longterm survival of the cells in tissue culture. Most significantly, the effector cytolytic activity of CTLs expanded and maintained in IL-15 for up to 60 days remained stable, indicating that these cells do not differentiate into a memory functional phenotype. The expression of IL-15Rα, which was detected on CD8+ CTLs but not on CD4+ helper T cells, suggests that this receptor subunit somehow participates in the transduction of the mitogenic signals of IL-15. The present findings have practical implications for the propagation of antigen-specific T-cell lines in vitro and could be useful for expansion of therapeutic T cells for adoptive transfer.