Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptidesin vivoand plays an important role in immunodominance

Abstract

CD8 ؉ T cells respond to short peptides bound to MHC class I molecules. Although most antigenic proteins contain many sequences that could bind to MHC class I, few of these peptides actually stimulate CD8 ؉ T cell responses. Moreover, the T cell responses that are generated often follow a very reproducible hierarchy to different peptides for reasons that are poorly understood. We find that the loss of a single enzyme, endoplasmic reticulum aminopeptidase 1 (ERAP1), in the antigen-processing pathway results in a marked shift in the hierarchy of immunodominance in viral infections, even when the responding T cells have the same T cell receptor repertoire. In mice, ERAP1 is the major enzyme that trims precursor peptides in the endoplasmic reticulum and, in this process, can generate or destroy antigenic peptides. Consequently, when ERAP1 is lost, the immune response to some viral peptides is reduced, to others increased, and to yet others unchanged. Therefore, many epitopes must be initially generated as precursors that are normally trimmed by ERAP1 before binding to MHC class I, whereas others are normally degraded by ERAP1 to lengths that are too short to bind to MHC class I. Moreover, peptide trimming and the resulting abundance of peptide-MHC complexes are dominant factors in establishing immunodominance.antigen presentation ͉ antigen processing ͉ peptidases C ells infected with a virus or otherwise producing foreign proteins can be recognized and eliminated by CD8 ϩ T cells. CD8 ϩ T cells recognize their targets through interactions between their T cell receptor (TCR) and MHC class I on the surface of the target cell. MHC class I is composed of a light chain (␤ 2 -microglobulin), a highly polymorphic heavy chain, and a small peptide that is produced by degradation of intracellular proteins.MHC class I alleles bind to peptides with a particular set of anchor residues that fit into pockets in the MHC class I peptide-binding groove. Virus proteomes typically contain many peptides with anchor residues suitable for particular MHC class I alleles, yet immune responses are generally directed toward a very limited number of epitopes. This phenomenon, in which only a few epitopes are functionally immunogenic, is known as immunodominance and is, as yet, incompletely understood (reviewed in ref. 1). Although many explanations for immunodominance have been proposed (1-9), their relative importance is not well established.The generation of most MHC class I epitopes requires proteolysis by proteasomes in the cytosol. Proteasomes can generate either the mature epitope that is ultimately presented by MHC class I molecules or precursors that are extended by several amino acids at the amino terminus. Such N-extended peptides are further processed by aminopeptidases to generate the final presented epitope. Although a number of peptidases have been proposed to play roles in MHC class I antigen presentation, few have been shown to play a major role in antigen presentation in intact cells. In cell lysates, aminopeptidases, includin...

Induction of Protective Antitumor Immunity through Attenuation of ERAAP Function

“…The increase in GSW11 generation occurred despite an overall decrease in MHC I levels; MHC I downregulation is typically observed in ERAAP-knockout cells (Fig. 1D) (11)(12)(13)(14). This confirmed that the generation of GSW11 is ERAAP sensitive.…”

“…In humans, two aminopeptidases perform this function, ERAP1 and ERAP2 (7)(8)(9); in mice, only one aminopeptidase exists, ERAAP (10). ERAAP is critical for the generation of many antigenic epitopes in vivo and can influence the generation of the antigenic peptide repertoire (11)(12)(13)(14). ERAAP can also destroy antigenic epitopes by trimming them to lengths too small for MHC binding, thus its characterization as an antigenic peptide editor (12).…”

ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency

“…The latter feature refers to the low ERAP1-trimming activity toward most peptides shorter than eight residues (12,16). Absence of ERAP activity has been shown to drastically change the profile of MHC class I-associated peptides (17) and/or alter Ag presentation in vitro and in vivo in numerous experimental systems (18)(19)(20). ERAP2 has been proposed to have an accessory role in ER peptide trimming, because of its complementary N-terminal specificity (12).…”

Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis

“…This trimming is critical for the generation of many antigenic epitopes in vivo and influences the generation of the antigenic peptide repertoire (6)(7)(8). Because the functions of ERAP1 and HLA-B27 intersect in the ER at the final stages of the antigen processing pathway, it is reasonable to postulate that the disease mechanism or pathogenicity arise from defects/variations in the function of molecules that lie on this pathway.…”