Table 1 Overview of relevant scientific findings in the field of regulatory T cells in hair regeneration and cutaneous wound healing

Tregs in hair regeneration

Ali et al. [109]

Tregs mediate HF cycling by enhancing HFSC differentiation and proliferation. Expression of the Notch ligand Jagged-1 on Tregs was identified as a major mechanism underlying Tregs’ promotion of the HFSC function and HF regeneration. Immunosuppressive properties of Tregs (i.e., suppression of the INF-γ signaling pathway) did not restore HFSC activation. A three-fold higher concentration of Tregs was detectable in telogen skin relative to the anagen state. Treg-depleted mice showed less than 20% of hair regrowth compared to the control group two weeks after depilation

Petukhova et al. [118]

In patients with AA, single nucleotide polymorphisms in genes controlling the nature of Tregs were found. These genes were IL-2/IL-21, IL-2RA (IL-2 receptor A; CD25), Eos (also known as Ikaros family zinc finger 4; IKZF4), and CTLA-4 as well as NOTCH-4

Zöller et al. [119], Hamed et al. [120], Mukhatayev et al. [121]

In both human studies and murine models of AA, both quality and quantity of Tregs were found to be reduced

Castela et al. [122]

Recruitment of Tregs in lesional AA skin promoted via low-dose subcutaneous IL-2 administration has been shown to be effective in AA treatment, with successful hair regeneration being observed in 80% of cases. Results were maintained at 6 months without serious complications

Lee et al. [123]

Expanding Tregs in murine skin alone did not trigger hair growth and failed to suppress autoreactive CD8⁺ T cells to reverse established AA. Upon intradermal injection of IL-2/anti-IL-2-antibody-complex, selective proliferation of Jagged-1⁺ Tregs was noted but immune privilege around hair follicles was not restored. Tregs were unable to promote hair growth by inducing telogen-to-anagen transitions

Tregs in healthy wound healing

Mathur et al. [124]

In a murine wound model, after depletion of Tregs, IL-17-producing CD4⁺ T cells proliferated, leading to an increased expression of the neutrophil chemoattractant CXCL5. The hyperinflammatory CXCL5-IL-17 response blocked HFSC differentiation and impaired their migration into the interfollicular epidermis, ultimately hindering skin repair. Tregs were found to control the local inflammatory environment by suppressing the CXCL5-IL-17 axis, thereby promoting HFSC differentiation during the reestablishment of the skin barrier

Truong et al. [125]

HFSCs may orchestrate the de novo generation of extrathymic Tregs during wound healing. HFSCs expressing CD80 deliver a stimulatory signal to effector CD4⁺ T cells infiltrating into the wound, stimulating them to differentiate into Tregs. These Tregs can protect HFSC from collateral damage induced by inflammatory wound neutrophils

Nosbaum et al. [15]

Tregs facilitate skin wound healing and mitigate wound-associated inflammation. Seven day after full-thickness wounding, the density of Tregs in the wounded skin peaked, reaching levels that were 20-fold higher than at baseline. Specifically, activated Tregs expressing high levels of CD25, CTLA-4, ICOS, and epidermal growth factor receptor (EGFR) (in contrast to Tregs of skin-draining lymph nodes) were observed among the accumulated Tregs. When these Tregs were ablated, there was a significant reduction in re-epithelialization and wound closure, along with an increase in IFN-γ-producing T cells and a buildup of proinflammatory macrophages. Specific deletion of EGFR led to delayed wound closure and significant cellular shift early during the inflammatory phase of wound healing with a decrease of Tregs and an increase in proinflammatory macrophages. Treg-depleting after the inflammatory phase did not influence wound healing kinetics markedly

Haertel et al. [126]

