Beyond Stressed Self: Evidence for NKG2D Ligand Expression on Healthy Cells

The activity of cytotoxic lymphocytes is regulated by the opposing function of stimulatory and inhibitory cell surface receptors. According to the now classical model of Natural Killer (NK) cell activity, the ligands for inhibitory receptors are constitutively expressed on healthy cells but can be lost on infection and on malignant cells. Loss of inhibitory checks will then allow activating signals to predominate, forming the basis of 'missing self recognition'. Natural Killer Group 2D (NKG2D) is an important member of the cohort of activating receptors expressed on Natural Killer (NK) cells and subsets of T cells. Ligands for the NKG2D receptor comprise a diverse array of self-proteins structurally related to MHC class I molecules. Expression of NKG2D ligands can be induced in cells during infection with pathogens, tumourigenesis, and by stimuli such as DNA damage, oxidative stress, and heat shock. Consequently NKG2D has been widely described as participating in 'stressed self' or 'damaged self' recognition. However, a body of evidence has recently emerged to suggest that this intuitive model of NKG2D function may be an oversimplification. NKG2D ligand expression has now widely been reported on cells that could not be described as stressed or damaged. For example activated T cells can express NKG2D ligands, and constitutive expression of NKG2D ligands has been reported on normal myelomonocytic cells, dendritic cells, and epithelial cells of the gut mucosa. In this article we will review the literature suggesting that NKG2D may function to recognise non-stressed cells and discuss the role NKG2D ligands could be playing in apparently healthy cells.