Foxp3-dependent programme of regulatory T-cell differentiation

Regulatory CD4(+) T cells (T-R cells), the development of which is critically dependent on X-linked transcription factor Foxp3 ( forkhead box P3), prevent self-destructive immune responses(1). Despite its important role, molecular and functional features conferred by Foxp3 to T-R precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of T-R precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and T-R suppressive capacity are intimately linked(2-4). Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of T-R cells. Although its function is required for T-R cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of T-R cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies T-R cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain T-R cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for T-R cell homeostasis.