Regulatory T cells in skin regeneration and wound healing

Abstract

As the body's integumentary system, the skin is vulnerable to injuries. The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality. To this end, multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue. Such temporally- and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation. In this context, regulatory T cells (Tregs) hold a key role in balancing immune homeostasis and mediating cutaneous wound healing. A comprehensive understanding of Tregs' multifaceted field of activity may help decipher wound pathologies and, ultimately, establish new treatment modalities. Herein, we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair. Further, we discuss how Tregs operate during fibrosis, keloidosis, and scarring.

Keywords: Regulatory T cells (Tregs); Skin injury; Skin regeneration; Wound healing; Wound repair.

Fig. 1

Cross-section of the human skin. The human skin is composed of the epidermis, dermis and subcutaneous tissue. The epidermis is a multilayered keratinizing squamous epithelium with keratinocytes representing the most common cell type in this skin layer. The stratum basale and stratum spinosum also harbor Merkel cells, melanocytes, T cells, and Langerhans cells. These four cell populations account for about 10% of epidermal cells. The dermis is home to immune cells, such as granulocytes and lymphocytes, and connective tissue-forming cells (fibroblasts). While collagen fibers and elastic fibers form the cellular fundament, blood and lymph vessels are also interwoven throughout this layer. As a form of elongated invagination, the hair follicle reaches out into the dermis. Sebaceous glands are located in close proximity to the hair follicle and its stem cells

Fig. 2

Wound healing stages. Wound healing is a biological process consisting of four overlapping phases (hemostasis, inflammation, proliferation and remodeling). Immediately after the injury, platelets migrate to the wound site. The release of chemical signaling reagents triggers the activation and polymerization of fibrin leading to the adhesion of platelets. Thus, fibrin (fibrin clot) and coagulated blood accumulate in the wound site. During the inflammation phase, monocytes migrate into the wound tissue, differentiate into tissue macrophages, and subsequently phagocytose the blood coagulum. Growth factors are released into the wound site, stimulating cells to proliferate. As a result, by secreting collagen and fibronectin, fibroblasts form a provisional extracellular matrix. Simultaneously, the squamous epithelium of the skin is renewed via the ingrowth of new epithelial cells from the wound edges (epithelialization). Finally, the final scar tissue is formed, which lacks hair follicles as well as sebaceous and sweat glands. Mφ macrophage

Fig. 3

Nature of regulatory T cells (Tregs). Representing a specialized subset of T lymphocytes, Tregs commonly exhibit a distinctive genetic phenotype with upregulation of genes encoding signature proteins, such as FOXP3. Essentially, Tregs originate from two sources: (1) the majority of Tregs arise during thymic T cell maturation (nTregs). They constitute a steady population carrying CD4 and expressing T cell receptors (TCRs) that enable them to recognize self-antigens. (2) Tregs can also be generated in the periphery from conventional CD4⁺ T cells upon antigenic exposure and stimulated by high levels of TGF-β, retinoic acid, and IL-10. Such iTregs are equipped with TCRs that can also detect foreign antigens. Different Treg subsets including nTregs, iTregs and Foxp3⁻ Tregs circulate in the bloodstream. APC antigen presenting cell, CD4 cluster of differentiation 4, Foxp3 forkhead box protein P3, IL-2 interleukin-2, iTregs induced Tregs, MHC II major histocompatibility complex II, nTregs natural Tregs, TGF-β tumor growth factor-beta

Fig. 4

Cellular cross-talks of regulatory T cells (Tregs) in the skin. In response to UVB radiation, Tregs secrete amphiregulin and enkephalin which bind to EGFR receptors and promote keratinocyte outgrowth. Tregs can suppress T effector cells (Teff) and M1 macrophages, as well as hinder the differentiation of M1 macrophages into M2 macrophages. Tregs can also secrete IL-10 hindering the extravasation of neutrophils and the production of proinflammatory cytokines such as TNF-α and IL-6. EGFR epidermal growth factor receptor, IFN interferon, IL-1β interleukin-1β, TNF tumor necrosis factor, UVB ultraviolet B, Mφ macrophage

Fig. 5

Regulatory T cells (Tregs) in keloid scarring. Tregs can downregulate the expression and cellular impact of TGF-β to target excessive matrix deposition as a hallmark of keloid scarring. Tregs can further reduce mRNA expression of type I collagen. Excessive collagen I and fibrin accumulations have been implicated with fibrosis as part of keloid formation. IL-10 interleukin-10, IL6R interleukin-6 receptor, TGFβR tumor growth factor beta receptor, α-SMA α-smooth muscle actin