A role for human skin–resident T cells in wound healing

Toulon, A.; Breton, Lionel; Taylor, Kristen R.; Tenenhaus, Mayer; Bhavsar, Dhaval; Lanigan, Caroline; Rudolph, Ross; Jameson, Julie; Havran, Wendy L.

doi:10.1084/jem.20081787

Cited by 292 publications

(267 citation statements)

References 22 publications

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“…By not being alt ered during delayed wound closure in diabetic rats, they are presumably preventing the timely closure of wounds. Igf1 is induced in wounds, both in animals (57,58) and humans (59,60), but is missing in chronic wounds (61). Pro liferation and migration of keratinocytes and fibroblasts is promoted by Igf1 in vitro (62,63) and, interestingly, its levels are reduced in cells isolated from diabetic foot ulcers (64) and in diabetic mouse wounds (65).…”

Section: Resultsmentioning

confidence: 99%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound-healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.

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Section: Resultsmentioning

confidence: 99%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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“…These T cells are important for efficient wound repair and respond to signals from stimulated keratinocytes (14,15). Similarly, populations of epidermal T cells are also present in humans and may also contribute to wound repair (16). To identify skin DETCs we used CXCR6 GFP/+ knock-in mice (17).…”

Section: Resultsmentioning

confidence: 99%

Persistence of skin-resident memory T cells within an epidermal niche

Zaid

Mackay

Rahimpour

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

271

310

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Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (T RM ). In the skin, these memory CD8 + T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal T RM preferentially at the site of prior infection despite sustained migration. Computational simulation of T RM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of T RM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin T RM . Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche. T he skin is a complex organ that acts as a primary barrier between the body and the environment. Multiple leukocyte subsets reside within the main compartments of the skin, the dermis and the epidermis, as well as the hair follicles that are contiguous with the epidermis. Populations of macrophages, dendritic cells, mast cells, γδ T cells and αβ T cells are present in the dermis, and Langerhans cells (LCs) and dendritic epidermal γδ T cells (DETCs) lie in a strategic network in the epidermis (1). We recently described a population of memory CD8 + T cells that enter the epidermis and hair follicles during infection or inflammation and become long-lived populations of tissue-resident memory T cells (T RM ) (2-5). These memory T cells are sequestered in this site and are distinct from circulating effector memory (T EM ) and central memory (T CM ) populations (3, 6). Memory CD8 + T cells in the epidermis display a dendritic morphology and move at a slower velocity than T cells within the dermis. These memory T cells are sequestered in the skin epithelial layer and do not recirculate to other tissues. In contrast, memory CD4 + T cells are found within the dermis and at least a proportion of these cells are capable of recirculating around the body (3, 7).In this study, we sought to further examine the mechanisms of T RM persistence within the skin. We reveal that skin T RM persist at the site of their formation and despite displaying a sustained mode of random migration, the slow rate of this movement locally constrains these memory cells. Examination of other cells in this environment showed that although epidermal T RM regularly interact with LC, these interactions were not required for persistence. In contrast, skin tissue-resident memory T cells replaced DETCs in the epidermis, seem...

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“…gd T cells are also found in human epidermis, together with ab T cells (50); similar to mice, their functional capabilities and homeostasis are not fully understood, but evidence suggests that they share biological roles in immunosurveillance and wound healing (43,51,52). Information gained on DETC in mice may provide new insights into their human counterparts.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Is Critical for Homeostasis of Invariant γδ T Cells in the Murine Epidermis

Kadow

Jux

Zahner

et al. 2011

The Journal of Immunology

134

123

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An immunoregulatory role of aryl hydrocarbon receptor (AhR) has been shown in conventional αβ and γδ T cells, but its function in skin γδ T cells (dendritic epidermal T cells [DETC]) is unknown. In this study, we demonstrate that DETC express AhR in wild-type mice, and are specifically absent in the epidermis of AhR-deficient mice (AhR-KO). We show that DETC precursors are generated in the thymus and home to the skin. Proliferation of DETC in the skin was impaired in AhR-KO mice, resulting in a >90% loss compared with wild type. Surprisingly, DETC were not replaced by αβ T cells or conventional γδ T cells, suggesting a limited time frame for seeding this niche. We found that DETC from AhR-KO mice failed to express the receptor tyrosine kinase c-Kit, a known growth factor for γδ T cells in the gut. Moreover, we found that c-kit is a direct target of AhR, and propose that AhR-dependent c-Kit expression is potentially involved in DETC homeostasis. DETC are a major source of GM-CSF in the skin. Recently, we had shown that impaired Langerhans cell maturation in AhR-KO is related to low GM-CSF levels. Our findings suggest that the DETCs are necessary for LC maturation, and provide insights into a novel role for AhR in the maintenance of skin-specific γδ T cells, and its consequences for the skin immune network.

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A role for human skin–resident T cells in wound healing

Cited by 292 publications

References 22 publications

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Persistence of skin-resident memory T cells within an epidermal niche

Aryl Hydrocarbon Receptor Is Critical for Homeostasis of Invariant γδ T Cells in the Murine Epidermis

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