Skin stem cells orchestrate de novo generation of extrathymic regulatory T cells to establish a temporary protective niche during wound healing

Adult stem cells reside in various tissues to govern homeostasis and repair damage. During wound healing, these stem cells must be mobilized to enter the center of the injury where they are exposed to many inflammatory immune cells infiltrating the wounded tissue. While these immune cells are indispensable for preventing infections and clearing dead cells, they can also create a harsh inflammatory environment which could potentially damage the stem cells and prevent their self-renewal and differentiation. Here, using a model of cutaneous wound healing in which hair follicle stem cells (HFSCs) repair the wound, we show that, upon migrating into the wound, skin stem cells acquire a strong immune modulatory capacity which allows them to sculpt a temporary immune suppressive niche for self-protection. We reveal that the HFSCs in the wound bed orchestrate extrathymic differentiation of regulatory T (Treg) cells by providing co-stimulation to the woundinfiltrating CD4 effector T cells. In this way, Treg cells can be generated de novo in close proximity to and can intimately protect HFSCs from the collateral damage inflicted by inflammatory neutrophils. This study uncovered a striking inflammatory adaptation capacity unique to adult tissue stem cells which allows them to shape their own immune suppressive niche during wound repair.