Coping with loss of perfection in the MHC class I peptide repertoire

Abstract

The MHC class I molecules present thousands of peptides (pMHC I) on the cell surface for immune surveillance by CD8 T cells. The pMHC I repertoire normally contains peptides of perfect length and sequences suitable for binding each MHC I. The peptides are made by first fragmenting cytoplasmic proteins. The fragments are then transported into the endoplasmic reticulum (ER), where they are trimmed to appropriate length by the ER aminopeptidase associated with antigen processing (ERAAP) to generate the final pMHC I. Here, we review studies on the role of ERAAP in generating pMHC I from endogenous or viral proteins and their ability to elicit CD8 T cell responses. The absence of ERAAP profoundly disrupts the pMHC I repertoire which can have major consequences on the immune responses to endogenous and viral antigens.

Figure 1

An overview of the MHC class I antigen processing pathway. Cytosolic proteases digest antigenic proteins into fragments that predominantly contain the correct C-terminus of the final peptide and a variable number of N-terminal flanking residues. These fragments are proteolytic intermediates which are transported into the ER where they are trimmed and assembled into the final pMHC I. The pMHC I exit the ER and are expressed on the cell surface as potential ligands for the antigen receptor of a CD8 T cell.

Figure 2

Schematic depiction of how the normally diverse pMHC I repertoire on the surface of cells from wild-type (WT) mice is profoundly disrupted in ERAAP-deficient mice. Some pMHC I are unchanged (~) compared to WT mice. Large number of other pMHC I are missing (↓) and expression of other pMHC I is dramatically enhanced (↑). In addition to these quantitative changes in the conventional pMHC I repertoire, ERAAP-deficient cells also express a significant number of “unedited” pMHC I. These novel pMHC I are not expressed in WT cells. The WT mice are thus not tolerant to these pMHC I and elicit a potent CD8 T cell response. The unedited pMHC I are likely to result from the lack of trimming in the ER where normal antigenic precursors arrive from the cytoplasm. Under normal conditions in WT mice, these precursors are trimmed and assembled with MHC I to yield pMHC I which exit the ER and reach the cell surface. In the absence of ERAAP-trimming (Trim), the MHC I may assemble only with the untrimmed precursors.