Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

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Abstract

The naturally occurring regulatory T cell (TR) is the pivotal cell type that maintains self-tolerance and exerts active immune suppression. The development and function of TRcells is controlled by Foxp3 (refs1, 2), a lack of which results in loss of TRcells and massive multi-organ autoimmunity in scurfy mice andIPEX(immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients3,4. It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of TRcells; however, emerging evidence associates decreased Foxp3 expression in TRcells with various immune disorders5-7. We hypothesized that Foxp3 regulates TRcell development and function in a dose-dependent, nonbinary manner, and that decreased Foxp3 expression can cause immune disease. Here, by generating a mouse model in which endogenousFoxp3gene expression is attenuated in TRcells, we show that decreased Foxp3 expression results in the development of an aggressive autoimmune syndrome similar to that of scurfy mice, but does not affect thymic development, homeostatic expansion/maintenance or transforming-growth-factor-β-inducedde novogeneration of Foxp3-expressing cells. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolishedin vitroandin vivo,whereas their anergic propertiesin vitrowere maintained. This was accompanied by decreased expression of TRcell 'signature genes'. Notably, T cells expressing decreased Foxp3 preferentially became T-helper 2 (TH2)-type effectors even in a TH1-polarizing environment. These cells instructed TH2 differentiation of conventional T cells, which contributed to the immune diseases observed in these mice. Thus, decreased Foxp3 expression causes immune disease by subverting the suppressive function of TRcells and converting TRcells into effector cells; these findings are important for understanding the regulation of TRcell function and the aetiology of various human immune diseases.

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