A surprising link between immune system and hair growth

Overview: Regulatory T cells interact with skin cells using glucocorticoid hormones to generate new hair follicles and promote hair growth. The findings may have positive implications for the development of new therapies to treat alopecia and other hair loss disorders.

Source: Salk Institute

Salk scientists have discovered an unexpected molecular target of a common treatment for alopecia, a condition in which a person’s immune system attacks their own hair follicles, causing hair loss.

The findings, published in Nature Immunology on June 23, 2022, describe how immune cells called regulatory T cells interact with skin cells using a hormone as a messenger to generate new hair follicles and hair growth.

“For the longest time, regulatory T cells have been studied for how they reduce excessive immune responses in autoimmune diseases,” said corresponding author Ye Zheng, an associate professor in Salk’s NOMIS Center for Immunobiology and Microbiological Pathogenesis.

“Now we have identified the upstream hormonal signal and downstream growth factor that actually promote hair growth and regeneration, completely separate from suppressing the immune response.”

The scientists didn’t start studying hair loss. They were interested in investigating the role of regulatory T cells and glucocorticoid hormones in autoimmune diseases. (Glucocorticoid hormones are cholesterol-derived steroid hormones produced by the adrenal gland and other tissues.) They first examined how these immune components worked in multiple sclerosis, Crohn’s disease and asthma.

They found that glucocorticoids and regulatory T cells did not function together to play a significant role in either of these conditions. So they thought they might have better luck looking at environments where regulatory T cells expressed particularly high levels of glucocorticoid receptors (which respond to glucocorticoid hormones), such as in skin tissue.

The scientists caused hair loss in normal mice and mice without glucocorticoid receptors in their regulatory T cells.

“After two weeks, we saw a noticeable difference between the mice — the normal mice grew their hair back, but the mice without glucocorticoid receptors could barely do that,” said first author Zhi Liu, a postdoctoral researcher in the Zheng lab.

“It was very striking and it showed us the right direction to go forward.”

The findings suggested that some kind of communication must take place between regulatory T cells and hair follicle stem cells to enable hair regeneration.

Using a variety of techniques for monitoring multicellular communication, the scientists next examined how the regulatory T cells and glucocorticoid receptors behaved in skin tissue samples.

They found that glucocorticoids instruct the regulatory T cells to activate the stem cells of the hair follicle, leading to hair growth. This crosstalk between the T cells and the stem cells depends on a mechanism whereby glucocorticoid receptors induce the production of the protein TGF-beta3, all within the regulatory T cells.

The findings suggested that some kind of communication must take place between regulatory T cells and hair follicle stem cells to enable hair regeneration. Image is in the public domain

TGF-beta3 then activates the stem cells of the hair follicles to differentiate into new hair follicles, which promotes hair growth. Additional analysis confirmed that this pathway was completely independent of the ability of regulatory T cells to balance the immune system.

However, regulatory T cells do not normally produce TGF-beta3, as here. When the scientists scanned databases, they found that 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 response in the skin so that they don’t keep attacking the hair follicles,” says Zheng. “Applying glucocorticoids has the dual benefit of triggering the regulatory T cells in the skin to produce TGF-beta3, thereby stimulating activation of hair follicle stem cells.”

This study revealed that regulatory T cells and glucocorticoid hormones are not only immunosuppressants, but also have regenerative function. Next, the scientists will look at other injury models and isolate regulatory T cells from damaged tissues to monitor elevated levels of TGF-beta3 and other growth factors.

Financing: This work was supported by a NOMIS grant and the NOMIS Foundation, the National Institute of Health (NCI CCSG P30-014195, NIA P01-454 AG073084, NIA-NMG RF1-AG064049, NIA P30-AG068635, R01-AI107027, R01- AI1511123, R21-AI154919, and S10-OD023689), the Leona M. and Harry B. Helmsley Charitable Trust, the Crohn’s and Colitis Foundation, the National Cancer Institute, and Salk’s Cancer Center Core Facilities (P30-CA014195).

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Other authors were Xianting Hu, Yuqiong Liang, Jingting Yu, and Maxim N. Shokhirev of Salk and Huabin Li of Fudan University in Shanghai.

About this immune system and research news about hair growth

Author: press office
Source: Salk Institute
Contact: Press Office – Salk Institute
Image: The image is in the public domain

Original research: Closed access.
“Glucocorticoid signaling and regulatory T cells work together to maintain the hair follicle stem cell niche” by Ye Zheng et al. Nature Immunology


Abstract

Glucocorticoid signaling and regulatory T cells work together to maintain hair follicle stem cell niche

Maintenance of tissue homeostasis relies on the communication between stem cells and supporting cells in the same niche. Regulatory T cells (Treg cells) emerge as a critical part of the stem cell niche for supporting their differentiation.

how treg cells detect dynamic signals in this microenvironment and communicate with stem cells is largely unknown. In the present study, by using hair follicles (HFs) to produce T. to studyreg cell-stem cell crosstalk, we show an unrecognized function of the steroid hormone glucocorticoid in instructing skin-resident Treg cells to facilitate HF stem cell (HFSC) activation and HF regeneration.

Ablation of the glucocorticoid receptor (GR) in Treg cells block hair regeneration without affecting immune homeostasis. Mechanistically, GR and Foxp3 work together in Treg cells to induce transforming growth factor 3 (TGF-β3), which activates Smad2/3 in HFSCs and facilitates HFSC proliferation.

The current study identifies crosstalk between Treg cells and HFSCs mediated by the GR-TGF-β3 axis, highlighting a potential means of manipulating Treg cells to support tissue regeneration.

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