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

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 pre-activation with IL-12, IL-15, and IL-18, which later exhibit enhanced functionality upon restimulation. However, investigation of the optimal cytokine receptors and signals for maintenance of enhanced function and homeostasis following pre-activation remains unclear. Here, we show that IL-12, IL-15, and IL-18 pre-activation 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 co-stimulate IFN-γ production by pre-activated 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, following adoptive transfer into immunodeficient NOD-SCID-γc−/− mice, human cytokine pre-activated 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 provide additional rationale for immunotherapeutic strategies that include brief cytokine pre-activation prior to adoptive NK cell transfer, followed by low dose IL-2 therapy.

IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion

“…Upregulation of CD25 on NK cells in HCMV-infected cocultures is partially IL-12 dependent. IL-12 has previously been described as upregulating CD25 on NK cells (26)(27)(28). CD25 represents the α chain of the high-affinity receptor for IL-2 and could therefore contribute to NK cell expansion in our coculture system containing low amounts of IL-2.…”

Natural killer cell memory in infection, inflammation and cancer

“…Expression of CD25 enables NK cells to respond to low amounts of IL-2 (REF. 55). Thus, inflammatory cytokines not only directly, but also indirectly, enhance NK cell expansion by facilitating NK cell responses to IL-2 produced by CD4 + T cells.…”

Adoptively transferred natural killer cells maintain long-term antitumor activity by epigenetic imprinting and CD4+T cell help

“…10 Human IL-12/15/18-pretreated NK cells showed similar properties when cultured in vitro with IL-2 9 or IL-15 11 and in NOD-SCID IL-2rg ¡/¡ (NSG) mice after adoptive transfer. 12 Thus, upon activation with cytokines, long-term competence for NK effector function, such as IFNg production, was generated resembling characteristics of memory cells. 13 The epigenetic configuration of the Ifng locus determines accessibility for transcription of Ifng by transcription factors.…”