TGFß Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion.

Transforming growth factor-beta (TGFß) is a potent immunosuppressive cytokine that inhibits the anti-tumor responses of NK cells and T cells. However, the stimulation of natural killer (NK) cells with pro-inflammatory cytokines decreases NK cell sensitivity to TGFß. Herein, we sought to determine if TGFß imprinting (TGFßi) during NK cell activation and expansion would decrease NK cell sensitivity to TGFß suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGFßi potently induces NK cell hypersecretion of interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα) in response to tumor targets which persists for at least one month in vitro after the removal of TGFß. TGFßi NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGFßi NK cells have a marked suppression of SMAD3 and T-bet which is associated with altered chromatin accessibility. In contrast to their heightened cytokine secretion, TGFßi NK cells downregulate several activating receptors, granzyme and perforin, and upregulate TRAIL, leading to cell-line-specific alterations in cytotoxicity. These findings may impact our understanding of how TGFß affects NK cell development and anti-tumor function.