Natural killer cells and the MHC class I pathway of peptide presentation

Natural killer (NK) cells are TcR-Ig- lymphocytes that can mediate resistance to tumor growth, virus infections and bone marrow transplants. The receptors and specificity of NK cells are not clear, although it has been suggested that cytolytic triggering may be facilitated by lack of host matched MHC expression in the target or the graft. This article reviews and analyzes the role of the MHC class I pathway of peptide presentation in regulation of NK cells. This subject is introduced by brief overviews on NK cells, the 'missing self hypothesis' and studies establishing that MHC class I molecules of the target and the host can influence NK reactivity against certain normal and malignant cells. The main focus is then set on recent studies indicating that this influence occurs through interactions involving the antigen binding groove or its bound peptides. This includes discussion of modulation of NK sensitivity by peptides, beta 2 microglobulin, allelic differences or point mutations in MHC class I heavy chains, virus infection and peptide loading deficiency. While it is clear that alterations affecting the groove and its contents can change NK sensitivity, the evidence should be interpreted with caution, as the structural integrity of the whole class I molecule is dependent on the conformation and the stability of the antigen binding groove. Two models for recognition, 'target interference' and 'effector inhibition', are discussed. Each of these (mutually non-exclusive) models can accommodate a role for the groove and its peptide.