Capturing the antigen landscape: HLA-E, CD1 and MR1

T cell receptor (TCR) recognition of antigens presented by relatively non-polymorphic MHC-like molecules is emerging as a significant contributor to health and disease. These evolutionarily ancient pathways have been inappropriately labelled 'non-conventional' because their roles were discovered after viral-specific peptide presentation by polymorphic MHC class I molecules. We suggest that these pathways are complementary to mainstream peptide presentation. HLA-E, CD1 and MR1 can present diverse self and foreign antigens to TCRs and therefore contribute to tissue homeostasis, pathogen defence, inflammation and immune responses to cancer. Despite presenting different classes of antigens, they share many features and are under common selective pressures. Through understanding their roles in disease, therapeutic manipulation for disease prevention and treatment should become possible.