Tgfβ imprinting during activation promotes natural killer cell cytokine hypersecretion

Jennifer A. Foltz, Jena E. Moseman, Aarohi Thakkar, Nitin Chakravarti, Dean A. Lee

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Transforming growth factor-beta (TGFβ) 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 TGFβ. Herein, we sought to determine if TGFβ imprinting (TGFβi) during NK cell activation and expansion would decrease NK cell sensitivity to TGFβ suppression. To this end, we demonstrate that the activation of NK cells during chronic IL-2 stimulation and TGFβi 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 TGFβ. TGFβi NK cell cytokine hypersecretion is induced following both cytokine and tumor activation. Further, TGFβi 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, TGFβi 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 TGFβ affects NK cell development and anti-tumor function.

Original languageEnglish
Article number423
Issue number11
StatePublished - Nov 5 2018


  • Cell therapy
  • Cytokines
  • Ifnγ
  • Il-2
  • Immune therapy
  • Natural killer cells
  • Tgfβ
  • Tumor microenvironment


Dive into the research topics of 'Tgfβ imprinting during activation promotes natural killer cell cytokine hypersecretion'. Together they form a unique fingerprint.

Cite this