Listeriolysin O expressed in a bacterial vaccine suppresses CD4+CD25high regulatory T cell function in vivo.
CD4(+)CD25(high) regulatory T cells (Treg) protect the host from autoimmune diseases but are also obstacles against cancer therapies. An ideal cancer vaccine would stimulate specific cytotoxic responses and reduce/suppress Treg function. In this study, we showed that Escherichia coli expressing listeriolysin O and OVA (E. coli LLO/OVA) demonstrated remarkable levels of protection against OVA-expressing tumor cells. By contrast, E. coli expressing OVA only (E. coli OVA) showed poor protection. High-avidity OVA-specific CTL were induced in E. coli LLO/OVA-vaccinated mice, and CD8(+) depletion--but not NK cell depletion, abolished the antitumor activity of the E. coli LLO/OVA vaccine. Phenotypic analysis of T cells following vaccination with either vaccine revealed preferential generation of CD44(high)CD62L(low) CD8(+) effector memory T cells over CD44(high)CD62L(high) central memory T cells. Unexpectedly, CD4(+) depletion turned E. coli OVA into a vaccine as effective as E. coli LLO/OVA suggesting that a subset of CD4(+) cells suppressed the CD8(+) T cell-mediated antitumor response. Further depletion experiments demonstrated that these suppressive cells consisted of CD4(+)CD25(high) regulatory T cells. We therefore assessed these vaccines for Treg function and found that although CD4(+)CD25(high) expansion and Foxp3 expression within this population was similar in all groups of mice, Treg cells from E. coli LLO/OVA-vaccinated animals were unable to suppress conventional T cells proliferation. These findings provide the first evidence that LLO expression affects Treg cell function and may have important implications for enhancing antitumor vaccination strategies in humans.
Nitcheu-Tefit
Josianne
J
Centre for Molecular Oncology, Institute of Cancer, Queen Mary's School of Medicine and Dentistry, London, United Kingdom.
Dai
Ming-Shen
MS
Critchley-Thorne
Rebecca J
RJ
Ramirez-Jimenez
Francisco
F
Xu
Man
M
Conchon
Sophie
S
Ferry
Nicolas
N
Stauss
Hans J
HJ
Vassaux
Georges
G
D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D049109:Cell Proliferation; D004527:Egg Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D022361:Escherichia coli Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006360:Heat-Shock Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D006460:Hemolysin Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics*; D007156:Immunologic Memory; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D001427:Bacterial Toxins; D004527:Egg Proteins; D022361:Escherichia coli Vaccines; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; C110366:OVA-8; D010446:Peptide Fragments; D015164:Vaccines, Inactivated; D010047:Ovalbumin; C038705:hlyA protein, Listeria monocytogenes