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

Abstract

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.