Pivotal Role of Dermal IL-17-Producing γδ T Cells in Skin Inflammation

Abstract

Summary Interleukin (IL)-23 and CD4+ T helper-17 (Th17) cells are thought to be critical in the development of psoriasis. Here, we report that IL-23 predominantly stimulated dermal γδT cells to produce IL-17 that led to disease progression. Dermal γδT cells constitutively expressed the IL-23 receptor (IL-23R), RORγt, and various chemokine receptors. IL-17 production from dermal γδT cells was independent of αβT cells. The epidermal hyperplasia and inflammation induced by IL-23 were significantly decreased in T cell receptor δ deficient (Tcrd−/−) and IL-17 receptor deficient (Il17ra−/−) mice but occurred normally in Tcra−/− mice. Imiquimod-induced skin pathology was also significantly decreased in Tcrd−/− mice. Perhaps further promoting disease progression, IL-23 stimulated dermal γδT cell expansion. In psoriasis patients, γδT cells were also greatly increased in affected skin and produced large amounts of IL-17. Thus, IL-23-responsive dermal γδ T cells are the major IL-17 producers in the skin and may represent a novel target for the treatment of psoriasis.

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…Interleukin‐23‐induced skin inflammation is another model of psoriasis. The IL‐17‐producing dermal cells are significantly reduced in Tcrd −/− mice accompanied with less skin inflammation and acanthosis, whereas Tcra −/− mice normally develop dermatitis,23 suggesting that γδ 17 cells play major roles in the pathogenesis of psoriatic dermatitis in this model. The involvement of γδ 17 cells in the development of psoriasiform dermatitis suggests that innate immune responses rather than an autoimmune reaction are important for the development of psoriatic dermatitis.…”

“…On the other hand, dermis contains V γ 4 + and V γ 6 + subsets responsible for IL‐17 production. The pathogenicity of γδ 17 cells in psoriasis is well studied in a mouse model of psoriasis, IMQ‐induced dermatitis 9, 23. Imiquimod is a Toll‐like receptor‐7/8 agonist and induces IL‐17‐dependent psoriasiform dermatitis by inducing IL‐23 63.…”

“…The IMQ‐induced epidermal thickening is significantly decreased in Tcrd –/– mice, but not in Tcrb –/– mice 9. Development of dermatitis is also suppressed by the deficiency of innate lymphoid cells (ILCs), suggesting that γδ 17 cells and IL‐17‐producing group 3 ILCs (ILC3s) are responsible for the development of psoriasiform dermatitis in mice 9, 23. Both V γ 4 + and V γ 6 + subsets produce IL‐17 after IMQ treatment of the skin 35.…”

“…High frequency of γδ T cells is detected in psoriasiform dermal lesions in mice induced by IMQ, and these cells produce IL‐17 through stimulation with IL‐23,23 indicating the innate immune nature of the disease. γδ T cells, especially V γ 9 + V δ 2 + cells which can produce IL‐17, are also accumulated in the skin of patients with psoriasis 93.…”

“…γδ T cells are the principal source of IL‐17 in some mouse inflammatory disease models and thereby exert considerable impact on disease development and progression 20, 21, 22, 23, 24. The IL‐17‐producing γδ T cells ( γδ 17 cells) share many features with Th17 cells, such as cell surface expression of IL‐23R and CCR6 and the expression of transcriptional factor retinoic‐acid‐receptor‐related orphan receptor γ t (ROR γ t).…”