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Genetic defects in the transcription factor forkhead box protein P3 (FOXP3) cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). IPEX is thought to be due to a defect in naturally arising CD4^sup +^ Tregs. In this issue of the JCI, Bacchetta and colleagues demonstrate that patients with IPEX and missense mutations in FOXP3 provide insight into the role of various domains of FOXP3 in the development and function of Tregs (see the related article beginning on page 1713).
Nonstandard abbreviations used: FKH. forkhead; FOXP3, forkhead box protein P3; GITR, glucocorricoid-induced TNF receptor, IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked.
In the past decade, naturally arising CD4^sup +^CD25^sup +^ Tregs have emerged as being critical for the maintenance of peripheral immunological tolerance (1). Neonatal thymectomy in mice and thymic hypoplasia in humans (DiGeorge syndrome) result in impaired Treg generation and in the development of organ-specific autoimmune diseases (2, 3). Treg generation in the thymus requires interaction with MHC class II molecules expressed by cortical epithelial cells (4). Other signals have also been implicated, including those delivered by CD28, CD40 ligand, and the cytokines TNF-α and TGF-β (5). However, IL-2, which is necessary for Treg survival in the periphery, is dispensable for their development (6, 7).
Tregs represent a small subset of CD4^sup +^ T cells (S-10%). They express several surface markers including CD25 (the IL-2 receptor α-chain), CTL-associated antigen 4 (CTLA4), and glucocorticoid-induced TNF receptor (GITR). However, these molecules are upregulated in naive CD4^sup +^CD25 T cells following TCR stimulation and cannot therefore serve as absolute Treg markers. Recently, several groups identified the forkhead family transcription factor forkhead box protein P3 (FOXP3) as a specific molecular marker of Tregs (8, 9). FOXP3 expression seems to be largely restricted to a small subset of TCRaP T cells and defines 2 pools of Tregs with suppressive activity: CD4^sup +^CD25^sup high^ cells and a minor population of CD4^sup +^CD25^sup low/-^ T cells. Thus, FOXP3 expression correlates better with suppressor activity than CD2S expression (10). Ectopic expression of Foxp3 in vitro and in vivo is sufficient to convert naive murine CD4^sup +^ T cells to Tregs (11). In contrast, overexpression of FOXP3 in human CD4^sup +^CD25^sup -^ T cells in vitro is not sufficient to generate potent suppressor activity, suggesting that...