Nonspecific induction of distinct regulatory T cell states in oncogene-driven hyperproliferative skin

Regulatory T cells (Tregs) recruited to peripheral tissues are associated with chronic diseases such as cancer. Tissue-specific signals and T cell receptor (TCR) specificity are critical to shape Treg phenotype diversity. We examined single-cell transcriptomic and TCR profiles of Tregs in human papillomavirus (HPV) E7-transformed hyperproliferative skin of mice. Tregs without evidence of E7 specificity were enriched in E7 transgenic skin grafts when compared with non-transgenic grafts. E7 transgenic skin grafts contained more Klrg1+ Tregs and Il1r2+ Tregs than non-transgenic grafts. These two Treg states had distinct effector phenotypes but shared a core gene signature with previously described tumour-infiltrating Tregs. Pseudotime trajectory of Tregs predicted phenotypic plasticity of TCR clonotypes, both within skin and between skin and draining lymph nodes. Together, we reveal that oncogene-driven hyperproliferative skin enables induction of nonspecific Tregs despite the presence of non-self antigen and Tregs exist in distinct cell states with unique effector gene signatures. Overall design: scRNA-seq and scTCR-seq of immune cells sorted from K14E7 and C57BL/6 skin grafts and graft draining lymph nodes from C57BL/6 recipients