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

• Published in: The Journal of experimental medicine 2000-06, Vol.191 (11), p.1957-1964
• Main Authors: Castellino, F, Boucher, P E, Eichelberg, K, Mayhew, M, Rothman, J E, Houghton, A N, Germain, R N
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antigen Presentation - immunology; Cattle; CD8 antigen; Cells, Cultured; Cysteine Endopeptidases - immunology; Egg Proteins - immunology; H-2 Antigens - immunology; HSP70 Heat-Shock Proteins - immunology; Hsp70 protein; Macrophage-1 Antigen - immunology; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - immunology; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular Sequence Data; Multienzyme Complexes - immunology; Original; Ovalbumin - immunology; Peptide Fragments; Proteasome Endopeptidase Complex
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.191.11.1957

Heat shock proteins (HSPs) derived from tumors or virally infected cells can 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) class I molecules, the cell biology underlying this presentation process remains poorly understood. Here we show that HSP 70 binds to the surface of antigen presenting cells by a mechanism with the characteristics of a saturable receptor system. After this membrane interaction, processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytosolic (transporter associated with antigen processing [TAP] and proteasome-dependent) or an endosomal (TAP and proteasome-independent) route, with the preferred pathway determined by the sequence context of the optimal antigenic peptide within the HSP-associated material. These findings not only characterize two highly efficient, specific pathways leading to the conversion of HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transport of HSP or HSP-associated ligands from the plasma membrane or lumen of endosomes into the cytosol.