Functions of Vγ4 T Cells and Dendritic Epidermal T Cells on Skin Wound Healing

Abstract

Wound healing is a complex and dynamic process that progresses through the distinct phases of hemostasis, inflammation, proliferation, and remodeling. Both inflammation and re-epithelialization, in which skin γδ T cells are heavily involved, are required for efficient skin wound healing. Dendritic epidermal T cells (DETCs), which reside in murine epidermis, are activated to secrete epidermal cell growth factors, such as IGF-1 and KGF-1/2, to promote re-epithelialization after skin injury. Epidermal IL-15 is not only required for DETC homeostasis in the intact epidermis but it also facilitates the activation and IGF-1 production of DETC after skin injury. Further, the epidermal expression of IL-15 and IGF-1 constitutes a feedback regulatory loop to promote wound repair. Dermis-resident Vγ4 T cells infiltrate into the epidermis at the wound edges through the CCR6-CCL20 pathway after skin injury and provide a major source of IL-17A, which enhances the production of IL-1β and IL-23 in the epidermis to form a positive feedback loop for the initiation and amplification of local inflammation at the early stages of wound healing. IL-1β and IL-23 suppress the production of IGF-1 by DETCs and, therefore, impede wound healing. A functional loop may exist among Vγ4 T cells, epidermal cells, and DETCs to regulate wound repair.

Keywords: IGF-1; IL-17A; Vgamma 4 T cell; dendritic epidermal T cell; re-epithelialization; wound healing.

Figure 1

Dendritic epidermal T cells (DETCs), keratinocytes, and Vγ4 T cells constitute two correlated loops to improve wound repair in diabetic mice. Upon skin injury in diabetic mice, keratinocyte-derived IL-15 increases IGF-1 production by DETCs, which in turn enhances keratinocytes to secrete IL-15. A positive correlation between IL-15 and IGF-1 is formed in wounded epidermis, and thereby amplifies IGF-1 production in epidermis for promoting re-epithelialization and wound healing. Meanwhile, keratinocytes could also interact with Vγ4 T cells, which infiltrate in epidermis to form an IL-17A-IL-1β/IL-23 feedback loop to augment local inflammation for efficient skin wound healing. In the wounds of diabetic mice, DETC-mediated IL-15-IGF-1 correlation and Vγ4 T cell-mediated IL-17A-IL-1β/IL-23 loop are coordinated to improve the defects of diabetic wound healing through enhancing re-epithelialization and local inflammation, respectively.

Figure 2

Vγ4 T cells inhibit the production of IGF-1 in dendritic epidermal T cells (DETCs) via IL-17A-IL-1β/IL-23 loop and thereby delay wound healing in normal mice. Once keratinocytes get stressed or damaged, DETCs are activated quickly through TCRs by sensing some as-yet-unknown antigens expressed by damaged keratinocytes in a non-major histocompatibility complex restricted manner. Dermal Vγ4 T cells are attracted to the epidermis around wounds by CCL20, which is increased in wounded epidermis, and provide an early source of IL-17A to delay skin wound healing. IL-17 secreted by Vγ4 T cells inhibits IGF-1 production by DETCs in an indirective way where IL-1β and IL-23 produced by keratinocytes act as the bridge between them. IL-1β and IL-23 are key cytokines to suppress IGF-1 production by DETCs. Besides, Vγ4 T cell-derived IL-17A facilitates keratinocytes to secrete IL-1β and IL-23, and thus forms a positive feedback with keratinocyte-derived IL-1β and IL-23. It is worthy to note that IL-1β is more effective than IL-23 in our investigation. NF-κB pathway plays a crucial role in IL-1β-suppressed IGF-1 expression in DETCs. In conclusion, for wounds in normal mice, Vγ4 T cell-mediated IL-17A-IL-1β/IL-23 loop has a negative impact on IGF-1 production by DETCs and thereby delays skin wound closure.