TGF-β downregulates the activating receptor NKG2D on NK cells and CD8⁺ T cells in glioma patients

The activating receptor NKG2D, expressed by natural killer (NK) cells and CD8⁺ T cells, has a role in the specific killing of transformed cells. We examined NKG2D expression in patients with glioblastoma multiforme and found that NKG2D was downregulated on NK cells and CD8⁺ T cells. Expression of NKG2D on lymphocytes significantly increased following tumor resection and correlated with an increased ability to kill NKG2D ligand-positive tumor targets. Despite the presence of soluble NKG2D ligands in the sera of glioblastoma patients, NKG2D downregulation was primarily caused by tumor-derived tumor growth factor-β, suggesting that blocking of this cytokine may have therapeutic benefit.