Heat shock protein 90 targets a chaperoned peptide to the static early endosome for efficient cross-presentation by human dendritic cells.
Bottom Line: In this study, we found that an Hsp90-cancer antigen peptide complex was efficiently cross-presented by human monocyte-derived DCs and induced peptide-specific CTLs.Furthermore, we observed that the internalized Hsp90-peptide complex was strictly sorted to the Rab5(+), EEA1(+) static early endosome and the Hsp90-chaperoned peptide was processed and bound to MHC class I molecules through an endosome-recycling pathway.Our data indicate that targeting of the antigen to a "static" early endosome by Hsp90 is essential for efficient cross-presentation.
Affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi, Japan.Show MeSH
Related in: MedlinePlus
Mentions: As we had shown that the Hsp90–survivin-2B75-93 precursor peptide complex was efficiently cross-presented, we next examined whether cross-presentation of Hsp90–peptide complex could activate and expand peptide-specific memory CD8+ T cells from patients who had been vaccinated with survivin-2B peptide with incomplete Freund's adjuvant. Activated and expanded survivin-2B-specific CD8+ T cells were detected by tetramer staining. As shown in Figure2, the survivin-2B75-93 precursor peptide chaperoned by Hsp90 was able to activate and expand survivin-2B-specific memory CD8+ T cells more vigorously than was the precursor peptide alone. Interestingly, peptide-specific T-cell frequency was higher when stimulated with Hsp90–survivin-2B75-93 precursor peptide complex than that with survivin-2B80-88 peptide, indicating that a long peptide chaperoned by Hsp90 was efficiently cross-presented and was able to stimulate peptide-specific CD8+ T cells. To confirm these observations, we compared the efficacy of activation of survivin-2B-specific memory CD8+ T cells by stimulation with survivin-2B80-88, survivin-2B75-93 precursor peptide, or Hsp90–survivin-2B75-93 precursor peptide complex in eight patients. As shown in Table1, stimulation with Hsp90–survivin-2B75-93 complex could expand survivin-2B-specific memory CD8+ T cells from seven out of eight patients compared with stimulation with survivin-2B75-93. More importantly, in six out of eight patients, stimulation with Hsp90–survivin-2B75-93 complex expanded survivin-2B-specific memory CD8+ T cells more efficiently compared with stimulation with survivin-2B80-88.
Affiliation: Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi, Japan.