Neonatal thymectomy in certain mouse strains is known to induce organ-specific autoimmunity due to impaired functions of T cells, including Foxp3⁺ regulatory T (T_reg) cells in the thymus. The precise mechanism underlying the induction of autoimmunity by neonatal thymectomy remains unclear. One possibility is that depletion of T_reg cells breaks down peripheral tolerance. We examined the functions of T_reg cells by using a murine Sjögren syndrome model of NFS/sld mice that underwent neonatal thymectomy. The ratio of T_reg cells to effector memory phenotype T cells in thymectomy mice was significantly lower than that of nonthymectomy mice. In addition, in vitro induction of peripherally induced T_reg cells by transforming growth factor-β (TGF-β) using naive T cells from Sjögren syndrome model mice was severely impaired. The mRNA expression of TGF-β receptor I and II and Smad3 and -4 in the TGF-β–induced signal transduction pathway of T_reg cells in this Sjögren syndrome model were lower than those of control mice. In addition, T_reg cells in this Sjögren syndrome model exhibited an interferon-γ–producing Th1-like phenotype that resembled effector T cells. In conclusion, these results suggest that abnormal expansion and differentiation of T_reg cells and inflammatory cytokines produced by T_reg cells contribute to the development of autoimmunity.