Epithelial expression of human papillomavirus type 16 E7 protein results in peripheral CD8 T-cell suppression mediated by CD4+CD25+ T cells.
The role of thymic versus peripheral epithelium in the regulation of the antigen-specific CD8 T-cell repertoire is still largely unresolved. We generated TCR-beta chain transgenic mice in which an increased frequency of peripheral CD8 T cells recognizes an epitope from a viral oncoprotein (HPV16E7) in the context of H-2D(b) MHC class I. When T cells from these mice developed through the thymus of mice expressing functional E7 protein from a keratin 14 promoter, no major perturbation to transgenic T-cell development in the thymus was observed in these double-transgenic mice. In contrast, peripheral CD8 T-cell responses in the single-transgenic, K14E7 mice, including those unrelated to E7 antigen, are reduced whereas CD4 T-cell responses and antibody production are unchanged in these mice. Peripheral non-responsiveness among CD8 T cells was mediated largely by CD4(+)CD25(+) T cells. This suggested that epithelium expressing HPV16E7 protein induces Treg that specifically down-regulate CD8 T-cell responses in the periphery. This may have important consequences for the treatment of cervical pre-cancers and provides a model for understanding differential suppression of T and B lymphocyte subsets by Treg.
Narayan
Sharmal
S
Diamantina Institute for Cancer, Immunology and Metabolic Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia.
Choyce
Allison
A
Linedale
Richard
R
Saunders
Nicholas A
NA
Dahler
Alison
A
Chan
Emily
E
Fernando
Germain J
GJ
Frazer
Ian H
IH
Leggatt
Graham R
GR
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004848:Epithelium / Q000276:immunology; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D053547:Keratin-14 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology*
D053645:Interleukin-2 Receptor alpha Subunit; D053547:Keratin-14; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16