Neonatal Thymic Dynamics Influence Autoimmune Pathology by Shaping the Suppressive Potential of Regulatory T Cells

Neonatal thymectomy (TX) has been known to induce experimental autoimmune disease models in mice for over half a century. The thymic microenvironment, including thymic epithelial cells (TECs), plays a crucial role in establishing self-tolerance in T cells. However, the extent to which the dynamic changes in the neonatal thymic environment contribute to the onset of autoimmunity remains incompletely understood. In this study, the detailed alterations in the neonatal thymus and peripheral lymphoid organs were analyzed using a mouse model of primary Sjögren disease. Mice treated with TX at 3 days after birth (day 3-TX) exhibited significantly more severe autoimmune pathology than those treated with TX at 7 days after birth. Around day 3, T-cell differentiation and the expansion of TECs, particularly medullary TECs, were markedly accelerated in the neonatal thymus. Furthermore, in day 3-TX mice, the expansion of peripherally induced regulatory T (Treg) cells was impaired, along with the loss of thymic-derived Treg cell output that typically undergoes robust expansion around day 3 after birth. The suppressive activity of Treg cells from day 3-TX mice was significantly impaired compared with that of control Treg cells. These findings suggest that the neonatal thymic environment plays a critical role in regulating peripheral immune tolerance and may influence the pathogenesis of autoimmune diseases.