Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation

Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.

Several subsets of Foxp3+ regulatory T (Treg) cells work in concert to maintain immune homeostasis. However, the molecular bases underlying the phenotypic and functional diversity of Treg cells remain obscure. We show that in response to interferon-γ, Foxp3+ Treg cells upregulated the T helper 1 (TH1)-specifying transcription factor T-bet. T-bet promoted expression of the chemokine receptor CXCR3 on Treg cells, and T-bet+ Treg cells accumulated at sites of TH1-mediated inflammation. Furthermore, T-bet expression was required for the homeostasis and function of Treg cells during type-1 inflammation. Thus, within a subset of CD4+ T cells, the activities of Foxp3 and T-bet are overlaid, resulting in Treg cells with unique homeostatic and migratory properties optimized for suppression of TH1 responses in vivo.

Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.