Figure 2.

Mechanisms of unconventional lymphocytes in mouse skin repair. ILC2 become activated in response to IL-18 released by damaged cells, resulting in the production of IL-13 which can drive the alternative activation of macrophages (AAM), IL-5 which recruits eosinophils (Eos), and potentially Areg which has been shown to have many pro-repair roles at other barrier sites but is yet to have a role defined in skin. MAIT cells become activated by TCR engagement and IL-18 which results in PDGF and IGF-1 production that enhances keratinocyte survival. These cells are also thought to modulate angiogenesis which is an important process for tissue remodeling in repair. MAIT cells can also produce IL-17, but a direct role for MAIT-derived IL-17 in skin repair has not yet been demonstrated. DETC are a mouse specific cell type that is maintained by IL-15 produced by keratinocytes. On damage DETC become activated in response to TCR signals, CD100 engagement with plexin B2 on epithelial cells and detection of stress ligands via NKG2D. This stimulates DETC to produce IGF1 which promotes keratinocyte survival. IGF1, alongside DETC-derived KGF and FGF10 also promote epidermal proliferation. DETC can produce IL-13, which in skin, regulates keratinocyte maturation and migration, but may also have other roles in common with that seen at other barrier sites. ILC3 can become activated downstream of Notch-dependent TNFα production by keratinocytes, or by IL-23 and IL-1β. Activated ILC3 produce CCL3 which recruits monocytes (Mon). ILC3 may also produce GM-CSF which promotes reepithelialisation and vascularization, and regulates collagen deposition. ILC3 are particularly well known for their ability to produce IL-17A which at low levels is pro-repair and acts by promoting the production of antimicrobial peptides and stimulating keratinocyte proliferation. ILCs can also produce IL-22 and IL-17F which upregulates AMPs. IL-22 which can also enhance the formation of granulation tissue, and stimulate vascularization. Similar to ILC3, dermal γδ T cells, which are mainly Vγ4⁺, produce IL-17 and can form a positive feedback loop by stimulating IL-23 and IL-1β production, leading to enhanced activation of both ILC3 and dermal γδ T cells, which is proposed to impair healing. These dermal γδ T cells can also produce FGF10 which promotes keratinocyte proliferation and FGF9 which stimulates hair follicle neogenesis and is thus associated with regeneration. HFSC, Hair follicle stem cells, Re-ep, Re-epithelialization. Created with BioRender.com.