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

Nat Immunol. 2004 May;5(5):508-15. doi: 10.1038/ni1059. Epub 2004 Apr 4.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CD8 Antigens / immunology*
  • Immune Tolerance / immunology*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Receptors, Cell Surface / metabolism*
  • Signal Transduction / immunology
  • Signal Transduction / physiology
  • T-Lymphocytes / immunology*
  • Toll-Like Receptors
  • Vaccines / immunology


  • CD8 Antigens
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • Toll-Like Receptors
  • Vaccines