Experience-driven development: Effector/memory-like alpha(+)(E)Foxp3(+) regulatory T cells originate from both naive T cells and naturally occurring naive-like regulatory T cells

Naturally occurring Foxp3(+)CD25(+)CD4(+) regulatory T cells (Treg) have initially been described as anergic cells; however, more recent in vivo studies suggest that Tregs vigorously proliferate under both homeostatic as well as inflammatory conditions. We have previously identified a subset of murine CD4(+) Tregs, which is characterized by expression of the integrin alpha(E)beta(7) and which displays an effector/memory-like phenotype indicative of Ag-specific expansion and differentiation. In the present study, the alpha(+)(E) Treg subset was found to contain a large fraction of cycling cells under homeostatic conditions in healthy mice. Using an adoptive transfer system of Ag-specific T cells, we could demonstrate that the vast majority of transferred natural, naive-like CD25(+)CD4(+) Tregs acquired expression of the integrin alpha(E)beta(7) upon tolerogenic application of Ag via the oral route. In addition, using the same system, Foxp3(+) Tregs could be de novo induced from conventional naive CD25(-)CD4(+) T cells, and this conversion was associated with concomitant expression of alpha(E). These findings suggest that Tregs expressing the integrin aE are effector/memory Tregs with a high turnover rate that can develop in the periphery upon Ag contact under tolerogenic conditions, both from thymic-derived CD25(+)CD4(+) Tregs with a naive-like phenotype as well as from conventional naive T cells.