Treg-Cell Control of a CXCL5-IL-17 Inflammatory Axis Promotes Hair-Follicle-Stem-Cell Differentiation During Skin-Barrier Repair

Restoration of barrier-tissue integrity after injury is dependent on the function of immune cells and stem cells (SCs) residing in the tissue. In response to skin injury, hair-follicle stem cells (HFSCs), normally poised for hair generation, are recruited to the site of injury and differentiate into cells that repair damaged epithelium. We used a SC fate-mapping approach to examine the contribution of regulatory T (Treg) cells to epidermal-barrier repair after injury. Depletion of Treg cells impaired skin-barrier regeneration and was associated with a Th17 inflammatory response and failed HFSC differentiation. In this setting, damaged epithelial cells preferentially expressed the neutrophil chemoattractant CXCL5, and blockade of CXCL5 or neutrophil depletion restored barrier function and SC differentiation after epidermal injury. Thus, Treg-cell regulation of localized inflammation enables HFSC differentiation and, thereby, skin-barrier regeneration, with implications for the maintenance and repair of other barrier tissues. [Display omitted] •Treg cells promote epidermal regeneration after injury•Treg cells control a CXCL5-IL-17 axis of inflammation during epidermal repair•Treg-cell control of CXCL5 and IL-17 diverts HFSC differentiation toward IFE cells•CXCL5 or IL-17 neutralization restores HFSC differentiation in Treg-depleted mice In response to skin injury, hair-follicle stem cells (HFSCs) differentiate into epithelial cells that contribute to the repair of damaged epithelium. Mathur et al. show that regulatory T cells facilitate HFSC differentiation via the control of the local inflammatory environment and, specifically, the prevention of an over-exuberant Th17 and neutrophil response mediated by CXCL5.