Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways
F. Castellino et al., Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways, J EXP MED, 191(11), 2000, pp. 1957-1964
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.