REVIEW Molecular mechanisms underlying the regulation and functional plasticity of FOXP3 þ regulatory T cells Y Gao 1 , F Lin 1 , J Su 1,2 , Z Gao 1,3 , Y Li 1 , J Yang 1 , Z Deng 1 , B Liu 2 , A Tsun 1 and B Li 1 1 Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; 2 Department of Surgery, Shanghai Public Health Center, Fudan University, Shanghai, China and 3 School of Life Sciences, Fudan University, Shanghai, China CD4 þ CD25 þ regulatory T (Treg) cells engage in the maintenance of immunological self-tolerance and homeostasis by limiting aberrant or excessive inflammation. The transcription factor forkhead box P3 (FOXP3) is critical for the development and function of Treg cells. The differentiation of the Treg cell lineage is not terminal, as developmental and functional plasticity occur through the sensing of inflammatory signals in the periphery. Here, we review the recent progress in our understanding of the molecular mechanisms underlying the regulation and functional plasticity of CD4 þ CD25 þ FOXP3 þ Treg cells, through the perturbation of FOXP3 and its complex at a transcriptional, translational and post-translational level. Genes and Immunity advance online publication, 3 November 2011; doi:10.1038/gene.2011.77 Keywords: Treg; FOXP3; miRNA; T cell plasticity; instability Forkhead box P3 þ (FOXP3 in human, Foxp3 in mice; hereafter referred to as FOXP3 unless specified) regula- tory T (Treg) cells have an important role during immune homeostasis through the maintenance of immune toler- ance and prevention of inflammatory disease. 1 The transcription factor FOXP3 is essential for the develop- ment and function of Treg cells. 2 The loss of expression and mutations of FOXP3 lead to the development of chronic autoimmunity and is presented as the scurfy phenotype in mice 3 and X-linked autoimmunity–allergic dysregulation and immunodysregulation, polyendocri- nopathy and enteropathy, X-linked syndrome in hu- mans. 4 Although Treg cells are essential for the tolerance of commensal microbiota in the gut, 5 an excessive Treg cell response may facilitate tumor growth and chronic infection by limiting anti-tumor or anti-pathogenic immune responses, respectively. 6,7 Thus, Treg cell func- tion must be tightly controlled to heighten or dampen inflammation according to the desired response. Recent studies have also identified FOXP3 expression in epithelial cells, multipotent mesenchymal stromal cells, invariant natural killer T cells and macrophages, 8–10 but CD4 þ CD25 þ T lymphocytes remain the most character- ized cell type. CD4 þ helper T (Th) cells are classified into several subsets according to the expression of various lineage- specific transcription factors and cytokines, such as T box expressed in T cells (T-bet) and interferon (IFN)-g in Th1 cells; GATA-binding protein-3 (GATA-3) and interleukin (IL)-4 in Th2 cells; retinoic acid (RA) receptor-related orphan receptor-gt (RORgt) and IL-17 in Th17 cells; and FOXP3 and IL-10 in Treg cells. 11 There are two major subtypes of Treg cells according to their differentiation origin; natural Treg (nTreg) and induced Treg (iTreg) cells differentiate and adopt FOXP3 expression in the thymus and periphery, respectively. Naı ¨ve T cells differentiate into iTreg cells in the presence of IL-2, transforming growth factor (TGF)-b and stimulation through the T-cell receptor (TcR). 12–15 TGF-b is also required for IL-6- dependent expression of the transcription factor RORgt and inhibition of FOXP3 expression during the genera- tion of Th17 cells from naı ¨ve T cells. 16–20 However, the expression of FOXP3 and RORgt are not always mutually exclusive, as Foxp3 þ T cells in the gut have been shown to co-express high levels of RORgt and concurrently secrete IL-17. 21–23 Human CD4 þ CD25  T cells can also transiently express FOXP3 after TcR stimulation without the requirement of other extrinsic signals, but whether or not they are suppressive during this period is still under debate. 24–30 The instability and plasticity of Treg cells A number of recent studies have shown that Treg cells harbor the propensity to reprogram into proinflamma- tory cells. 31–39 For instance, Th1-like FOXP3 þ Treg cells have been identified in human subjects with multiple sclerosis. 40 The evolutionary advantage of this process could be explained during inflammation, whereby the suppressive nature of Treg cells should be limited for protective and proinflammatory responses to ensue. Received 27 July 2011; revised 22 September 2011; accepted 26 September 2011 Correspondence: Dr A Tsun or Dr B Li, Unit of Molecular Immunology, Key Laboratory of Molecular Virology and Immunol- ogy, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 37 Jianguo Middle Road, Shanghai, 200025, China. E-mail: andy@sibs.ac.cn or binli@sibs.ac.cn Genes and Immunity (2011), 1–13 & 2011 Macmillan Publishers Limited All rights reserved 1466-4879/11 www.nature.com/gene