Langerhans cells are one of the first immune cells to appear in the developing epidermis from the yolk sac (Hoeffel et al., 2012). At the time of the placode formation (6–12 weeks EGA (4–10 PCW), E12.5), the phenotype and distribution of these cells differ from that observed in adult skin (Foster et al., 1986) (Figure 1A). Epcam, typically expressed in epidermal Langerhans cells, is a direct transcriptional target of the canonical Wnt-β-catenin signaling pathway. At the same time, the Wnt antagonist, Dkk (limiting the area of Wnt activation and promoting placode formation), also affects Langerhans cells and reduces their proliferation (Becker et al., 2011). In adult skin, mechanical stretching also affects the functioning of Langerhans cells by induction of SFRP2/Wnt/beta-catenin (Ledwon et al., 2022). Although Wnt singling affects both LC maturation and hair follicle development, LC depletion did not affect HF formation (Kaplan et al., 2005). This suggests that LCs do not directly regulate hair follicle development.

Macrophages appear in developing humans at 7 weeks EGA (5 PCW) and mouse skin at E9.5–12.5 (Hoeffel et al., 2015; Kolter et al., 2019; Dhariwala et al., 2020; Reynolds et al., 2021).

Because of the lethal phenotype of macrophage-null mice, the precise functions of these cells during the initiation and early development of hair follicles are not known. However, early fetal macrophages involve clearing debris associated with developmental tissue remodeling and vascularization (Fantin et al., 2010). Macrophages can modulate the Wnt/beta-catenin pathway, either directly through the secretion of Wnt ligands or indirectly by influencing the microenvironment (Malsin et al., 2019) (Figure 1A). A Wnt-mediated connection between macrophages and hair follicle stem cells has been demonstrated (Castellana et al., 2014). At the same time, hair follicle stem cells with activated sonic hedgehog (Shh) and BMP signaling can attract macrophages and influence polarization (Petty et al., 2019; Chakrabarti et al., 2022; Wang et al., 2023). All this suggests that macrophages may play an essential role in the early morphogenesis of hair follicles and provide initiation or regionalization of this process.

Treg cells are observed in developing mouse skin from E6–12 (Scharschmidt et al., 2017), and in humans from the second trimester, 20–23 weeks EGA (18–21 PCW). The density of Treg cells is higher in areas with a higher density of future hair (Dhariwala et al., 2020). The Shh signaling pathway, active during the middle stages of neonatal hair follicle development, has been observed in association with Treg cell activation in a model of atypical dermatitis or in response to mycobacterial infection (Holla et al., 2016; Papaioannou et al., 2019) (Figure 1A). One of the important characteristics of Treg cells in fetal skin is density and the presence of a FOXP3+ memory function (Dhariwala et al., 2020). Recent studies have shown that FOXP3+ CD4⁺ Treg cells are involved in various tissue healing and regeneration by controlling neutrophils and macrophages and local activation of satellite stem cells of the skeletal muscle (Castiglioni et al., 2015; Hou et al., 2021; Goral et al., 2023). These suggest that Treg cells assist the intensive processes of tissue remodeling that occur in the early stages of skin and hair follicle development, regulating homeostasis and tolerance.

Working with human embryos has many limitations including ethical problems. Therefore, many studies suggest mechanisms of human hair follicle development in humans by parallel comparisons with the development in mice. Since the developmental timing of human and mouse hair follicles is different, many comparisons rely on rough morphological similarity (Reynolds et al., 2021). Future studies with advanced single-cell sequencing and spatial transcriptomics technologies will provide accurate and novel cellular and molecular mechanisms of hair follicle development in humans (Rosenberg et al., 2018; Clark et al., 2023; Komatsu et al., 2023).

The growth of hair follicles is associated with the activation of Wnt10b, fibroblast growth factor (FGF)-2, and FGF-7, and the suppression of BMP (Li et al., 2011; Hwang et al., 2012). In experiments on mice, it was shown that the release of Wnt ligands is associated with apoptosis of macrophages, which leads to the proliferation of hair germ cells via activation of Shh signaling, in hair follicle stem cells (Castellana et al., 2014; Ali et al., 2017). Additionally, a specialized subset of macrophages, known as TREM2+ trichophages, has been identified to produce oncostatin M, which inhibits hair follicle stem cell proliferation and differentiation, thus fine-tuning the growth phase duration (Oro and Higgins, 2003). At the same time, Treg cells are attracted adjacent to the hair bulge and activate hair follicle stem cells via Notch signaling with the high level of Jagged 1 (Ali et al., 2017). Adipocytes also participate in the precise control and synchronization of the growth phase. Secretion from adipocytes, such as leptin, adiponectin, and growth factors, supports the active proliferation of hair cells (Park et al., 2010; Won et al., 2012; Cruz et al., 2023) (Figure 1B).

