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 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.
Castellino
F
F
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
Boucher
P E
PE
Eichelberg
K
K
Mayhew
M
M
Rothman
J E
JE
Houghton
A N
AN
Germain
R N
RN
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002417:Cattle; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000276:immunology; D004527:Egg Proteins / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology*; D010446:Peptide Fragments; D046988:Proteasome Endopeptidase Complex
D004527:Egg Proteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D018840:HSP70 Heat-Shock Proteins; D016177:Macrophage-1 Antigen; D009097:Multienzyme Complexes; C110366:OVA-8; D010446:Peptide Fragments; D010047:Ovalbumin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex