title: Cytokine activation induces human memory-like NK cells.
abstract: Natural killer (NK) cells are lymphocytes that play an important role in the immune response to infection and malignancy. Recent studies in mice have shown that stimulation of NK cells with cytokines or in the context of a viral infection results in memory-like properties. We hypothesized that human NK cells exhibit such memory-like properties with an enhanced recall response after cytokine preactivation. In the present study, we show that human NK cells preactivated briefly with cytokine combinations including IL-12, IL-15, and IL-18 followed by a 7- to 21-day rest have enhanced IFN-γ production after restimulation with IL-12 + IL-15, IL-12 + IL-18, or K562 leukemia cells. This memory-like phenotype was retained in proliferating NK cells. In CD56(dim) NK cells, the memory-like IFN-γ response was correlated with the expression of CD94, NKG2A, NKG2C, and CD69 and a lack of CD57 and KIR. Therefore, human NK cells have functional memory-like properties after cytokine activation, which provides a novel rationale for integrating preactivation with combinations of IL-12, IL-15, and IL-18 into NK cell immunotherapy strategies.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Romee
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Schneider
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Leong
authors.forename: Julie M
authors.initials: JM
authors.lastname: Chase
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Keppel
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Sullivan
authors.forename: Megan A
authors.initials: MA
authors.lastname: Cooper
authors.forename: Todd A
authors.initials: TA
authors.lastname: Fehniger
mesh_terms: D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology* / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D019409:Interleukin-15 / Q000276:immunology / Q000494:pharmacology; D020382:Interleukin-18 / Q000276:immunology / Q000494:pharmacology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000276:immunology / Q000378:metabolism; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000276:immunology / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D016207:Cytokines; D007371:Interferon-gamma; D018664:Interleukin-12; D019409:Interleukin-15; D020382:Interleukin-18; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D053707:Receptors, Interleukin-12; D053724:Receptors, Interleukin-18; D000099192:CD69 Antigens