Abstract
NKG2D is a major regulator of the activity of cytotoxic cells and interacts with eight different ligands (NKG2DL) from two families of MIC and ULBP proteins. The selective forces that drove evolution of NKG2DL are uncertain, but are likely to have been dominated by infectious disease and cancer. Of interest, NKG2DL are some of the most polymorphic genes outside the MHC locus and the study of these is uncovering a range of novel observations regarding the structure and function of NKG2DL. Polymorphism is present within all NKG2DL members and varies markedly within different populations. Allelic variation influences functional responses through three major mechanisms. First, it may drive differential levels of protein expression, modulate subcellular trafficking, or regulate release of soluble isoforms. In addition, it may alter the affinity of interaction with NKG2D or modulate cytotoxic activity from the target cell. In particular, ligands with high affinity for NKG2D are associated with down regulation of this protein on the effector cell, effectively limiting cytotoxic activity in a negative-feedback circuit. Given these observations, it is not surprising that NKG2DL alleles are associated with relative risk for development of several clinical disorders and the critical role of the NKG2D:NKG2DL interaction is demonstrated in many murine models. Increased understanding of the biophysical and functional consequences of this polymorphism is likely to provide insights into novel immunotherapeutic approaches.