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

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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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