Generation of cytotoxic T lymphocytes by MHC class I ligands fused to heat shock cognate protein 70

Udono, Heiichiro; Yamano, Toshihisa; Kawabata, Yuko; Ueda, Masakatsu; Yui, Katsuyuki

doi:10.1093/intimm/13.10.1233

Cited by 78 publications

(81 citation statements)

References 39 publications

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“…However, alum cannot efficiently switch on the innate responses and is thus unable to direct the adaptive immune responses. HSP70, another member of the HSP family, has been found to promote immunogenic APC function, elicit a strong CTL response, and prevent the induction of tolerance (45)(46)(47)(48)(49). Our results together with these previous findings point to the potential of using HSPs as a T cell adjuvant to induce CTLs targeting viral pathogens or cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Zhou

Han

et al. 2005

The Journal of Immunology

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Previously, we reported that a 7-mer HLA-A11-restricted peptide (YVNTNMG) of hepatitis B virus (HBV) core Ag (HBcAg88–94) was associated with heat shock protein (HSP) gp96 in liver tissues of patients with HBV-induced hepatocellular carcinoma (HCC). This peptide is highly homologous to a human HLA-A11-restricted 9-mer peptide (YVNVNMGLK) and to a mouse H-2-Kd-restricted 9-mer peptide (SYVNTNMGL). To further characterize its immunogenicity, BALB/c mice were vaccinated with the HBV 7-mer peptide. It was found that a specific CTL response was induced by the 7-mer peptide, although the response was ∼50% of that induced by the mouse H-2-Kd-restricted 9-mer peptide, as detected by ELISPOT, tetramer, and 51Cr release assays. To evaluate the adjuvant effect of HSP gp96, mice were coimmunized with gp96 and the 9-mer peptide, and a significant adjuvant effect was observed with gp96. To further determine whether the immune effect of gp96 was dependent on peptide binding, the N- and C-terminal fragments of gp96, which are believed to contain the putative peptide-binding domain, were cloned and expressed in Escherichia coli. CTL assays indicated that only the N-terminal fragment, but not the C-terminal fragment, was able to produce the adjuvant effect. These results clearly demonstrated the potential of using gp96 or its N-terminal fragment as a possible adjuvant to augment CTL response against HBV infection and HCC.

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Section: Discussionmentioning

confidence: 99%

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Zhou

Han

et al. 2005

The Journal of Immunology

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“…Cytotoxic T lymphocytes (CTLs) specific to each peptide were generated and maintained as described (11).…”

Section: Methodsmentioning

confidence: 99%

Hsp90-mediated Assembly of the 26 S Proteasome Is Involved in Major Histocompatibility Complex Class I Antigen Processing

Yamano

Mizukami

Murata

et al. 2008

Journal of Biological Chemistry

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Heat shock protein 90 (hsp90) and the proteasome activator PA28 stimulate major histocompatibility complex (MHC) class I antigen processing. It is unknown whether hsp90 influences the proteasome activity to produce T cell epitopes, although association of PA28 with the 20 S proteasome stimulates the enzyme activity. Here, we show that hsp90 is essential in assembly of the 26 S proteasome and as a result, is involved in epitope production. Addition of recombinant hsp90␣ to cell lysate enhanced chymotrypsinlike activity of the 26 S proteasome in an ATP-dependent manner as determined by an in-gel hydrolysis assay. We successfully pulled down histidine-tagged hsp90␣-and PA28␣-induced, newly assembled 26 S proteasomes from the cell extracts for in vitro epitope production assay, and we found these structures to be sensitive to geldanamycin, an hsp90 inhibitor. We found a cleaved epitope unique to the proteasome pulled down by both hsp90␣ and PA28␣, whereas two different epitopes were identified in the hsp90␣-and PA28␣-pulldowns, respectively. Processing of these respective peptides in vivo was enhanced faithfully by the protein combinations used for the proteasome pulldowns. Inhibition of hsp90 in vivo by geldanamycin partly disrupted the 26 S proteasome structure, consistent with down-regulated MHC class I expression. Our results indicate that hsp90 facilitates MHC class I antigen processing through epitope production in a complex of the 26 S proteasome.

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“…Finally, recombinant HSP-antigen fusion proteins 36,37 were able to elicit CD4 þ -independent CD8 þ cytotoxic T-lymphocyte (CTL) responses. [38][39][40] In the present study, we sought to enhance the potency of DNA vaccines by using HSP70 as a DC-targeting molecule to enhance antigen cross-presentation and DC maturation. This novel strategy (Figure 1a) uses the human papilloma virus type-16 E7 oncoprotein (HPV16 E7) as a model antigen and HSP70 as a DC binding domain.…”

Section: Introductionmentioning

confidence: 99%

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Shen

et al. 2004

Gene Ther

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DNA vaccines are an appealing strategy for inducing cytotoxic T-lymphocyte and antibody responses against tumor cells as well as infectious agents. Dendritic cells (DCs) play a critical role in inducing immune responses, but their potential is not fully utilized in the DNA vaccine setting since they take up only a minor fraction of the injected DNA. Here we describe a novel DNA vaccination strategy based on the targeting of a modified tumor-associated antigen, the human papilloma virus (HPV) type 16 E7 protein, to DCs by a heat-shock protein (HSP) to enhance antigen presentation and immune responses. Specifically, a chimerical HPV-E7 and HSP70 fusion gene preceded with a leader sequence was constructed. When mice were immunized with this construct, the DNA is taken up by various types of cells, which then produce and secrete an HPV-E7-HSP70 fusion protein that is targeted to DCs by the HSP70 portion of the chimerical molecule for antigen presentation. In studies to test the efficacy of this strategy, we demonstrated that DNA vaccination with this secretory HPV-E7-HSP70 construct strongly enhanced an antigen-specific CD8 þ T-cell response as well as a specific B-cell response in mice. Furthermore, this immunization approach not only protected mice against lethal challenge with an HPV E7-expressing tumor line (TC-1), but also showed a therapeutic effect against established tumors. The results of this study indicate that secretory HSPs can be broadly used to target tumorassociated antigens to DCs to enhance antigen-specific immune responses. Gene Therapy (2004) 11, 924-932.

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Generation of cytotoxic T lymphocytes by MHC class I ligands fused to heat shock cognate protein 70

Cited by 78 publications

References 39 publications

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Generation of Murine CTL by a Hepatitis B Virus-Specific Peptide and Evaluation of the Adjuvant Effect of Heat Shock Protein Glycoprotein 96 and Its Terminal Fragments

Hsp90-mediated Assembly of the 26 S Proteasome Is Involved in Major Histocompatibility Complex Class I Antigen Processing

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

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