Potential role of IL-17-producing CD4/CD8 double negative αβ T cells in psoriatic skin inflammation in a TPA-induced STAT3C transgenic mouse model

Abstract

Background: Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders and is accompanied by erythematous scaly plaques. There is growing evidence that the IL-23/Th17 axis plays a critical role in development of the disease. It was recently shown that in addition to CD4⁺ Th17 cells, various IL-17-producing cell subsets such as CD8⁺ Tc17 cells, dermal γδ T cells, and innate lymphoid cells are also involved in the development of psoriatic inflammation in humans.

Objective: To investigate which subsets of IL-17-producing cells are involved in psoriasis-like skin inflammation in a TPA (tumor promoter 12-O-tetradecanoylphorbol-13-acetate)-induced K14.Stat3C mouse model.

Method: Skin-infiltrating cells were isolated from inflamed lesions of TPA-treated K14.Stat3C transgenic mice, and analyzed for IL-17 producing cell subsets by flow cytometry.

Results: We observed significantly increased numbers of IL-17-producing CD4⁺ T cells, CD8⁺ T cells and dermal γδ T cells in TPA-induced skin lesions of K14.Stat3C mice. Additionally, we found that another IL-17-producing T cell subset, αβ-TCR⁺ CD4CD8 double negative T cells (DN αβ T cells), was also increased in lesional skin. These IL-17-producing DN αβ T cells are NK1.1 negative, suggesting they are not natural killer T cells or mucosal associated invariant T cells. As well as other IL-17-producing cells, DN αβ T cells in the inflamed skin can also respond to IL-23 stimulation to produce IL-17. It is also suggested that DN αβ T cells may express retinoic acid-related orphan receptor gamma t and CC chemokine receptor 6.

Conclusion: In TPA-induced lesional skin of K14.Stat3C mice, IL-17-producing CD4⁺ Th17 cells, CD8⁺ Tc17 cells, dermal γδ T cells and TCR^- cells probably containing ILCs all participated in skin inflammation, which is similar to human clinical psoriatic features. Furthermore, we showed for the first time the possibility that an IL-17-producing DN αβ T cell subset is also involved in psoriatic inflammation.

Keywords: Double negative αβ T cell; IL-17; IL-23; Psoriasis model; Stat3 transgenic mouse; Th17.