A Skulk of Foxes Controls Treg Cell Development and Function
CITATION: Kerdiles YM, Stone EL, Beisner DR, McGargill MA, Ch'en IL, Stockmann C, et al. Foxo transcription factors control regulatory T cell development and function. Immunity 2010; 33: 890–904.
CITATION: Ouyang W, Liao W, Luo CT, Yin N, Huse M, Kim MV, et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 2012; 491: 554–559.
CITATION: Samstein RM, Arvey A, Josefowicz SZ, Peng X, Reynolds A, Sandstrom R, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012; 151: 153–166.
SUMMARY AND ANALYSIS: Preventing graft rejection by establishing specific tolerance has long been the goal of transplantation. A major breakthrough in understanding immune tolerance came nearly 20 years ago, when Sakaguchi and colleagues identified CD4+ regulatory T cells (Tregs) that are highly immunosuppressive and essential for maintaining self-tolerance. Since this discovery, Tregs have been used to promote graft acceptance in a variety of transplantation models. However, challenges to the clinical implementation of Treg-based therapies include a limited understanding of the mechanisms used by Tregs, and knowledge of the cell-intrinsic and -extrinsic factors that control Treg development, stability and function.
The transcription regulator Foxp3 has been identified as a “master transcription factor” that specifies Treg fate. Foxp3 establishes a gene expression signature that controls immunosuppressive function, including the target genes IL-2, CD25 and CTLA-4. Work over the last several years has identified other transcription factors that function in tandem or in parallel with Foxp3 to control Treg development, homeostasis and function. Among these are the related transcription factors Foxo1 and Foxo3. Unlike Foxp3, these molecules are broadly expressed in multiple hematopoietic and nonhematopoietic lineages and control cellular metabolism, proliferation and survival. Their essential functions in Treg have only recently been established.
Kerdiles and colleagues found that mice specifically lacking Foxo1 in all T cells developed autoimmunity associated with expanded populations of activated T cells, germinal center formation, autoantibodies and spontaneous encephalitis. Although no autoimmune phenotype was observed in Foxo3-deficient mice, loss of both Foxo1 and Foxo3 dramatically accelerated autoimmune disease, demonstrating that these factors have overlapping functions. Importantly, the presence of Foxo1-sufficient T cells in mixed bone marrow chimeras completely prevented disease, indicating that a defect in Treg function underlies the immune dysregulation. Indeed, Treg development in the thymus was impaired in the absence of Foxo1, and peripheral Treg showed diminished expression of CTLA-4.
Samstein and colleagues used genome-wide DNAse hypersensitivity analysis to examine the “enhancer landscape” in Foxp3- and Foxp3+ CD4+ T cells. In naïve CD4+ T cells, Foxp3 predominantly bound to sites in the genome that were already accessible and bound by other transcription factors. They identified Foxo1 as a key transcription factor that was bound to many of these enhancers and was displaced by Foxp3 upon Treg differentiation. Displacement of Foxo1 by Foxp3 resulted in changes in target gene expression, and this capacity of Foxo1 to act as a “predecessor” for Foxp3 provides a key mechanistic insight into how related Fox-family transcription factors can cooperatively control cell fate. Ouyang and colleagues demonstrated the need for continued Foxo1 expression and activity in Treg cells by generating mice specifically lacking Foxo1 in Foxp3-expressing cells. Because Foxo1 is deleted in these cells only after Foxp3 is expressed, its function in Treg cell development remains intact and these animals show no decrease in Treg differentiation in the thymus. However, continued Treg function is impaired, and this is due at least in part to a failure to repress expression of pro-inflammatory cytokines such as IFN-ɣ in Foxo1-deficient Treg cells.
Although the aforementioned studies highlight the crucial role of Foxo transcription factors in Treg cell function, many unanswered questions remain. In particular, the activity of Foxo transcription factors is dynamically regulated by a number of cellular signals, including those related to nutrient sensing, T cell receptor activation and cytokine receptor signaling, and it will be interesting to determine how these various stimuli influence Treg stability and homeostasis via regulation of Foxo function. Nonetheless, these and other recent studies have dramatically enhanced our understanding of the molecular control of Treg cell development and function, which in turn will aid in the application of therapeutic strategies to manipulate Treg activity to modulate immune responses in the context of graft rejection, autoimmunity, cancer and chronic infection.
Dr. Campbell is an associate member at the Benaroya Research Institute in Seattle. Dr. Bromberg is professor of Surgery and Microbiology and Immunology, and is the chief of the Division of Transplantation, University of Maryland Medical Center, Baltimore. Dr. Bromberg is also section editor for “Literature Watch.”