Nonclassical MHC class Ib–restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum

NA Nagarajan, F Gonzalez, N Shastri - Nature immunology, 2012 - nature.com
NA Nagarajan, F Gonzalez, N Shastri
Nature immunology, 2012nature.com
The aminopeptidase ERAAP is essential for trimming peptides presented by major
histocompatibility complex (MHC) class I molecules. Inhibition of ERAAP by cytomegalovirus
results in evasion of the immune response by this virus, and polymorphisms in ERAAP are
associated with autoimmune disorders. How normal ERAAP function is monitored is
unknown. We found that inhibition of ERAAP rapidly induced presentation of the peptide
FYAEATPML (FL9) by the MHC class Ib molecule Qa-1b. Antigen-experienced T cells …
Abstract
The aminopeptidase ERAAP is essential for trimming peptides presented by major histocompatibility complex (MHC) class I molecules. Inhibition of ERAAP by cytomegalovirus results in evasion of the immune response by this virus, and polymorphisms in ERAAP are associated with autoimmune disorders. How normal ERAAP function is monitored is unknown. We found that inhibition of ERAAP rapidly induced presentation of the peptide FYAEATPML (FL9) by the MHC class Ib molecule Qa-1b. Antigen-experienced T cells specific for the Qa-1b–FL9 complex were frequent in naive mice. Wild-type mice immunized with ERAAP-deficient cells mounted a potent CD8+ T cell response specific for Qa-1b–FL9. MHC class Ib–restricted cytolytic effector cells specifically eliminated ERAAP-deficient cells in vitro and in vivo. Thus, nonclassical Qa-1b–peptide complexes direct cytotoxic T cells to targets with defective antigen processing in the endoplasmic reticulum.
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