The Role of T Helper 22 Cells in Dermatological Disorders

Abstract

T helper 22 (Th22) cells are a newly identified subset of CD4+ T cells that secrete the effector cytokine interleukin 22 (IL-22) upon specific antigen stimulation, barely with IFN-γ or IL-17. Increasing studies have demonstrated that Th22 cells and IL-22 play essential roles in skin barrier defense and skin disease pathogenesis since the IL-22 receptor is widely expressed in the skin, especially in keratinocytes. Herein, we reviewed the characterization, differentiation, and biological activities of Th22 cells and elucidated their roles in skin health and disease. We mainly focused on the intricate crosstalk between Th22 cells and keratinocytes and provided potential therapeutic strategies targeting the Th22/IL-22 signaling pathway.

Keywords: IL-22; Th22 cells; inflammation; keratinocyte; skin.

Figure 1

The characterization, differentiation of Th22 and the signaling pathway of Th22/IL-22. Native T cells induced by IL-6, IL-23, IL-1β and TNF-α, mediated by LC, DC or activated B cells could differentiate into Th22, while TGFβ could inhibit Th22 polarization. AHR, the master transcription factor of Th22, could be upregulated by ultraviolet B, microbiota, PGE2 and Notch signaling. Th22 secreted its effector cytokine IL-22, as well as IL-13, IL-26, TNF- α and granzyme B. Th22 might converted to Th1, Th2, Th17 under certain conditions. IL-22 could bind to receptor complex of IL-22R and IL-10R, activating TYK2 and JAK1, thus mediating multiple pathways. In contrast, the decoy receptor IL-22BP blocks the roles of IL-22. Th22, T helper 22 cell; LC, Langerhans cell; DC, dendritic cell; AHR, aryl hydrocarbon receptor; IL-22R, IL-22 receptor; IL-10R, IL-10 receptor; IL-22BP, IL-22 binding protein; PGE2, Prostaglandin E2. Created with Biorender.com.

Figure 2

Cutaneous biological roles of Th22 cells and IL-22. Th22 cells exert biological functions through its effector cytokine IL-22 in the skin. Besides, IL-22 could also be secreted by ILC, NK cells, LTi, NKT, γδT, Th1/17, CD8+ T cell, DC, macrophage, mast cell, neutrophil and fibroblast in the skin. Both positive inducers and negative controllers could regulate the expression of IL-22. IL-22 plays a vital role in Th22-mediated host defense by communicating with keratinocytes, promoting antimicrobial peptides and keratinocytes proliferation, inhibiting keratinocyte differentiation, and regulating tissue remodeling as well as inflammation. Furthermore, IL-22 could amplify its biological activities through a positive feedback loop by inducing IL-20 production in keratinocytes, which has similar effects on keratinocytes. ILC, innate lymphoid cell; NKT, natural killer T cell; LTi, Lymphoid tissue inducer; γδT, gamma-delta T cell; DC, dendritic cell; Th, T helper cell; IL-22BP, IL-22 binding protein; MMP, matrix metalloproteinases; AHR, aryl hydrocarbon receptor. Created with Biorender.com.