Regulatory T cells in skin utilize the Cxcr4-Cxcl12 axis to promote hair follicle regeneration

TL;DR

Regulatory T cells in the skin use the Cxcr4-Cxcl12 pathway to help hair follicles regenerate, which could lead to new treatments for hair loss.

Contribution

The study identifies the Cxcr4-Cxcl12 axis as a conserved mechanism for Treg accumulation in hair follicles, essential for hair growth.

Findings

Tregs use Cxcr4, partially regulated by glucocorticoid receptor signaling, to accumulate in hair follicles.

Cxcl12 is enriched in upper hair follicle keratinocytes, and disrupting the Cxcr4-Cxcl12 axis impairs hair growth.

Human and mouse skin show similar Cxcr4 ligand expression patterns, indicating evolutionary conservation.

Abstract

Regulatory T cells (Tregs) play important immunosuppressive and tissue-regenerative functions in skin. A subset of Tregs localizes to hair follicles (HFs), where they promote hair growth through activation of HF stem cells. However, the mechanisms driving Treg accumulation in HFs remain to be identified. We find that Tregs utilize Cxcr4 to accumulate in HF epithelium and that its expression is partially dependent on glucocorticoid receptor signaling. Additionally, we show that Cxcl12, the main cognate ligand of Cxcr4, is enriched in keratinocytes of the upper HF and that disruption of the Cxcr4-Cxcl12 axis results in suboptimal hair growth. Finally, we demonstrate that upper HF keratinocytes in human skin express Cxcr4 ligands in a pattern similar to that in murine skin. Collectively, these results reveal an evolutionary conserved pathway of Treg trafficking within a barrier tissue that promotes hair regeneration, which may have implications for immunotherapeutic modulation of human alopecia.

Cohen et al. show that glucocorticoid receptor-dependent Cxcr4 expression by skin Tregs is partially required for accumulation to Cxcl12-expressing isthmic/infundibular regions of the hair follicle. The Cxcr4/Cxcl12 axis is required for optimal hair growth in mice and is an evolutionally conserved chemotactic pathway in human skin.

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