%0 Journal Article
%T TGF¦Â Imprinting During Activation Promotes Natural Killer Cell Cytokine Hypersecretion
%A Aarohi Thakkar
%A Dean A. Lee
%A Jena E. Moseman
%A Jennifer A. Foltz
%A Nitin Chakravarti
%J Archive of "Cancers".
%D 2018
%R 10.3390/cancers10110423
%X Transforming growth factor-beta (TGF¦Â) 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 TGF¦Â. Herein, we sought to determine if TGF¦Â imprinting (TGF¦Âi) during NK cell activation and expansion would decrease NK cell sensitivity to TGF¦Â suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGF¦Âi potently induces NK cell hypersecretion of interferon-gamma (IFN¦Ã) and tumor necrosis factor-alpha (TNF¦Á) in response to tumor targets which persists for at least one month in vitro after the removal of TGF¦Â. TGF¦Âi NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGF¦Âi 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, TGF¦Âi 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 TGF¦Â affects NK cell development and anti-tumor function
%K natural killer cells
%K TGF¦Â
%K IFN¦Ã
%K cell therapy
%K IL-2
%K cytokines
%K immune therapy
%K tumor microenvironment
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267005/