Receptor-mediated Uptake of Antigen/Heat Shock Protein Complexes Results in Major Histocompatibility Complex Class I Antigen Presentation via Two Distinct Processing Pathways

doi:10.1084/jem.191.11.1957

Published online 6 June 1999.

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© The Rockefeller University Press, 0022-1007/2000/6/1957/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 11, June 5, 2000 1957-1964

Original Article

Receptor-mediated Uptake of Antigen/Heat Shock Protein Complexes Results in Major Histocompatibility Complex Class I Antigen Presentation via Two Distinct Processing Pathways

Flora Castellino^a, Philip E. Boucher^b, Katrin Eichelberg^a, Mark Mayhew^c, James E. Rothman^c, Alan N. Houghton^d, and Ronald N. Germain^a
^a Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892
^b Division of Bacterial Products, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20892
^c Cellular Biochemistry and Biophysics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021
^d Department of Medicine and the Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Correspondence to: Ronald N. Germain, Lymphocyte Biology Section, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Bldg. 10, Rm. 11N311, 10 Center Dr., MSC 1892, Bethesda, MD 20892-1892. Tel:301-496-1904 Fax:301-496-0222 E-mail:rgermain{at}niaid.nih.gov.

Heat shock proteins (HSPs) derived from tumors or virally infectedcells can stimulate antigen-specific CD8⁺ T cell responses invitro and in vivo. Although this antigenicity is known to arisefrom HSP-associated peptides presented to the immune systemby major histocompatibility complex (MHC) class I molecules,the cell biology underlying this presentation process remainspoorly understood. Here we show that HSP 70 binds to the surfaceof antigen presenting cells by a mechanism with the characteristicsof a saturable receptor system. After this membrane interaction,processing and MHC class I presentation of the HSP-associatedantigen can occur via either a cytosolic (transporter associatedwith antigen processing [TAP] and proteasome–dependent)or an endosomal (TAP and proteasome–independent) route,with the preferred pathway determined by the sequence contextof the optimal antigenic peptide within the HSP-associated material.These findings not only characterize two highly efficient, specificpathways leading to the conversion of HSP-associated antigensinto ligands for CD8⁺ T cells, they also imply the existenceof a mechanism for receptor-facilitated transmembrane transportof HSP or HSP-associated ligands from the plasma membrane orlumen of endosomes into the cytosol.

Key Words: immunology, vaccines, macrophages, T cells, peptides

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