RORγt antagonist improves Sjögren's syndrome-like sialadenitis through downregulation of CD25

Objective: We reported previously that T-cell-specific RORγt-transgenic mice under human CD2 promoter (RORγt-Tg mice) developed severe spontaneous Sjögren's syndrome (SS)-like sialadenitis, induced by RORγt-overexpressing CD4⁺T cells and reduced regulatory T cells. The purpose of this study was to clarify the effectiveness and mechanisms of action of A213, a RORγt antagonist, in RORγt-Tg mice with SS-like sialadenitis. Methods: Six-week-old RORγt-Tg mice were administered orally of A213 or phosphate-buffered saline every 3 days for 2 weeks. We analyzed saliva volume, histopathology of salivary glands, populations of T cells in splenocytes and cervical lymph nodes (cLNs), and the protein expression levels of CD69 on CD4⁺CD25⁺Foxp3⁻ and CD4⁺CD25⁺Foxp3⁺ cells in cLNs. We also investigated in vitro the potential immunomechanisms of action of A213. Results: A213 significantly increased saliva volume, reduced mononuclear cell infiltration in salivary glands, and reduced the focus score of sialadenitis. Analysis of the immunomechanisms using cLNs showed A213 significantly reduced the proportion of CD4⁺CD25⁺/CD4⁺ T cells and the protein expression levels of CD69 on CD4⁺CD25⁺Foxp3⁻ cells. In vitro experiments showed that A213 suppressed CD25 expression on CD4⁺ T cells and reduced IL-2 production from CD4⁺ T cells derived from RORγt-Tg mice. Conclusion: A213 improves SS-like sialadenitis through the inhibition of CD4⁺CD25⁺ cells in cLNs.