Keep your hair on

Regulatory T (T_reg) cells are known for suppressing inflammation, but they are increasingly thought to exert specialized, tissue-dependent functions. It was unclear whether skin-resident T_reg cells, which localize to hair follicles, have a role in the hair follicle cycle. Ali et al. now show that T_reg cells regulate the hair follicle cycle by modulating hair follicle stem cells (HFSCs).

Credit: David R. Frazier Photolibrary, Inc. / Alamy

Hair follicles go through cyclic phases of growth (anagen) or quiescence (telogen), which are driven by the proliferation and differentiation of HFSCs. The researchers tested the role of T_reg cells by carrying out flow cytometric analyses of cells resident in mouse skin during different phases of hair growth. T_reg cells were more abundant in the telogen phase and, furthermore, T_reg cells present in telogenic skin had a more activated phenotype. To test the function of skin T_reg cells, a mouse model of hair follicle regeneration was used, in which a telogen-to-anagen transition is induced by the removal of hair shafts; wild-type mice regrow hair by 14 days post-depilation. By contrast, transgenic mice, which could be induced to be transiently depleted of T_reg cells, did not efficiently enter the anagen phase and had substantially less hair regrowth after depilation. These data suggest a role for T_reg cells in hair follicle regeneration.

Next, immunofluorescent microscopy was used to examine the location of HFSCs and T_reg cells. Notably, a subset of T_reg cells (hair follicle 'bulge'-resident cells) colocalized with HFSCs. Furthermore, intravital microscopy suggested that the bulge T_reg cell population may be more dynamically active as they show an increase in protrusive activity. A functional link between HFSCs and T_reg cells was established by flow cytometric analyses, which showed that the induction of HFSC proliferation following depilation was attenuated in mice depleted of T_reg cells. Moreover, whole transcriptome RNA sequencing (RNA-seq) of bulge HFSCs from T_reg cell-depleted mice showed a decrease in the expression of genes that are associated with differentiation. Thus, T_reg cells are important for inducing the proliferation and differentiation of HFSCs. Interestingly, this is probably not mediated by T_reg cell suppression of inflammation, as mice that were transiently depleted of T_reg cells and depilated had no increase in skin markers of inflammation.

mice engineered to have jagged 1-deficient T_reg cells had attenuated hair follicle regeneration

To investigate the mechanisms of T_reg cell-induced HFSC proliferation, the researchers compared the transcriptome of telogenic skin T_reg cells to that of skin-draining lymph node T_reg cells and found that jagged 1 (a ligand of the Notch signalling pathway) was one of the most differentially expressed genes. Furthermore, HFSCs isolated after depilation had differential expression of Notch target genes in mice depleted of T_reg cells. Finally, mice engineered to have jagged 1-deficient T_reg cells had attenuated hair follicle regeneration. These data show the importance of jagged 1-mediated Notch signalling in T_reg cell induction of HFSC proliferation.

In summary, hair follicle-resident T_reg cells have an important and novel tissue-specific function; they regulate the hair follicle cycle by inducing Notch-dependent HFSC proliferation and differentiation.