Dendritic epidermal T cells regulate skin antimicrobial barrier function
Amanda S. MacLeod, … , Deborah A. Witherden, Wendy L. Havran
Amanda S. MacLeod, … , Deborah A. Witherden, Wendy L. Havran
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4364-4374. https://doi.org/10.1172/JCI70064.
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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 3

DETC produce IL-17A upon skin injury in vivo.

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DETC produce IL-17A upon skin injury in vivo. (A) Increased frequency of...
(A) Increased frequency of IL-17A–producing Vγ3+ DETC in wounded skin. Epidermal cells were isolated from skin areas directly surrounding wounds or from nonwounded skin, 18 hours after wounding. Intracellular IL-17A production was analyzed by flow cytometry. Data are pooled and shown as the mean ± SEM of Vγ3 cells producing IL-17A from independent analyses of 4 mice and are expressed as percentage of Vγ3+ cells producing IL-17A. **P < 0.01. (B) Signaling through the Vγ3Vδ1 TCR is required for DETC-mediated IL-17A expression in vivo. Vγ3+ DETC from WT and epidermal TCRβ+ cells from Tcrd–/– mice were isolated and sorted from the epidermis of wounded and nonwounded skin areas 18 hours following skin injury. IL-17A was measured by qPCR. Data are pooled and shown as mean ± SEM from 3 independent experiments with at least 4 mice per genotype per experiment. (C) RORγt increases in DETC upon skin injury. DETC were isolated 12 hours following skin injury from nonwounded and wounded skin areas and were stained for RORγt. Cells are gated on Vγ3+Thy1.2+. (D) Ifng is upregulated upon skin injury. Vγ3+ DETC were isolated and sorted from the epidermis of wounded and nonwounded skin areas 18 hours following skin injury. Ifng was measured by qPCR. Data are pooled and shown as mean ± SEM from 3 independent experiments with at least 4 mice per genotype per experiment.