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Neonatal-derived IL-17 producing dermal ?? T cells are required to prevent spontaneous atopic dermatitis.

ABSTRACT: Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing ?? T (T??17) cells, from birth resulted in spontaneous, highly penetrant AD with many of the major hallmarks of human AD. In T??17 cell-deficient mice, basal keratinocyte transcriptome was altered months in advance of AD induction. T??17 cells respond to skin commensal bacteria and the fulminant disease in their absence was driven by skin commensal bacteria dysbiosis. AD in this model was characterized by highly expanded dermal ?? T clonotypes that produce the type three cytokines, IL-17 and IL-22. These results demonstrate that neonatal T??17 cells are innate skin regulatory T cells that are critical for skin homeostasis, and that IL-17 has dual homeostatic and inflammatory function in the skin.

SUBMITTER: Spidale NA

PROVIDER: S-EPMC7025821 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Neonatal-derived IL-17 producing dermal γδ T cells are required to prevent spontaneous atopic dermatitis.

Spidale Nicholas A NA Malhotra Nidhi N Frascoli Michela M Sylvia Katelyn K Miu Bing B Freeman Coral C Stadinski Brian D BD Huseby Eric E Kang Joonsoo J

eLife 20200217

Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing γδ T (Tγδ17) cells, from birth ...[more]

PMID: 32065580

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Project description:BackgroundVision loss in patients with wet/exudative age-related macular degeneration (AMD) is associated with choroidal neovascularization (CNV), and AMD is the leading cause of irreversible vision impairment in older adults. Interleukin-17A (IL-17A) is a component of the microenvironment associated with some autoimmune diseases. Previous studies have indicated that wet AMD patients have elevated serum IL-17A levels. However, the effect of IL-17A on AMD progression needs to be better understood. We aimed to investigate the role of IL-17A in a laser-induced CNV mouse model.MethodsWe established a laser-induced CNV mouse model in wild-type (WT) and IL-17A-deficient mice and then evaluated the disease severity of these mice by using fluorescence angiography. We performed enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS) to analyze the levels of IL-17A and to investigate the immune cell populations in the eyes of WT and IL-17A-deficient mice. We used ARPE-19 cells to clarify the effect of IL-17A under oxidative stress.ResultsIn the laser-induced CNV model, the CNV lesions were larger in IL-17A-deficient mice than in WT mice. The numbers of γδ T cells, CD3+CD4+RORγt+ T cells, Treg cells, and neutrophils were decreased and the number of macrophages was increased in the eyes of IL-17A-deficient mice compared with WT mice. In WT mice, IL-17A-producing γδ T-cell numbers increased in a time-dependent manner from day 7 to 28 after laser injury. IL-6 levels increased and IL-10, IL-24, IL-17F, and GM-CSF levels decreased in the eyes of IL-17A-deficient mice after laser injury. In vitro, IL-17A inhibited apoptosis and induced the expression of the antioxidant protein HO-1 in ARPE-19 cells under oxidative stress conditions. IL-17A facilitated the repair of oxidative stress-induced barrier dysfunction in ARPE-19 cells.ConclusionsOur findings provide new insight into the protective effect of IL-17A in a laser-induced CNV model and reveal a novel regulatory role of IL-17A-producing γδ T cells in the ocular microenvironment in wet AMD.

Dataset Information

Neonatal-derived IL-17 producing dermal ?? T cells are required to prevent spontaneous atopic dermatitis.

Publications

Neonatal-derived IL-17 producing dermal γδ T cells are required to prevent spontaneous atopic dermatitis.

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