CD8
            <sup>+</sup>
            T Cell Cross-Priming via Transfer of Proteasome Substrates

Norbury, Christopher C.; Basta, Sameh; Donohue, Keri B.; Tscharke, David C.; Princiotta, Michael F.; Berglund, Peter; Gibbs, James S.; Bennink, Jack R.; Yewdell, Jonathan W.

doi:10.1126/science.1096378

Cited by 265 publications

(235 citation statements)

References 21 publications

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“…Both HSP70 and HSP90 can facilitate the presentation of antigenic peptides on MHC class I molecules, but HSC70 can facilitate TAA processing and presentation on MHC class II molecules (52). Recent studies have shown that crosspriming is based on the transfer of proteasome substrates that are transcriptionally up-regulated by heat treatment in human cells (53,54). This concept offers additional effects by which heat treatment might enhance Ag processing and presentation in MHC class I and II molecules on the surfaces of FCs.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- γ at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-γ+CD8+ T cells and CD154+ IFN-γ+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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“…In fact, much of what is known about the cross-presentation of virus antigens is derived from studies relying on antigen donor cells (ADC) transfected with a single virus protein [7][8][9][10]. The ability of antigens to escape cytosolic degradation in ADC is important during cross-presentation [7,[11][12][13]. Interestingly, it appears that the capacity of an epitope to access cross-priming may support its immunodominance when considering the overall hierarchy [8,10,14].…”

Section: Introductionmentioning

confidence: 99%

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

et al. 2010

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The initiation of CD8 1 T cell (CTL) immune responses can occur via cross-priming. Recent data suggested a relationship between cross-presentation and immunodominance of epitope-specific T cells. To test this association, we evaluated the efficacy of crosspresentation for several virus epitopes in vitro and examined if this can be extrapolated in vivo. Employing lymphocytic choriomeningitis virus (LCMV), we demonstrate that the cross-presentation and cross-priming of LCMV antigens were dominated by NP396, but not NP205 when analyzing the LCMV-NP. Although with LCMV-GP, cross-presentation was dominated by GP276, and cross-priming was dominated by GP33. Importantly, although NP396 was significantly more efficient than GP33 in cross-presentation, cross-priming of their specific CTL was comparable. In a subsequent virus challenge after cross-priming, GP33-specific CTL dominated the response. Accordingly, based on our data, the ability of viral epitopes to be cross-presented in vitro does not entirely reflect what would occur in cross-priming. Thus, weak cross-presenting antigens may still cross-prime an efficient CTL response depending on other in vivo elements such as the naïve T-cell precursor frequencies.

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“…Cross-priming is a crucial pathway of exogenous antigen presentation on the HLA class I molecules by APCs, enabling antiviral or antitumour responses (den Haan et al 2000;Sigal et al 1999). It has been shown that intact proteins or non-chaperoned proteasome products can be a source of antigens used for cross-presentation (Norbury et al 2004;Serna et al 2003;Shen and Rock 2004). However, these molecules were shown not to be as effective in cross-priming as peptides chaperoned by HSPs (Binder et al 2001;Binder and Srivastava 2005).…”

Section: Introductionmentioning

confidence: 99%

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Stocki

Morris

Preisinger

et al. 2010

Cell Stress and Chaperones

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Heat shock protein 70 (HSPA) is a molecular chaperone which has been suggested to shuttle human leukocyte antigen (HLA) epitope precursors from the proteasome to the transporter associated with antigen processing. Despite the reported observations that peptides chaperoned by HSPA are an effective source of antigens for cross-priming, little is known about the peptides involved in the process. In this study, we investigated the possible involvement of HSPA in HLA class I or class II antigen presentation and analysed the antigenic potential of the associated peptides. HSPA was purified from CCRF-CEM and K562 cell lines, and using mass spectrometry techniques, we identified 44 different peptides which were copurified with HSPA. The affinity of the identified peptides to two HSPA isoforms, HSPA1A and HSPA8, was confirmed using a peptide array. Four of the HSPAassociated peptides were matched with 13 previously reported HLA epitopes. Of these 13 peptides, nine were HLA class I and four were HLA class II epitopes. These results demonstrate the association of HSPA with HLA class I and class II epitopes, therefore providing further evidence for the involvement of HSPA in the antigen presentation process.

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CD8 ⁺ T Cell Cross-Priming via Transfer of Proteasome Substrates

Cited by 265 publications

References 21 publications

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

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CD8 + T Cell Cross-Priming via Transfer of Proteasome Substrates

Cited by 265 publications

References 21 publications

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

The outcome of cross‐priming during virus infection is not directly linked to the ability of the antigen to be cross‐presented

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

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CD8 ⁺ T Cell Cross-Priming via Transfer of Proteasome Substrates