The Exception that Reinforces the Rule: Crosspriming by Cytosolic Peptides that Escape Degradation

SummaryThe nature of crosspriming immunogens for CD8+ T cell responses is highly controversial. By using a panel of T cell receptor-like antibodies specific for viral peptides bound to mouse Db major histocompatibility complex class I molecules, we show that an exceptional peptide (PA224-233) expressed as a viral minigene product formed a sizeable cytosolic pool continuously presented for hours after protein synthesis was inhibited. PA224-233 pool formation required active cytosolic heat-shock protein 90 but not ER g96 and uniquely enabled crosspriming by this peptide. These findings demonstrate that exceptional class I binding oligopeptides that escape proteolytic degradation are potent crosspriming agents. Thus, the feeble immunogenicity of natural proteasome products in crosspriming can be attributed to their evanescence in donor cells and not an absolute inability of cytosolic oligopeptides to be transferred to and presented by professional antigen-presenting cells.