The saga of MHC-bound peptides: a renaissance for antigen presentation?

Abstract

In this issue of the JCI, two separate studies on MHC-bound peptides reopen the debate on the utility of peptides for the purposes of vaccination and treatment of autoimmune diseases. In the first study, by Wahlström et al., peptides bound to HLA-DR17 from bronchoalveolar lavage cells of sarcoidosis patients were analyzed in order to identify target antigens of the autoimmune response (see the related article beginning on page 3576). In the second study, by Le Gall et al., the modulation of epitope immunodominance and the processing and presentation of HIV peptides for MHC class I recognition were shown to be dependent on flanking residues that were N terminal to the natural epitopes (see the related article beginning on page 3563). Both studies highlight the tremendous therapeutic potential of MHC-bound peptides. They also emphasize that technical issues are still plaguing this field and hindering our understanding of MHC presentation in vivo.

Figure 1. Role of flanking amino acid residues in MHC class I and class II peptide biology.

For MHC class II molecules (A), N and C terminal flanking residues protrude outside the MHC class II groove and are sometimes involved in MHC binding and/or TCR recognition. For MHC class I residues (B), amino acids N and C terminal of the 8- to 9-mer core peptide have multiple functions: (i) binding and processing by the proteasome and cytoplasmic aminopeptidases (AP); (ii) binding and transport into the ER by the TAP heterodimer and further digestion by ER aminopeptidases; and (iii) T cell recognition when a longer peptide is tethered by its extremities and bulging outside of the MHC class I groove. The observation made by Le Gall et al. (7) in this issue of the JCI is likely to be linked to steps i and ii, in which the N terminal sequence of the peptide will control the accessibility of aminopeptidases and the overall abundance of the final MHC class I peptide.