Journal
INTERNATIONAL IMMUNOLOGY
Volume 23, Issue 4, Pages 223-237Publisher
OXFORD UNIV PRESS
DOI: 10.1093/intimm/dxq475
Keywords
antigen presentation; processing; cytotoxic T cell; tumor immunity
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [19590357]
- Grants-in-Aid for Scientific Research [21590400, 21249025, 23390398, 23590427, 21590401, 22659075, 19590357] Funding Source: KAKEN
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Extracellular heat shock protein can deliver associated antigens into the MHC class I presentation pathway of antigen-presenting cells, a process called cross-presentation, thus inducing antigen-specific CD8(+) T-cell responses; however, the precise mechanism for intracellular antigen translocation and the processing pathway has not been fully elucidated. Here we demonstrate that cross-presentation of extracellular Hsp90-ovalbumin (OVA) protein complexes to specific CD8(+) T cells involves both classical proteasome-transporter-associated antigen processing (TAP)-dependent and TAP-independent-endosomal pathways. Using confocal microscopy, we found that the internalized extracellular Hsp90 and OVA co-localized with cytosolic proteasomes. When anti-Hsp90 mAb was introduced to dendritic cells (DCs), we observed that the co-localization of internalized Hsp90-chaperoned OVA and proteasomes was abolished, resulting in the inhibition of TAP-dependent cross-presentation of OVA. Thus, extracellular Hsp90 may play a pivotal role for the translocation of chaperoned antigens for proteasomal degradation in the cytosol. In contrast, OVA chaperoned by Hsp90 was not presented by MHC class II molecules in vitro or in vivo, although the antigen was exogenously loaded onto DCs. Our data indicate that extracellular Hsp90 might be essential for the translocation of chaperoned antigens from the extracellular milieu into cytosol, resulting in proteasomal degradation for cross-presentation.
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