Alternative generation of MHC class II-restricted epitopes: not so exceptional?

By convention, peptides presented at the cell surface by MHC class II molecules (MHCII) are derived from internalized ("exogenous") antigen that is denatured and fragmented in the endocytic compartment and loaded onto MHC in the late endosome with the assistance of the H2-DM chaperone. Over the past two decades several alternatives to this pathway have been described but the extent to which they contribute to natural CD4(+) T cell (T(CD4+))) responses has not been assessed, mainly because studies have focused primarily on individual epitopes. My laboratory has begun to address this issue in virus infection models and a picture is emerging in which classical presentation plays a relatively minor role, with a number of alternative presentation pathways collectively accounting for the majority of peptide presentation. The potential ramifications for this fundamentally altered view of MHCII peptide supply are discussed.