Efficient and qualitatively distinct MHC class I-restricted presentation of antigen targeted to the endoplasmic reticulum

For most nascent glycoprotein Ags, the MHC class I-restricted processing pathway begins in the endoplasmic reticulum (ER). From this location, they are translocated to the cytosol for degradation by the proteasome. A reasonable assumption is that processing of exocytic Ags is less efficient than that of cytosolic Ags, due to the requirement for additional handling, but that the processing pathways for the two types of proteins are otherwise similar. To test this, we compared the presentation of three epitopes within influenza nucleoprotein (NP) when this Ag is targeted to the cytosol or the ER. Surprisingly, under conditions of limited Ag expression, presentation of two proteasome-dependent epitopes is comparable when NP is targeted to the ER while presentation of a third is negatively impacted. Furthermore, presentation of the third epitope is unaffected by the addition of proteasome inhibitor when cytosolic NP is expressed but is significantly enhanced when exocytic NP is expressed. These results indicate that delivery of Ag to the ER need not preclude efficient presentation and that processing of cytosolic and ER-targeted Ag is qualitatively distinct.