Dendritic epidermal T cells regulate skin antimicrobial barrier function
Amanda S. MacLeod, Saskia Hemmers, Olivia Garijo, Marianne Chabod, Kerri Mowen, Deborah A. Witherden, Wendy L. Havran
Amanda S. MacLeod, Saskia Hemmers, Olivia Garijo, Marianne Chabod, Kerri Mowen, Deborah A. Witherden, Wendy L. Havran
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Research Article Immunology

Dendritic epidermal T cells regulate skin antimicrobial barrier function

Abstract

The epidermis, the outer layer of the skin, forms a physical and antimicrobial shield to protect the body from environmental threats. Skin injury severely compromises the epidermal barrier and requires immediate repair. Dendritic epidermal T cells (DETC) reside in the murine epidermis where they sense skin injury and serve as regulators and orchestrators of immune responses. Here, we determined that TCR stimulation and skin injury induces IL-17A production by a subset of DETC. This subset of IL-17A–producing DETC was distinct from IFN-γ producers, despite similar surface marker profiles. Functionally, blocking IL-17A or genetic deletion of IL-17A resulted in delayed wound closure in animals. Skin organ cultures from Tcrd–/–, which lack DETC, and Il17a–/– mice both exhibited wound-healing defects. Wound healing was fully restored by the addition of WT DETC, but only partially restored by IL-17A–deficient DETC, demonstrating the importance of IL-17A to wound healing. Following skin injury, DETC-derived IL-17A induced expression of multiple host-defense molecules in epidermal keratinocytes to promote healing. Together, these data provide a mechanistic link between IL-17A production by DETC, host-defense, and wound-healing responses in the skin. These findings establish a critical and unique role of IL-17A–producing DETC in epidermal barrier function and wound healing.

Authors

Amanda S. MacLeod, Saskia Hemmers, Olivia Garijo, Marianne Chabod, Kerri Mowen, Deborah A. Witherden, Wendy L. Havran

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Figure 6

IL-17A is critical for induction of epidermal host-defense molecules to mediate wound repair.

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IL-17A is critical for induction of epidermal host-defense molecules to ...
(A) IL-17RA expression increases upon wounding. Epidermal cells isolated from nonwounded and wounded sites were stained for IL-17RA 18 hours following wounding. Cells are gated on CD45–. (B) IL-17A induces murine Defb3 and S100a8 in primary murine keratinocytes. **P < 0.01; ***P < 0.001. (C and D) Induction of AMP upon wounding is impaired in Il17a–/– mice. Levels of epidermal β-defensin 3, S100A8, and RegIIIγ were analyzed (C) by qPCR of epidermal sheets from nonwounded and wounded skin or (D) by immunofluorescence staining of wounded and nonwounded skin from WT and Il17a–/– animals 24 hours after wounding. (C) For qPCR, data are pooled from 4–6 wounds and expressed as mean ± SEM from 3 independent experiments. Data are expressed as relative fold change compared with nonwounded controls. *P ≤ 0.05. (D) Antibodies recognizing β-defensin 3, S100A8, or RegIIIγ were used (red staining). DAPI was used to visualize cell nuclei (blue staining). Dotted white lines represent the epidermal-dermal border. Scale bar: 50 μm. (E) β-Defensin 3 but not S100A8 ameliorates defective wound healing in Il17a–/– mice in vivo. Skin wounds were treated with recombinant β-defensin 3 or S100A8, and wound-healing kinetics were measured over time. Data shown represent mean ± SEM of 4 to 8 wounds per condition. *P ≤ 0.05; **P ≤ 0.01, Il17a–/– versus Il17a–/–+ β-defensin 3.