title: Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor.
abstract: Interleukin 15 (IL-15) is a novel cytokine that has recently been cloned 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 present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct populations of highly purified human natural killer (NK) cells. The CD56bright subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-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 effects of IL-2 on CD56bright NK cells could be inhibited by both antibodies. CD56dim NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56dim NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibody-dependent cellular cytotoxicity, and NK cell production of interferon gamma, tumor necrosis factor alpha, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-2R beta monoclonal antibody. The binding of radiolabeled IL-2 and IL-15 to CD56dim NK cells was inhibited in the presence of anti-IL-2R beta. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lymphocytes revealed the presence of high and intermediate affinity receptors 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 understanding of how monocytes/macrophages participate in the regulation of NK cell function.
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: W E
authors.initials: WE
authors.lastname: Carson
authors.forename: J G
authors.initials: JG
authors.lastname: Giri
authors.forename: M J
authors.initials: MJ
authors.lastname: Lindemann
authors.forename: M L
authors.initials: ML
authors.lastname: Linett
authors.forename: M
authors.initials: M
authors.lastname: Ahdieh
authors.forename: R
authors.initials: R
authors.lastname: Paxton
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: J
authors.initials: J
authors.lastname: Eisenmann
authors.forename: K
authors.initials: K
authors.lastname: Grabstein
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D019002:CD56 Antigen; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D019409:Interleukin-15; D007376:Interleukin-2 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D015375:Receptors, Interleukin-2 / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D016207:Cytokines; D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; D015375:Receptors, Interleukin-2