Heat shock protein-chaperoned peptides but not free peptides introduced into the cytosol are presented efficiently by major histocompatibility complex I molecules

The studies reported here bear on the events in the cytosol that lead to tr afficking of peptides during antigen processing and presentation by major h istocompatibility complex (MHC) I molecules. We have introduced free antige nic peptides or antigenic peptides bound to serum albumin or to cytosolic h eat shock proteins hsp90 (and its endoplasmic reticular homologue gp96) or hsp70 into the cytosol of living cells and have monitored the presentation of the peptides by appropriate MHC I molecules. The experiments show that ( i) free peptides or serum albumin-bound peptides, introduced into the cytos ol, become ligands of MHC I molecules at a far lower efficiency than peptid es chaperoned by any of the heat shock proteins tested and (ii) treatment o f cells with deoxyspergualin, a drug that binds hsp70 and hsp90 with appare nt specificity, abrogates the ability of cells to present antigenic peptide s through MHC I molecules, and introduction of additional hsp70 into the cy tosol overcomes this abrogation. These results suggest for the first time a functional role font cytosolic chaperones in antigen processing.