Skin γδ T Cells and Their Function in Wound Healing

Abstract

For the skin immune system, γδ T cells are important components, which help in defensing against damage and infection of skin. Compared to the conventional αβ T cells, γδ T cells have their own differentiation, development and activation characteristics. In adult mice, dendritic epidermal T cells (DETCs), Vγ4 and Vγ6 γδ T cells are the main subsets of skin, the coordination and interaction among them play a crucial role in wound repair. To get a clear overview of γδ T cells, this review synopsizes their derivation, development, colonization and activation, and focuses their function in acute and chronic wound healing, as well as the underlining mechanism. The aim of this paper is to provide cues for the study of human epidermal γδ T cells and the potential treatment for skin rehabilitation.

Keywords: DETCs; Vγ4; Vγ6; homeostasis; wound healing; γδT cells.

Figure 1

Development of αβ and γδ T cells. Hematopoietic stem cells migrating into thymus get lymphocytes commitment, the lymphocytes then get αβ commitment and γδ commitment. αβ cells passing through sequential single positive selection and negative selection get matured. Somatic recombination of V, D, J genes forms different γδ chain, which produces varied γδ precursors. Among them, cells with valid γδ chain, getting enough stimulation and appropriate environment get survived, cells with invalid γδ chain and getting insufficient ligand stimulation get apoptosis. Survived γδ T cells then undertake effector commitment and get matured.

Figure 2

γδ T cells in maintaining skin homeostasis. DETCs in epidermis proliferate and maintain a homeostatic population by themselves, they secrete IL-13, IGF-1 and GM-CSF to help keeping steady state of themselves and other cells. IL-7 and IL-15 secreted by epithelial cells contribute to the survival and proliferation of DETCs, PALPs of the apically oriented dendrites contribute to the anchoring of DETCs to the keratinocyte junctions. Vγ4 and Vγ6 T subsets in the dermis traffic between tissues and lymph nodes at a slow but steady rate, CCR6 expressed on their surface combining with the CCL20 expressed in mucocutaneous sites and subcapsular region of primate LNs is an important pathway.

Figure 3

γδ T cells in acute wound healing. Upon activation, DETCs and Vγ4 T cells secrete chemokines to recruit neutrophils and macrophages into lesion site. Activated Vγ4 T cells migrate to epidermis via CCR6-CCL20 pathway, in addition, the traffic of Vγ4 and Vγ6 T subsets between skin and lymph nodes increases, the traffic from skin to lymph nodes is CCR6/CCR7-independent, while that from lymph nodes to skin is CCR2-dependent. Keratinocytes-derived IL-15 and DETCs-derived IGF-1 forms a positive feedback loop and promotes re-epithelialization. The positive feedback loop between wound-derived IL-1β/IL-23 and Vγ4-derived IL-17 can amplify the local inflammation, the IL-1β/IL-23 suppresses IGF-1 production of DETCs.

Figure 4

γδ T cells in chronic wound healing. (A) The robust activation of EPSCs and efficient recruitment of their progeny towards an epidermal lineage are crucial in the re-establishment of an intact keratinocyte layer during wound healing. The balance of proliferation of pluripotent EPSCs (maintaining healing potent) and their differentiation into terminally differentiated cells (wound healing) are pivotal; (B) In chronic or refractory wound, persistent inflammatory condition leads to excessive proliferation and differentiation, with the sacrifice of subsequent loss of the stem cell reservoir. (C) In chronic or refractory wound, continuous secretion of IL-17A by Vγ4 leads sustained inflammation which promotes the excessive differentiation, while suppresses the level of IGF-1 produced by DETCs beneficial for the proliferation of EPSCs, this inference is worthy to be tested.