Regulatory T cells in skin promote hair follicle stem cell activation and hair growth through glucocorticoid signaling (ChIP-Seq)

The maintenance of tissue homeostasis in steady state or under stress is dependent on the proper communication between tissue-resident stem cells (SCs) and immune cells in their microenvironment or “niche”. In addition to promoting immune tolerance, regulatory T cells (Tregs) have recently emerged as a critical component of stem cell niche in the hair follicle (HF), injured muscle, bone marrow and intestine to support stem cell differentiation. How Treg cells sense the dynamic signals in the niche environment and communicate with stem cells during tissue regeneration is largely unknown. Here, by using HF as a model, we uncover a hitherto unrecognized function of glucocorticoid receptor (GR) signaling pathway in skin-resident Treg cells to facilitate hair follicle stem cell (HFSC) activation and HF regeneration. Ablation of GR signaling in Tregs blocked HFSCs activation and proliferation after hair depilation and during the natural hair growth cycle. Mechanistically, GR signaling induces skin-resident Tregs to produce TGF-b3, which activates Smad2/3 in HFSCs and promotes HFSC proliferation and hair growth. Our study identifies a novel crosstalk between skin-resident Tregs and HFSCs mediated by the GR/TGF-b3 axis, highlighting a new avenue to manipulate Tregs to support tissue regeneration. Overall design: Chromatin immunoprecipitation and sequencing (ChIP-seq) in skin Treg and Tcon cells treated with ETOH and DEX using antiodies against Foxp3 and GR.