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Uncovering the role of regulatory T cells in tissue regeneration

Salk Institute for Biological Studies

The maintenance of tissue homeostasis in steady state or under stress is dependent on the proper communication between the stem cells and the supporting cells in their microenvironment or “niche”. In addition to promoting immune tolerance, regulatory T cells (Tregs) have recently emerged as a critical component of the stem cell niche in the hair follicle (HF), injured muscle, bone marrow, and small intestine to support stem cell differentiation or maintain their quiescence. 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 steroid hormone glucocorticoid that instructs skin-resident Treg cells through glucocorticoid receptor (GR) to facilitate hair follicle stem cell (HFSC) activation and HF regeneration. Ablation of GR signaling in Tregs blocked depilation-induced hair regeneration and natural hair growth without affecting Treg’s immune suppressive function. Mechanistic study revealed that GR signaling induces skin-resident Tregs to produce TGF-b3, which directly activates Smad2/3 in HFSCs and facilitates HFSC activation and proliferation. 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.

 

Dr. Ye Zheng is an associate professor in the NOMIS Center for Immunobiology and Microbial Pathogenesis at the Salk Institute for Biological Studies. He was the first to map the Foxp3 cistrome in Tregs, which served as a blueprint for subsequent studies on molecular mechanisms of Treg function. His lab is currently investigating in three areas of Treg biology. First, they are dissecting the molecular pathways that regulate Treg cell homeostasis and function, which has important implications in treating autoimmune diseases and cancer immunotherapy. Second, they are exploring how T cell differentiation and function are regulated by metabolic regulators such as nuclear hormone receptors in the context of autoimmune diseases and metabolic diseases. Third, they are investigating Treg cell’s non-canonical role in crosstalk with stem cells and promoting tissue repair and regeneration.