Treg-depleted mice showed impaired wound healing (i.e., decreased wound contraction, delayed re-epithelization, and compromised vessel maturation). Mechanistically, Treg depletion resulted in a significant increase in IL-4 levels combined with an overexpression of T-box transcription factor 21 (TBX21 or T-bet)⁺ and GATA-3⁺ αβ T cells. In addition, an expansion of IL-17A- and IFN-γ-producing CD4⁺ and CD4⁻ αβ T cells was noted. In short, depletion of Tregs was associated with an accumulation of specific αβ T cell population, with alternations in the cytokine (micro)milieu interfering with the healthy wound healing program

Influence of UVB on healing and repair functionality of Tregs

Shime et al. [127]

After UVB irradiation, Tregs expanded in the skin, featuring a unique T cell receptor repertoire and expressing genes associated with wound healing, including those encoding proenkephalin (PENK, an opioid precursor) and amphiregulin (AREG, an EGFR ligand). In a skin explant assay, Treg-derived PENK and AREG promoted the outgrowth of keratinocytes. In addition, UVB-expanded skin Tregs promoted wound healing in vivo. Conversely, the depletion of Tregs exacerbated inflammation in the UVB-exposed skin of mice and impaired wound healing. More precisely, the absence of Tregs was reflected in an increased expression of IL-1β, IFN-γ, TNF-α, and accumulation of Ly6C^high proinflammatory macrophages, and clinically by an aggravation of ear swelling induced by UVB irradiation

Tregs in scarring and fibrosis

Kalekar et al. [17]

Acute and chronic depletion of Tregs in mice led to upregulated profibrotic gene expression, uncontrolled skin fibroblast activation, and dermal fibrosis. Upon Treg-specific deletion of GATA-3, the quantity of skin-infiltrating proinflammatory macrophages and neutrophils did not change markedly, whereas the levels of IL-13 and IL-4-producing Th2 cells along with dermal fibroblast activation increased significantly, ultimately leading to skin fibrosis characterized by dense collagen, increased skin thickness, and reduced dermal adipose tissue. Taken together, Tregs were found to serve as key regulators of skin fibroblast activation and, hence, suppression of profibrotic skin immune responses, expressing a dedicated transcriptional program mediated (in part) by GATA-3

Murao et al. [128]

Co-culturing keloid fibroblasts with Treg-enriched CD4⁺ T cells elevated profibrotic IL-6 but decreased mRNA expression of type I collagen and TGF-β – findings indicative of an anti-fibrotic and protective function of Tregs in the pathogenesis of keloids. The ratio of Tregs/CD4⁺ T cells in keloid tissue was reduced in comparison to other inflammatory skin disorders and rather similar to healthy skin. In sum, a local imbalance of Tregs may underlie keloidosis and could provide a therapeutic avenue for keloid management in the future

Chen et al. [129]

Compared to healthy skin, Treg-associated gene expression, including IL-10 and TGF-β, was significantly upregulated in human keloid tissue. In addition, a correlation between the frequency of Tregs (i.e., the expression of Foxp3) and collagen expression was noted. These findings suggest that Treg dysregulation is limited to the keloid lesion sites. In fibrocytes incubated with activated Tregs (i.e., those pre-stimulated via anti-CD3/CD28 antibodies), the collagen expression was increased. This observation was more pronounced in keloid patients than in non-keloid controls and was postulated to require the secretion of TGF-β. In conclusion, the researchers deduced a link between collagen overexpression/imbalance and Treg dysregulation in keloids

Tregs in chronic and diabetic wound healing

Barros et al. [130]

In a full-thickness murine diabetic wound model, CCR4 and Tregs were found to negatively affect wound healing. Reduced Treg migration into wounded skin was seen in CCR4 knockout diabetic mice. When neutralizing antibodies against the CCR4 ligands, CCL17 and CCL22, were applied, reduced Treg levels and improved wound healing were noted in diabetic wildtype mice (despite worsened diabetes status) as compared to untreated control mice. Neutralization of CCL17/22 also resulted in a decrease in Foxp3 transcripts in the wound bed. Treg depletion via anti-CD25 administration led to improved wound healing kinetics in diabetic mice, indicating a negative effect of Tregs during wound repair