Growing hair follicles eventually enter the regression phase. The size of hair follicles dramatically decreased within a few days by apoptosis and extrusion (Elliott et al., 1999; Müller-Röver et al., 2001; Purba et al., 2014). This regression is influenced by signals from the microenvironment, including BMP from adipose tissue and TGF-β from the dermal papilla. The catagen can be regulated by macrophages that secrete FGF-5. In humans, FGF-5 mutations lead to trichomegaly and eyelash loss, as well as retention of hair follicles at the catagen stage (Müller-Röver et al., 2001; Higgins et al., 2014). Depletion of mast cells in mice also showed a delay in entry into catagen (Arck et al., 2005). This is apparently due to the inability of such mice to secrete substance P, which is usually contained in mast cell granules and is released during mast cell degranulation during entry into catagen (Peters et al., 2007) (Figure 1B).

The hair follicles enter a resting phase after the catagen. During this time, both hair follicle stem cells and dermal papilla become quiescent. This quiescence is maintained by inhibitory signals from various niche components, including the Keratin6 +inner bulge cells, arrector pili muscle, subdermal adipocytes, and immune cells (Fujiwara et al., 2011; Hsu et al., 2011; Wang et al., 2019). Immune cells, especially Treg cells and macrophages, vary in number throughout the hair cycle, playing key roles in tissue maintenance. Macrophage and Treg numbers are abundant in early-mid telogen and gradually decrease until the onset of Anagen (Castellana et al., 2014; Ali et al., 2017). Experiments on mice showed macrophage ablation during telogen can trigger the transition to anagen (Castellana et al., 2014; Wang et al., 2019). While Treg cells activate hair follicle stem cells via Notch signaling for initiation of anagen, macrophages maintain telogen by activity of JAK-STAT signaling (Ali et al., 2017; Dalessandri and Kasper, 2019) (Figure 1B).

The elucidation of immune cell roles across different phases of the hair cycle opens promising avenues for therapeutic interventions targeting hair loss and other follicle-related disorders. Future research should aim to further dissect the molecular dialogues between hair follicles and immune cells. In particular, recent advance in technologies in single-cell analyses, such as single-cell RNA sequencing and intravital imaging, offers an opportunity to uncover novel cell types and signaling pathways involved in hair follicle regulation, potentially identifying targets for enhancing hair growth or delaying hair loss. Additionally, the therapeutic manipulation of immune pathways, such as modulating Treg cell activity or macrophage phenotypes, holds potential for novel treatments. Ultimately, integrating these insights with advances in gene editing and regenerative medicine could lead to groundbreaking strategies for hair restoration, emphasizing the importance of a detailed understanding of the hair follicle immune microenvironment.

Keratinocytes in the hair follicle, particularly those in the outer root sheath, contribute to the immune privilege by expressing lower levels of major histocompatibility complex (MHC) molecules, which are crucial for antigen presentation to T cells (Paus et al., 1998). This reduced expression limits the follicle’s ability to trigger an immune response.

Melanocytes in the hair bulb are responsible for pigment production in the hair and also play a role in immune regulation. Melanocytes in the hair follicle can produce immunosuppressive factors, such as alpha-melanocyte-stimulating hormone (α-MSH), which helps in maintaining the immune-privileged status by suppressing inflammation (Billingham and Silvers, 1971; Clemson et al., 2017).

Treg cells help suppress immune responses and prevent autoimmunity, expressing high-affinity IL-2 receptors, which are crucial for their suppressive function, thereby protecting hair follicles from inflammation and autoimmune attacks (Cohen et al., 2024). Tregs are found in higher concentrations around hair follicles compared to other skin areas, contributing to the immunosuppressive microenvironment (Cohen et al., 2024).

In the hair follicle, mast cells can contribute to immune privilege by releasing mediators such as histamine and tryptase, which modulate local immune responses and reduce inflammation around the hair follicles, suppress inflammation, and modulate the activity of other immune cells (Maurer et al., 1997; Bertolini et al., 2016).

Dermal papilla works as a signaling center of hair follicle homeostasis by secreting several factors (Rahmani et al., 2014). Among them, transforming growth factor-beta (TGF-β) and hepatocyte growth factor (HGF) impact not follicular keratinocytes as well as local immune cells. Therefore, these factors can contribute to the immunosuppressive microenvironment and help to maintain the immune privilege (Park et al., 2021).

Endothelial cells express immunosuppressive molecules like indoleamine 2,3-dioxygenase (IDO). IDO recruits Treg cells near the hair follicles and fosters a microenvironment that limits inflammatory responses. This immunosuppressive network is essential for protecting the hair follicle from immune-mediated damage (Ito et al., 2008).

The sophisticated interplay of diverse cell types within the hair follicle microenvironment controls a unique immune privilege state for maintaining follicular integrity. Future researches that elucidate precise molecular mechanisms of sustaining the follicular immune privilege could unlock novel strategies for enhancing hair growth or preventing hair disorders.