NKG2D-ligands: Putting everything under the same umbrella can be misleading

NKG2D is a key receptor for the activation of immune effector cells, mainly Natural Killer cells and T lymphocytes, in infection, cancer and autoimmune diseases. Since the detection of ligands for NKG2D in sera of cancer patients is, in many human models, indicative of prognosis, a large number of studies have been undertaken to improve understanding of the biology regulating this receptor and its ligands, with the aim of translating this knowledge into clinical practice. Although it is becoming clear that the NKG2D system can be used as a tool for diagnosis and manipulated for therapy, some questions remain open due to the complexity associated with the existence of a large number of ligands, each one of them displaying distinct biological properties. In this review, we have highlighted some key aspects of this system that differ between humans and mice, including the properties of NKG2D, as well as the genetic and biochemical complexity of NKG2D-ligands. All of these features affect the characteristics of the immune response exerted by NKG2D-expressing cells and are likely to be important factors in the clearance of a tumour or the development of autoimmunity. Implementation of more global analyses, including information on genotype, transcription and protein properties (cellular vs released to the blood stream) of NKG2D-ligands expressed in patients will be necessary to fully understand the links between this system and disease progression.