Regulatory T Cells but Not IL-10 Impair Cell-Mediated Immunity in Human Papillomavirus E7+ Hyperplastic Epithelium

J Invest Dermatol. 2021 May;141(5):1264-1273.e3. doi: 10.1016/j.jid.2020.10.011. Epub 2020 Oct 29.


High-risk human papillomavirus infection can induce cervical and other intraepithelial neoplasia and invasive cancers. A transgenic mouse expressing keratin 14 promotor-driven HPV16 E7 oncoprotein exhibits epithelial hyperplasia and mimics many features of human papillomavirus-related intraepithelial precancers. We have previously demonstrated that HPV16 E7-mediated epithelial hyperplasia suppresses T helper type 1 responses to intradermally delivered antigen and directs differentiation of CD4+ T cells towards a Foxp3+ regulatory phenotype (Treg). Here we establish that Foxp3+ Treg expansion from a transferred naive T-cell population is driven directly by the hyperplastic skin and is independent of pre-existing immune-modulated lymphocytes. However, depletion of endogenous CD25+ Tregs before priming of adoptively transferred T cells significantly improves antigen-specific CD8+ T-cell responses but not T helper type 1 responses. Deletion of IL-10 had no effect on Treg expansion, epidermal dendritic cell alteration, and suppression of induced T helper type 1 immunity in HPV16 E7-driven hyperplastic mice. Thus, HPV16 E7-mediated epithelial hyperplasia promotes expansion of peripheral Tregs in response to intradermal immunization that suppress antigen-specific CD8+ T-cell responses independently of IL-10, but depletion of these Tregs is not sufficient to restore T helper type 1 immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Dendritic Cells / immunology
  • Epithelial Cells / immunology
  • Epithelial Cells / pathology*
  • Female
  • Homeodomain Proteins / physiology
  • Hyperplasia
  • Immune Tolerance
  • Interleukin-10 / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Papillomavirus E7 Proteins / physiology*
  • T-Lymphocytes, Regulatory / physiology*
  • Th1 Cells / immunology


  • Homeodomain Proteins
  • Papillomavirus E7 Proteins
  • oncogene protein E7, Human papillomavirus type 16
  • RAG-1 protein
  • Interleukin-10