Tissue immune homeostasis is dependent upon a dynamic balance between effector T-cells (Teff) and regulatory T cells (Tregs). In cases of autoimmunity, this ratio is perturbed and can lead to chronic tissue inflammation. Understanding the pathogenesis of autoimmunity requires the identification of the critical determinants of the Teff-Treg interaction. Hair follicles and especially the bulge region is the best characterised niche for adult skin epithelial stem cell residence and central to hair follicle function. Skin hair follicles undergo bouts of regeneration, cycling between highly synchronised phases of quiescence and growth. Treg function association with tissue immune homeostasis is illustrated in Alopecia Areata, a human autoimmune disorder characterised by defects in hair follicle cycling. Patients present with polymorphisms in genes that control Treg function and their augmentation has proved clinically efficacious. The scope of the EU-funded DCMERT (The role of dendritic cell subsets in the maintenance of effector and regulatory T-cells in the skin) was to dissect the role of Tregs in hair follicle-associated stem cell biology. For this purpose, they employed a well-characterised model of depilation-induced hair follicle regeneration. Researchers observed that Treg abundance, proliferative index and activation state were directly linked with hair follicle stage. Depletion of Tregs in this model markedly reduced hair regrowth compared to wild type mice. This was attributed to the lower proliferation of hair follicle stem cells, indicating that Tregs directly stimulated stem cell function during skin regeneration. Whole transcriptome RNA sequencing on skin Tregs unveiled various molecular pathways such as Notch signalling. Exogenous administration of Jagged 1 – the Notch signalling ligand – partially rescued the stem cell defect in mice lacking Tregs. Similar results were obtained in transgenic mice with Tregs lacking Jagged1. Collectively, these experiments underscored the role of Notch in Treg interaction with epithelial stem cells. The DCMERT study provided evidence for the first time of the role of Tregs on hair follicle biology. The functional requirement of skin Tregs for stem cell activation and differentiation provides a foundation for the development of new therapeutic strategies. Targeting the Treg-Notch axis could be extended beyond skin regeneration to other tissue regenerative disorders.
Regulatory T cells, skin, hair follicle, autoimmunity, stem cell, DCMERT, Notch signalling, Jagged 1