Although the development of regulatory T cells (T_reg cells) in the thymus is defined by expression of the lineage marker Foxp3, the precise function of Foxp3 in T_reg cell lineage commitment is unknown. Here we examined T_reg cell development and function in mice with a Foxp3 allele that directs expression of a nonfunctional fusion protein of Foxp3 and enhanced green fluorescent protein (Foxp3^ΔEGFP). Thymocyte development in Foxp3^ΔEGFP male mice and Foxp3^ΔEGFP/+ female mice recapitulated that of wild-type mice. Although mature EGFP⁺ CD4⁺ T cells from Foxp3^ΔEGFP mice lacked suppressor function, they maintained the characteristic T_reg cell 'genetic signature' and failed to develop from EGFP⁻ CD4⁺ T cells when transferred into lymphopenic hosts, indicative of their common ontogeny with T_reg cells. Our results indicate that T_reg cell effector function but not lineage commitment requires the expression of functional Foxp3 protein.

NOTE: In the version of this article initially published online, the ‘Foxp2^EGFP’ and ‘Foxp2^ΔEGFP’ labels in Figure 7 are incorrect. The correct labels should be ‘Foxp3^EGFP’ and ‘Foxp3^ΔEGFP’, respectively. Also, Supplementary Tables 1-3 truncated early. The errors have been corrected for all versions of the article.