Regulatory T cell development in the absence of functional Foxp3

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(Delta EGFP)). Thymocyte development in Foxp3(Delta EGFP) male mice and Foxp3(Delta EGFP/+) female mice recapitulated that of wild-type mice. Although mature EGFP(+) CD4(+) T cells from Foxp3(Delta EGFP) 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.