title: Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells.
abstract: Natural killer (NK) cells are effector lymphocytes that are under clinical investigation for the adoptive immunotherapy of hematologic malignancies, especially acute myeloid leukemia. Recent work in mice has identified innate memory-like properties of NK cells. Human NK cells also exhibit memory-like properties, and cytokine-induced memory-like (CIML) NK cells are generated via brief preactivation with IL-12, IL-15, and IL-18, which later exhibit enhanced functionality upon restimulation. However, the optimal cytokine receptors and signals for maintenance of enhanced function and homeostasis after preactivation remain unclear. Here, we show that IL-12, IL-15, and IL-18 preactivation induces a rapid and prolonged expression of CD25, resulting in a functional high-affinity IL-2 receptor (IL-2Rαβγ) that confers responsiveness to picomolar concentrations of IL-2. The expression of CD25 correlated with STAT5 phosphorylation in response to picomolar concentrations of IL-2, indicating the presence of a signal-competent IL-2Rαβγ. Furthermore, picomolar concentrations of IL-2 acted synergistically with IL-12 to costimulate IFN-γ production by preactivated NK cells, an effect that was CD25 dependent. Picomolar concentrations of IL-2 also enhanced NK cell proliferation and cytotoxicity via the IL-2Rαβγ. Further, after adoptive transfer into immunodeficient NOD-SCID-γc(-/-) mice, human cytokine-preactivated NK cells expand preferentially in response to exogenous IL-2. Collectively, these data demonstrate that human CIML NK cells respond to IL-2 via IL-2Rαβγ with enhanced survival and functionality, and they provide additional rationale for immunotherapeutic strategies that include brief cytokine preactivation before adoptive NK cell transfer, followed by low-dose IL-2 therapy.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Leong
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Chase
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Romee
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Schneider
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Sullivan
authors.affiliation: Division of Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Megan A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri. Electronic address: tfehnige@wustl.edu.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D055612:Cytokine-Induced Killer Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: D019409:Interleukin-15; D020382:Interleukin-18; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D018664:Interleukin-12
keywords: Adoptive immunotherapy; Cytokine; IL-2; IL-2 receptor; NK cell