INTERLEUKIN (IL)-15 IS A NOVEL CYTOKINE THAT ACTIVATES HUMAN NATURAL-KILLER-CELLS VIA COMPONENTS OF THE IL-2 RECEPTOR

Interleukin 15 (IL-15) is a novel cytokine that has recently been clon ed and expressed. Whereas it has no sequence homology with IL-2, IL-15 interacts with components of the IL-2 receptor (IL-2R). In the presen t study we performed a functional analysis of recombinant IL-15 on phe notypically and functionally distinct populations of highly purified h uman natural killer (NK) cells. The CD56(bright) subset of human NK ce lls constitutively expresses the high affinity IL-2R and exhibits a br isk proliferative response after the binding of picomolar amounts of I L-2. Using a proliferation assay, IL-15 demonstrated a very steep dose -response curve that was distinct from the dose-response curve for IL- 2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R beta (p75), but not by anti-IL-2R alpha (p55). The proliferative effe cts of IL-2 on CD56(bright) NK cells could be inhibited by both antibo dies. CD56(dim) NK cells express the intermediate affinity IL-2R in th e absence of the high affinity IL-2R. Activation of CD56(dim) NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytot oxic activity, antibody-dependent cellular cytotoxicity, and NK cell p roduction of interferon gamma, tumor necrosis factor alpha, and granul ocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cyto toxic activity could be completely blocked by anti-IL-2R beta monoclon al antibody. The binding of radiolabeled IL-2 and IL-15 to CD56(dim) N K cells was inhibited in the presence of anti-IL-2R beta. Scatchard an alysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lym phocytes revealed the presence of high and intermediate affinity recep tors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our unders tanding of how monocytes/macrophages participate in the regulation of NK cell function.