Alopecia is an autoimmune disorder where immune cells attack and destroy hair follicles, causing hair loss. Uncovering a molecular target of a common treatment for alopecia in a new study, scientists at the Salk Institute claim regulatory T cells (Tregs) and glucocorticoids do not just suppress the immune system, they also make hair grow.

Originally discovered as a specialized subset of T lymphocytes that suppress excessive immune response and maintain balance in immune functions, recent studies have shown Tregs also play a role in tissue repair and regeneration.

First author of the study, Zhi Liu PhD, a research associate at Salk Institute said, “We were fascinated by Treg’s non-traditional function in tissue repair and the way they communicate with tissue stem cells to facilitate tissue regeneration.”

Balance in tissue niches depends on communications between stem cells and supporting cells. That Tregs communicate with stem cells and play a critical role in balancing self-renewal and differentiation in stem cell niches has been reported in earlier studies. Yet, how Tregs sense signals in tissue microenvironments and communicate with stem cells has been unclear until now.

Liu said, “Our study identified the glucocorticoid hormone as the upstream signal that alerts Tregs, and the growth factor TGF-beta3 as the downstream signal that promotes stem cell activation and hair regeneration. These signals could be potentially conserved in other tissue injury and repair processes.”

The study, led by Ye Zheng, PhD, an associate professor at Salk Institute for Biological Studies in La Jolla, California, was published on June 23, 2022, in an article in the journal Nature Immunology  titled ‘Glucocorticoid signaling and regulatory T cells cooperate to maintain the hair-follicle stem-cell niche.’ The findings explain how Tregs interact with stem cells in the skin using the steroid hormone glucocorticoid as a messenger to generate new hair follicles and promote hair growth. This regenerative role of Treg cells is independent of its immunosuppressive functions.

Ye Zheng, PhD, (left) and Zhi Liu, PhD (right) (Salk Institute).

Zheng’s team was initially interested in uncovering the role of Tregs and glucocorticoids in autoimmune dysfunctions such as multiple sclerosis, Crohn’s disease, and asthma. However, they detected no functional significance of glucocorticoids or Tregs in these diseases. They then focused on the skin because here Tregs express high levels of glucocorticoid receptors.

The researchers shaved hair off the back of adult mice that lacked the gene encoding the glucocorticoid receptor in their Tregs or had a normal set of genes. “After two weeks, the normal mice grew back their hair, but the mice without glucocorticoid receptors barely could,” said Liu. “It was very striking, and it showed us the right direction for moving forward.”

The findings indicated a glucocorticoid-mediated communication between Tregs and stem cells in hair follicles that need to be activated for hair regeneration. Moreover, the authors showed lack of the glucocorticoid receptor in Tregs blocked hair regeneration without affecting immune balance.

After hair loss, skin cells stained blue, from a normal mouse can activate hair follicle stem cells, stained red [left], whereas skin cells in mice without glucocorticoid receptors in their regulatory T cells cannot activate hair follicle stem cells [right] (Salk Institute).
The authors found glucocorticoids instruct Tregs to activate hair follicle stem cells (HFSCs), which leads to hair growth. This crosstalk between the T cells and the stem cells depends on a mechanism whereby glucocorticoid receptors cooperate with a regulatory protein in Tregs called Foxp3, to induce a growth factor called transforming growth factor beta3 (TGF-beta3), which then activates the signaling molecules Smad2/3 in HFSCs to stimulate stem cell proliferation and differentiation into new hair follicles, promoting hair growth. The authors uncovered Tregs don’t usually produce TGF-beta3, as they do in the skin. Databases analysis revealed this phenomenon occurs in injured muscle and heart tissue, similar to how hair removal simulated a skin tissue injury in this study.

“In acute cases of alopecia, immune cells attack the skin tissue, causing hair loss. The usual remedy is to use glucocorticoids to inhibit the immune reaction in the skin, so they don’t keep attacking the hair follicles,” said Zheng. “Applying glucocorticoids has the double benefit of triggering the regulatory T cells in the skin to produce TGF-beta3, stimulating the activation of the hair follicle stem cells.”

In future studies, Zheng and his team would like to explore whether compromised glucocorticoid signaling in Tregs of the skin can cause alopecia. Zheng said, “It will be interesting to see if skin Treg cells can be targeted for the treatment of alopecia patients.”

Beyond the regeneration of hair follicles, Zheng would like to build upon studies that have shown Tregs help repair and regenerate multiple tissue types. They will study other injury models and isolate Tregs from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.  “We’d like to explore whether glucocorticoids function as a universal signal to trigger Treg’s non-traditional function to promote tissue regeneration.”