Persistent Toll-like receptor signals are required for reversal of regulatory T cell–mediated CD8 tolerance

Abstract

One chief barrier to cancer immunotherapy is tumor-specific T cell tolerance. Here we compared the ability of hemagglutinin (HA)-encoding recombinant viruses versus 'HA-loaded' dendritic cells to reverse HA-specific CD8 tolerance and to protect mice from tumor challenge. Both vaccines were comparable in activating naive HA-specific CD8+ T cells. However, in circumstances of established tolerance, viral vaccines could break CD8 tolerance in the presence of CD4+CD25+ regulatory T cells, whereas dendritic cell–based vaccines achieved this only after removal of regulatory T cells or the coadministration of a Toll-like receptor (TLR) ligand or irrelevant virus. These results demonstrate that virus provides TLR signals required for bypassing regulatory T cell–mediated tolerance and emphasize the importance of persistent TLR signals for immunotherapy in the setting of established tolerance.

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Figure 1: Lentivirus-mediated gene transfer to mouse DCs.
Figure 2: Both DC and viral vaccines activate HA-specific CD8+ T cells in nontransgenic B10.D2 mice.
Figure 3: Reactivation of tolerized HA-specific CD8+ T cells with recombinant vaccinia virus.
Figure 4: Breaking of CD8 tolerance by rVV-HA protects HA-transgenic mice from tumor challenge.
Figure 5: Breaking of CD8 tolerance by DC vaccines is dependent on removal of CD4+CD25+ T cells.
Figure 6: Ex vivo LPS–treated DCs fail to reverse CD8 tolerance in vivo.
Figure 7: In vivo ligation of TLRs is required for reversal of CD8 tolerance by DCs.

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Acknowledgements

Supported in part by National Institutes of Health (CA93659 to Y.Y.).

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Correspondence to Yiping Yang or Drew M Pardoll.

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Yang, Y., Huang, C., Huang, X. et al. Persistent Toll-like receptor signals are required for reversal of regulatory T cell–mediated CD8 tolerance. Nat Immunol 5, 508–515 (2004). https://doi.org/10.1038/ni1059

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