Abstract
A brief in vitro stimulation of natural killer (NK) cells with interleukin (IL)-12, IL-15, and IL-18 endow them a memory-like behavior, characterized by higher effector responses when they are restimulated after a resting period of time. These preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have several properties that make them a promising tool in cancer immunotherapy. In the present study, we have described the effect that different combinations of IL-12, IL-15, and IL-18 have on the generation of human CIML NK cells. Our data points to a major contribution of IL-15 to CIML NK cell-mediated cytotoxicity against target cells. However, the synergistic effect of the three cytokines grant them the best polyfunctional profile, that is, cells that simultaneously degranulate (CD107a) and produce multiple cytokines and chemokines such as interferon γ, tumor necrosis factor α, and C-C motif chemokine ligand 3. We have also analyzed the involvement of each cytokine and their combinations in the expression of homing receptors CXCR4 and CD62L, as well as the expression of CD25 and IL-2-induced proliferation. Furthermore, we have tested the effects of the Jak1/2 inhibitor ruxolitinib in the generation of CIML NK cells. We found that ruxolitinib-treated CIML NK cells expressed lower levels of CD25 than non-treated CIML NK cells, but exhibited similar proliferation in response to IL-2. In addition, we have also found that ruxolitinib-treated NK cells displayed reduced effector functions after the preactivation, which can be recovered after a 4 days expansion phase in the presence of low doses of IL-2. Altogether, our results describe the impact that each cytokine and the Jak1/2 pathway have in the phenotype, IL-2-induced proliferation, and effector functions of human CIML NK cells.
Highlights
Natural killer (NK) cells are innate lymphocytes with a crucial role in the defense against transformed cells and viral infections
In order to study the contribution of each cytokine to the generation of cytokine-induced memory-like (CIML) NK cells, we have analyzed the involvement of IL-12, IL-15, and IL-18 either alone or in different combinations
Given that IL-15R acts through the Jak1/3 pathways and IL-12R involves signaling through Jak2 and Tyk2 pathways [46, 47], we investigated whether the presence of ruxolitinib during the preactivation phase could affect the cytolytic potential of CIML NK cells
Summary
Natural killer (NK) cells are innate lymphocytes with a crucial role in the defense against transformed cells and viral infections. They perform their work through different processes such as cell-mediated cytotoxicity and secretion of cytokines and chemokines including interferon (IFN)γ, tumor necrosis factor (TNF)α, and C-C motif chemokine ligand (CCL)3 [1,2,3,4]. NK cells express a wide repertoire of activating receptors, including the natural cytotoxicity receptors (NKp30, NKp44, NKp46), C-type lectin-like receptors (CD94/NKG2C, CD94/NKG2E, and the homodimer NKG2D), activating KIRs, the antibody-binding receptor CD16 (or FcγRIIIa), DNAM-1, 2B4, NKp80, CD300c, etc. NK cells express a wide repertoire of activating receptors, including the natural cytotoxicity receptors (NKp30, NKp44, NKp46), C-type lectin-like receptors (CD94/NKG2C, CD94/NKG2E, and the homodimer NKG2D), activating KIRs, the antibody-binding receptor CD16 (or FcγRIIIa), DNAM-1, 2B4, NKp80, CD300c, etc. [1, 4, 5, 9, 10]
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