Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance.
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.
Yang
Yiping
Y
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. yang0029@mc.duke.edu
Huang
Ching-Tai
CT
Huang
Xiaopei
X
Pardoll
Drew M
DM
D000818:Animals; D016827:CD8 Antigens / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D051193:Toll-Like Receptors; D014612:Vaccines / Q000276:immunology
D016827:CD8 Antigens; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014612:Vaccines