Cutting Edge: Regulatory T Cells Facilitate Cutaneous Wound Healing

Abstract

Foxp3-expressing regulatory T cells (Tregs) reside in tissues where they control inflammation and mediate tissue-specific functions. The skin of mice and humans contain a large number of Tregs; however, the mechanisms of how these cells function in skin remain largely unknown. Here, we show that Tregs facilitate cutaneous wound healing. Highly activated Tregs accumulated in skin early after wounding and specific ablation of these cells resulted in delayed wound re-epithelialization and kinetics of wound closure. Tregs in wounded skin attenuated IFNγ production and pro-inflammatory macrophage accumulation. Upon wounding, Tregs induce expression of the epidermal growth factor receptor (EGFR). Lineage-specific deletion of EGFR in Tregs resulted in reduced Treg accumulation and activation in wounded skin, delayed wound closure and increased pro-inflammatory macrophage accumulation. Taken together, our results reveal a novel role for Tregs in facilitating skin wound repair and suggest that Tregs utilize the EGFR pathway to mediate these effects.

‘Repair’ Treg Cells in Tissue Injury

“…The skin, lung and intestine are barrier surfaces that are constantly exposed to environmental stimuli and lead to inflammation and tissue damage [27]. Tregs have been implicated in the repair of damaged skin by attenuating IFN-γ production and pro-inflammatory macrophage accumulation [28]. Treg-driven wound repair was associated with EGFR expression in Tregs, while specific deletion of EGFR in Tregs resulted in delayed skin wound closure [28].…”

“…Tregs have been implicated in the repair of damaged skin by attenuating IFN-γ production and pro-inflammatory macrophage accumulation [28]. Treg-driven wound repair was associated with EGFR expression in Tregs, while specific deletion of EGFR in Tregs resulted in delayed skin wound closure [28]. In lung tissues, Tregs also protect against tissue damage and maintain barrier integrity [29].…”

“…In vivo , the expression of EGFR was not detected in CD4 + Foxp3 + T cells isolated from skin or draining lymph nodes prior to wounding. After injury, a marked induction of EGFR expression was detected in skin Treg, but not in Tregs from draining lymph nodes [28]. The results suggest that the induction of EGFR occurs preferentially on Tregs in inflamed environments.…”

“…Compared with EGFR - Tregs, EGFR + Tregs significantly inhibited IFN-γ, TNF-α, perforin and granzyme B production and robustly inhibited CD8 + T cell proliferation [57]. Similarly, mice with a conditional deletion of EGFR in Tregs have reduced expression of CD25 and CTLA-4 [28]. EGFR on Tregs might also enhance Treg survival in inflamed tissues [28].…”

Wounds that heal and wounds that don’t − The role of the IL-33/ST2 pathway in tissue repair and tumorigenesis

“…In addition, the protective effect of IL-33 was diminished after depletion of T-regulatory (Treg) cells [46], which are known to facilitate wound healing [47]. and creating a protective layer of mucus that repels future attacks [51].…”