From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target?

The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-gamma) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-gamma in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-gamma-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4(+)CD161(+)CCR6(+)CXCR3(+)IL-17(+)IFN-y(+) (Th17.1) and CD4(+)CD161(+)CCR6(+)CXCR3(+)IL-17(-)IFN-y(+) (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target.

Automated summary

This review summarizes the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders, highlighting the importance of certain pathogenic Th17 cell subsets in Th1-mediated autoimmunity. These cell subsets are resistant to conventional immunosuppressants, and a deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of potential new treatment targets.