Importance of TAP-independent processing pathways

Abstract

The majority of peptides presented in MHC class I at the cell surface originate from the conventional antigen processing pathway, involving the proteasome and TAP peptide transporter. Alternative pathways, however, certainly contribute to the diversity of the total peptide repertoire. The importance of such TAP-independent processing pathways is nicely illustrated by the finding that individuals with an inherited deficiency in this peptide transporter still sufficiently mount T cell responses against viruses. Although defects in TAP do result in strongly decreased surface display of MHC class I molecules, the residual levels are capable to educate and elicit T cell immunity. In our work, we have shown that a broad repertoire of peptides is presented on processing-deficient cells. The characterization of these peptides, which we called TEIPP - "T-cell epitopes associated with impaired peptide processing", showed that they derive from housekeeping proteins, are diverse in length and amino-acid composition, and are not presented on normal cells. So, TAP-deficiency promotes the emergence of neo-antigens. These TAP-independent peptides might be processed via the two already known pathways, signal sequence liberation or furin-mediated cleavage in the Golgi, or via yet other routes. Our study on TEIPP antigens reveals that there is a world to be discovered in the alternative antigen processing field. Autophagy, vesicular routing, membrane-associated proteolysis, invariant chain involvement and recycling of MHC class I molecules all might come to the stage in this interesting research area.