Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible HIV infection

CD4(+)CD25(+) human regulatory T cells (T-reg cells), which express the transcription factor FoxP3, suppress T cell activation. In this study, we sought to define cellular and molecular mechanisms of human T-reg cell differentiation. A subset of human naive CD4(+) T cells that are CD25(+) express high levels of FoxP3. We show that upon activation through the TCR, these FoxP3-expressing naive T cells (termed T-Nreg cells) greatly expand in vitro. Expanded T-Nreg cells acquire a full Treg phenotype with potent suppressive activity and display low IL-2 production upon TCR stimulation. T-Nreg cells in which FoxP3 expression was reduced through RNA interference lost their suppressive activity, but retained their low IL-2 secretion in response to TCR stimulation. Furthermore, in support of the notion that T-Nreg cells represent a separate lineage of naive cells, we found that they were more susceptible to HIV infection as compared with naive CD4(+) T cells. Based on these findings, we propose that T-Nreg cells are precursors for human T-reg cells and that these cells require a high level of FoxP3 expression to maintain their suppressive function. Accordingly, modulation of T-Nreg cell numbers during infections such as HIV may disrupt human T-reg cell development, and contribute to chronic immune activation.