Chapter Five – NK cell immune recognition: NKG2D ligands and stressed cells

Publisher Summary Natural killer (NK) cells are important in the innate immune response against tumor igenic or virally infected cells. The mechanism involved in the recognition of these cells has been difficult to discern. During the past two decades, there has been a substantial increase in the understanding of how NK cells recognize diseased cells. One of these mechanisms is mediated by NKG2D, which is one of the best characterized NK cell activating receptors. NKG2D binds to a variety of ligands that are not expressed on normal cells, but up-regulated in response to cellular stress, which is frequently observed during microbial infection or cellular transformation. Engagement of NKG2D ligands by its receptor potently activates NK cells and co-stimulates effector T cells, favouring the elimination of the stressed cell by the immune system. This characteristic has sustained the development of the “induced self” or “stress self” theory, which is complementary to the “missing self” theory. The immune system always has to maintain a delicate balance between rejecting the foreign and tolerating the self. Therefore, stimuli that induces the aberrant expression of NKG2D ligands in cells may trigger or exacerbate several T-cell–mediated autoimmune diseases. The importance of NKG2D in infection, cancer and autoimmunity suggests that there is great potential for manipulation of this system with therapeutic purposes. Inappropriate expression of NKG2D ligands may lead to an activation of the immune system against autologous cells, which might trigger or exacerbate a T cell-mediated autoimmune diseases.