The OX40 / OX40L Axis Promotes Th2 Activity and Impairs Regulatory T Cell Function in Atopic Dermatitis

ABSTRACT Background Clinical trials using monoclonal antibodies targeting the OX40/OX40L axis (AMG451, GBR830, KHK4083, and KY1005) have shown promise in long‐term disease modification of atopic dermatitis (AD). OX40/OX40L enhances survival of effector T cells and inhibits regulatory T cells (Tregs) function in other inflammatory diseases, but its mechanism of action in AD is unelucidated. We aimed to evaluate OX40‐ and OX40L‐expressing cells in the skin and blood of AD patients to understand how the axis promotes T cell activity and inflammation. Methods Skin samples from AD and healthy controls (HCs) were evaluated using immunohistochemistry (IHC) and immunofluorescence (IF). Flow cytometry was used to analyze peripheral blood mononuclear cells (PBMCs), and RT‐qPCR and ELISA were performed on purified effector CD4 + T cells and from AD patients and HCs. RNA‐seq analysis was conducted on effector CD4 + T cells and Tregs stimulated with anti‐CD3/28, with and without OX40L, in both AD patients and HCs. Results IHC showed increased OX40 + and OX40L + cell expression in AD skin lesions. Circulating CLA + CD4 + T cells and CLA + Tregs upregulate OX40 expression in AD patients compared to HCs. OX40 + CLA + CD4 + Tregs correlated with SCORAD. RNA‐seq, RT‐qPCR, and ELISA revealed that the OX40/OX40L axis maintained the Th2 phenotype of effector CD4+ T cells and decreased IL‐10 produced by Tregs. Conclusion AD patients exhibit significant upregulation of OX40 expression in effector and regulatory CD4 + T cells. Both subsets interact with OX40L‐expressing cells in the skin, leading to the promotion of skin inflammation by downregulation of function and anti‐inflammatory capacity of Tregs.