The OX40/OX40L Axis Promotes Th2 Activity and Impairs Regulatory T Cell Function in Atopic Dermatitis.
| Publication Type | Academic Article |
| Authors | Yamamura K, Dahabreh D, Del Duca E, Lozano-Ojalvo D, Kim M, Murai-Yamamura M, Garcet S, Gonzalez J, Miura S, Williams S, Hur H, Li X, Liu Y, Lin X, Metukuru R, Zhou J, Estrada Y, Krueger J, Guttman-Yassky E |
| Journal | Allergy |
| Volume | 81 |
| Issue | 7 |
| Pagination | 2403-2416 |
| Date Published | 03/07/2026 |
| ISSN | 1398-9995 |
| Keywords | Dermatitis, Atopic, T-Lymphocytes, Regulatory, Receptors, OX40, OX40 Ligand, Th2 Cells |
| 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. |
| DOI | 10.1111/all.70252 |
| PubMed ID | 41793700 |