HPV16 E7-Driven Epithelial Hyperplasia Promotes Impaired Antigen Presentation and Regulatory T-Cell Development

J Invest Dermatol. 2019 Dec;139(12):2467-2476.e3. doi: 10.1016/j.jid.2019.03.1162. Epub 2019 Jun 15.


Human papillomaviruses infect keratinocytes and can lead to hyperproliferative dysplasia and malignant transformation if not cleared by the immune system. Human papillomavirus has evolved an array of mechanisms to evade and manipulate the immune system to improve replication efficiency and promote persistent infection. We here demonstrate that hyperproliferative skin expressing the high-risk human papillomavirus 16 E7 oncogene as a transgene drives immunomodulation of dendritic cells (DCs), resulting in reduced capacity to take up antigen and prime effector CD4+ T cell responses. The phenotype of DCs in the E7-expressing hyperproliferative skin was not reversible by activation through intradermal immunization. Naïve CD4+ T cells primed by E7-driven hyperproliferative skin acquired FoxP3 expression and an anergic phenotype. DC and T help modulation was dependent on E7-retinoblastoma protein interaction-driven epithelial hyperproliferation, rather than on expression of E7. Inhibition of binding of E7 to retinoblastoma protein, and of consequent epithelial hyperplasia, was associated with normal skin DC phenotype, and T helper type 1 effector responses to immunization were restored. We conclude that human papillomavirus-induced epithelial hyperplasia modulates epithelial DCs and inhibits T helper type 1 immunity while polarizing T-cell differentiation to a regulatory or anergic phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation / immunology*
  • Dendritic Cells / immunology
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Human papillomavirus 16 / immunology*
  • Humans
  • Hyperplasia
  • Keratinocytes / immunology
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Transgenic
  • Neoplasms, Experimental*
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus E7 Proteins / metabolism*
  • T-Lymphocytes, Regulatory / immunology*
  • Uterine Cervical Neoplasms / immunology*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology


  • Papillomavirus E7 Proteins
  • oncogene protein E7, Human papillomavirus type 16