Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to influence immune responses, the effects of low-dose TCDD on the development of autoimmunity are unclear. In this study, using NFS/sld mice as a model for human Sjögren's syndrome, in which the lesions are induced by the thymectomy on day 3 after birth, the autoimmune lesions in the salivary glands, and in later phase, inflammatory cell infiltrations in the other organs were developed by neonatal exposure to nonapoptotic dosage of TCDD without thymectomy on day 3 after birth. We found disruption of thymic selection, but not thymic atrophy, in TCDD-administered mice. The endogenous expression of aryl hydrocarbon receptor in the neonatal thymus was significantly higher than that in the adult thymus, suggesting that the neonatal thymus may be much more sensitive to TCDD compared with the adult thymus. In addition, the production of T(H)1 cytokines such as IL-2 and IFN-gamma from splenic CD4(+) T cells and the autoantibodies relevant for Sjögren's syndrome in the sera from TCDD-exposed mice were significantly increased compared with those in control mice. These results suggest that TCDD/aryl hydrocarbon receptor signaling in the neonatal thymus plays an important role in the early thymic differentiation related to autoimmunity.