Abstract
The well described conventional antigen-processing pathway is accountable for most peptides that end up in MHC class I molecules at the cell surface. These peptides experienced liberation by the proteasome and transport by the peptide transporter TAP. However, there are multiple roads that lead to Rome, illustrated by the increasing number of alternative processing pathways that have been reported during last years. Interestingly, TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways. To date, a diversity of viral and endogenous TAP-independent peptides have been identified in the grooves of different MHC class I alleles. Some of these peptides are not displayed by normal TAP-positive cells and we therefore called them TEIPP, for “T-cell epitopes associated with impaired peptide processing.” TEIPPs are hidden self-antigens, are derived from normal housekeeping proteins, and are processed via unconventional processing pathways. Per definition, TEIPPs are presented via TAP-independent pathways, but recent data suggest that part of this repertoire still depend on proteasome and metalloprotease activity. An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences. The intramembrane cleaving SPP is thereby an important contributor of TAP-independent peptides. Its family members, like the Alzheimer’s related presenilins, might contribute as well, according to our preliminary data. Finally, alternative peptide routing is an emerging field and includes processes like the unfolded protein response, the ER-associated degradation, and autophagy-associated vesicular pathways. These data convince us that there is a world to be discovered in the field of unconventional antigen processing.
Highlights
Reviewed by: Rajiv Khanna, QIMR Berghofer Medical Research Institute, Australia Josef Mautner, Technische Universität München, Germany
TAP-deficient individuals do not succumb to viral infections, suggesting that CD8 T cell immunity is sufficiently supported by alternative TAP-independent processing pathways
An exception is the C-terminal peptide of the endoplasmic reticulum (ER)-membrane-spanning ceramide synthase Trh4 that is surprisingly liberated by the signal peptide peptidase (SPP), the proteolytic enzyme involved in cleaving leader sequences
Summary
Antigen-specific CD8 T-cells recognize peptides of 8–10 amino acids long that are associated with MHC class I/β2m complexes. The molecular identification of some TEIPP peptides revealed that they can be diverse in length (from 9-mer to 18-mer), amino acid composition, and MHC class I binding, as some are presented by classical MHC class I molecules and others by the non-classical MHC molecule HLA-E and the mouse homolog Qa-1b (Table 1) [35, 89,90,91,92] They are derived from normal housekeeping proteins with ubiquitous expression, but are surprisingly not loaded on MHC class I in cells with an intact antigen-processing machinery. Identification of additional human TEIPP antigens at the molecular level will enable CD8 T cell targeting of otherwise CTL-resistance TAP-negative tumor variants [98, 99] Together, these findings support the model of peptide competition in the ER as a factor that prevents presentation of peptides from alternative sources, and shape a picture of alternative processing pathways that emerge upon defects in the conventional one (Figure 1). The PLC molecule tapasin tethers MHC class I molecules to the peptide transporter acting together with the chaperone calreticulin and TABLE 1 | TEIPP peptide-epitopes defined far based on CD8 T-cell recognition
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