Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways

Heat shock proteins (HSPs) derived from tumors or virally infected cells ca rl stimulate antigen-specific CD8(+) T cell responses in vitro and in vivo. Although this antigenicity is known to arise from HSP-associated peptides presented to the immune system by major histocompatibility complex (MHC) cl ass I molecules, the cell biology underlying this presentation process rema ins poorly understood. Here we show that HSP 70 binds to the surface of ant igen presenting cells by a mechanism with the characteristics of a saturabl e receptor system. Alter this membrane interaction processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytoso lic (transporter associated with antigen processing [TAP] and proteasome-de pendent) or an endosomal (TAP and proteasome-independent) route, with the p referred pathway determined by the sequence context of the optimal antigeni c peptide within the HSP-associatsd material. These findings not only chara cterize two highly efficient, specific pathways leading to the conversion o f HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transpo rt of HSP or HSP-associated ligands from the plasma membrane or lumen of en dosomes into the cytosol.