Regulatory T cell development in the absence of functional Foxp3

Abstract

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 (Foxp3DeltaEGFP). Thymocyte development in Foxp3DeltaEGFP male mice and Foxp3DeltaEGFP/+ female mice recapitulated that of wild-type mice. Although mature EGFP(+) CD4(+) T cells from Foxp3DeltaEGFP 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.

Cutting Edge: Human CD4−CD8− Thymocytes Express FOXP3 in the Absence of a TCR

“…Although our results are at variance with murine data, recent work suggests that in mice also the induction of a Treg cell genetic program may be an early event (23) and precedes the expression of FoxP3 (24,25). It is also important to note that our results do not dispute the crucial role of TCR in human Treg cell commitment.…”

Fox family ties

“…Following these observations, Foxp3 was quickly shown to be essential for the development and function of regulatory T (Treg) cells. However, experiments that replaced Foxp3 with EGFP or a non-functional Foxp3-EGFP fusion protein showed that developing Treg cells, although lacking regulatory function, retained a portion of the Treg cell transcriptome [3,4]. These observations suggested that a higher order of transcriptional regulation was necessary in addition to Foxp3 expression for Treg cell development.…”

Maintaining immunological tolerance with Foxp3

“…A recent paper, however, argues that, while the function of Tregs is Foxp3 dependent, development of this lineage may not entirely depend upon Foxp3 [72]. It is true that when Foxp3 is deficient, T cells lack regulatory function and mice develop autoimmunity.…”