BACKGROUND: Sjogren's syndrome (SS) is distinguished by immune cells infiltration of exocrine glands, with T helper (Th) cells playing a crucial role in its progression. Total glucosides of paeony (TGP), the main compounds of Chinese medicine Paeonia lactiflora Pall, can treat many autoimmune diseases including SS. PURPOSE: To explore the impact and mechanism of TGP on differentiation and functionality of Th1 and Th17 cells in the SS model, and to provide novel insights into potential therapeutic strategies for this condition. STUDY DESIGN: Non-Obese Diabetic (NOD) mice and spleenic naive CD4 METHODS: NOD mice were intragastrically administered with TGP (720, 360 mg/kg), Hydroxychloroquine (HCQ, 80 mg/kg), and Paeoniflorin (PF, 300 mg/kg) for 16 weeks, respectively. In vitro, naive CD4 RESULTS: In comparison to NOD mice administered with vehicle, TGP treatment enhanced tear and saliva flow, ameliorated pathological damage in SMG and LG, down-regulated the percentages of Th1 and Th17 lymphocytes, and suppressed the expression of Th1 and Th17 cell-related factors in SMG and LG at both mRNA and protein levels. Moreover, TGP could prevent naive CD4 CONCLUSION: TGP inhibits differentiation and function of Th1 and Th17 cells, which facilitates the amelioration of SS symptoms.