Abstract

Major histocompatibility complex (MHC) class I chain related (MIC) molecules show homology with classical human leukocyte antigen (HLA) molecules, but they do not combine with beta2 microglobulin, do not bind peptide and are not expressed on normal circulating lymphocytes. In response to stress, MIC proteins are expressed on the cell surface of freshly isolated gastric epithelium, endothelial cells and fibroblasts and engage the activating natural killer cell receptor NKG2D, which is found on many cells within the immune system. Despite the highly polymorphic nature of MIC genes, only one polymorphic position has been identified that appears to affect the binding of NKG2D. Alleles with a methionine at codon 129 have a 10-50-fold greater capacity to complex NKG2D than alleles with a valine at this position. Renal and pancreatic grafts with evidence of both acute and chronic rejection have been shown to express MIC proteins, and anti-MIC antibodies have been identified in the serum of these patients. Some MIC molecules which are expressed by tumours appear to shed and solubilize in plasma. This soluble form of MIC engages cells expressing NKG2D, rendering them inactive, and impairs tumour cytolysis. Similarly, a protein encoded by human cytomegalovirus (CMV) prevents MICB surface expression and subsequent NKG2D interaction. Whereas the benefit of solid organ transplantation may be hindered by the expression of MIC molecules on grafts, tumours and viruses may take advantage of the expression of MIC molecules on transformed and virus-infected cells in order to evade this recognition pathway.