The study investigates the impact of decreased Foxp3 expression on regulatory T (T<H>) cell function and development. By generating a mouse model with attenuated endogenous Foxp3 expression in T<H> cells, the researchers found that reduced Foxp3 levels lead to an aggressive autoimmune syndrome similar to that seen in scurfy mice and IPIX patients. This condition does not affect thymic development, homeostatic expansion, or de novo generation of Foxp3-expressing cells. In vitro and in vivo, the immune-suppressive activities of T<H> cells with decreased Foxp3 expression were nearly abolished, while their anergic properties were maintained. These cells preferentially became T-helper 2 (T<H>2)-type effectors, even in a T<H>1-polarizing environment, and contributed to immune diseases. The findings suggest that decreased Foxp3 expression causes immune disease by subverting the suppressive function of T<H> cells and converting them into effector cells, providing insights into the regulation of T<H> cell function and the etiology of various human immune disorders.The study investigates the impact of decreased Foxp3 expression on regulatory T (T<H>) cell function and development. By generating a mouse model with attenuated endogenous Foxp3 expression in T<H> cells, the researchers found that reduced Foxp3 levels lead to an aggressive autoimmune syndrome similar to that seen in scurfy mice and IPIX patients. This condition does not affect thymic development, homeostatic expansion, or de novo generation of Foxp3-expressing cells. In vitro and in vivo, the immune-suppressive activities of T<H> cells with decreased Foxp3 expression were nearly abolished, while their anergic properties were maintained. These cells preferentially became T-helper 2 (T<H>2)-type effectors, even in a T<H>1-polarizing environment, and contributed to immune diseases. The findings suggest that decreased Foxp3 expression causes immune disease by subverting the suppressive function of T<H> cells and converting them into effector cells, providing insights into the regulation of T<H> cell function and the etiology of various human immune disorders.