Repertoire of Nonclassical MHC I (HLA-E, HLA-F, HLA-G, and Orthologues)

Abstract

The recognition of invading pathogens by the immune system is achieved by both classical and nonclassical MHC class I molecules. Classical MHC class I molecules (MHC Ia) are highly polymorphic, widely expressed, and are primarily involved in the adaptive immune response. They present peptide ligands to T cells and are crucial for differentiating between self and nonself. Polymorphism within classical MHC class I molecules is focused around the peptide binding cleft, such that different alleles bind and present distinct peptide repertoires. Conversely, nonclassical MHC molecules (MHC Ib) are relatively nonpolymorphic, exhibit limited tissue distribution, have lower expression levels than classical molecules, and are key mediators of innate immunity. Nonclassical MHC class I genes in humans include HLA-E, -F, and -G; Hfe (HLA-H); CD1; MR1 (MHC class I related); and MIC (MHC-class-I-polypeptide-related sequence). In addition to their role in innate immunity, emerging evidence indicates a number of these molecules are also important in the adaptive response to invading pathogens. While some nonclassical class I molecules interact with T cell receptors others bind to natural killer cell receptors and presentation of ligands is not restricted to peptide antigen. For those nonclassical HLA molecules that do bind peptides, the most striking feature of their repertoire is the greatly reduced diversity of their ligands.