1. Departments of Immunology and,
2. Pharmacology, and the,
3. Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA
4. National Heart, Lung, and Blood Institute, NIH, 9000 Rockville Pike, Bethesda, Maryland 20892, USA
5. Present address: Amgen Corporation, Seattle, Washington 98101, USA.

Correspondence to: Alexander Y. Rudensky^1,3 Correspondence and requests for materials should be addressed to A.Y.R. (Email: aruden@u.washington.edu).

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 responses¹. 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, 3, 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.

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