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

Abstract

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-1b MHC Ib molecule. Antigen-experienced T cells specific for the Qa-1b-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-1b-FL9- complex. MHC Ib-restricted cytolytic effectors specifically eliminated ERAAP-deficient cells in vitro and in vivo. Thus, non-classical peptide-Qa-1b complexes direct cytotoxic T cells to targets with defective antigen processing in the ER.

Induction of Protective Antitumor Immunity through Attenuation of ERAAP Function

“…ERAAP-deficient cells were shown to present peptides with Nterminal extensions, as well as novel peptides uncovered in the absence of ERAAP (21,25,26). Interestingly, some peptide epitopes were overtrimmed by ERAAP, highlighting its role as a peptide editor (12).…”

“…Alteration of ERAAP activity was shown to induce immune responses to tumors (mediated by NK cells) (29) and ERAAP- (25,26), but a link between ERAAP expression/function and immune control of human tumors has yet to be made. There is growing evidence for the importance of tumor-infiltrating lymphocytes (including CTL) in controlling the progression of tumors, including colorectal cancer (30,31).…”

Novel selective inhibitors of aminopeptidases that generate antigenic peptides

“…Down-regulation of ERAP1 protein expression in experimental models has been shown to elicit novel cytotoxic responses in mice, 7 to induce Natural Killer cell responses against malignant cells leading to tumor rejection, 12 and to elicit nonclassical Major Histocompatibility Class Ib cytotoxic T-lymphocyte responses in vivo. 13 Some of these effects could be reproduced using the non-specific metalloprotease inhibitor Leucinethiol. [7][8][9][10][11][12][13] These findings, along with the recent elucidation of the crystallographic structures of ERAP1, 14,15 ERAP2, 16 and the accumulation of a large amount of specificity data for these peptidases, 17 have spurred interest towards the development of potent and selective inhibitors for these enzymes that could potentially control the generation of specific subsets of antigenic epitopes.…”

“…Down-regulation of ERAP1 protein expression in experimental models has been shown to elicit novel cytotoxic responses in mice, 7 to induce Natural Killer cell responses against malignant cells leading to tumor rejection, 12 and to elicit nonclassical Major Histocompatibility Class Ib cytotoxic T-lymphocyte responses in vivo. 13 Some of these effects could be reproduced using the non-specific metalloprotease inhibitor Leucinethiol. …”

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8+ T‐cell recognition of stressed cells

“…In fact, Qa-1 b is potentially able to present a set of unique peptides; the conserved nonpolymorphic peptides are readily replaced with the ones derived from a rather diverse set of self-proteins under the TAP-deficient condition [46]. In addition, Qa-1 b presents another unique peptide that is processed and produced only in the absence of ER-resident aminopeptidase ERAAP [47]. This peptide is derived from endogenous Fam49b and the antigen-experienced CD8 + T cells were frequently observed in naïve mice.…”