Non-classical MHC class Ib-restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum

The ER aminopeptidase associated with antigen processing, ERAAP, is essential for trimming peptides presented by MHC I molecules. ERAAP inhibition by cytomegalovirus causes immune evasion, and ERAAP polymorphisms are associated with autoimmune disorders. How normal ERAAP function is monitored is unknown. We found that ERAAP inhibition rapidly induced presentation of the FL9 peptide by the Qa-1(b) MHC Ib molecule. Antigen-experienced T cells specific for the Qa-1(b)-FL9 complex were frequent in naïve mice. Wild-type mice immunized with ERAAP-deficient cells mounted a potent CD8(+) T cell response specific for the Qa-1(b)-FL9- complex. MHC Ib-restricted cytolytic effectors specifically eliminated ERAAP-deficient cells in vitro and in vivo. Thus, non-classical peptide-Qa-1(b) complexes direct cytotoxic T cells to targets with defective antigen processing in the ER.