An Essential Role of the Forkhead-Box Transcription Factor Foxo1 in Control of T Cell Homeostasis and Tolerance

Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Immunity (Impact Factor: 21.56). 04/2009; 30(3):358-71. DOI: 10.1016/j.immuni.2009.02.003
Source: PubMed


Members of the Forkhead box O (Foxo) family of transcription factors are key regulators of cellular responses, but their function in the immune system remains incompletely understood. Here we showed that T cell-specific deletion of Foxo1 gene in mice led to spontaneous T cell activation, effector T cell differentiation, autoantibody production, and the induction of inflammatory bowel disease in a transfer model. In addition, Foxo1 was critical for the maintenance of naive T cells in the peripheral lymphoid organs. Transcriptome analyses of T cells identified Foxo1-regulated genes encoding, among others, cell-surface molecules, signaling proteins, and nuclear factors that control gene expression. Functional studies validated interleukin-7 receptor-alpha as a Foxo1 target gene essential for Foxo1 maintenance of naive T cells. These findings reveal crucial functions of Foxo1-dependent transcription in control of T cell homeostasis and tolerance.

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    • "Sirt1, a histone deacetylase, was shown to inhibit AP-1 and is required for T cell tolerance [26]. Foxo1 is also required for inhibiting T cell activation and acts as a T cell-intrinsic regulator of tolerance [34]. The levels of Sirt1 and Foxo1 expression were significantly down-regulated in PPARγ-deficient T cells following TCR stimulation, suggesting that PPARγ controls the stability or expression of Sirt1 and Foxo1 to inhibit NF-kB or AP-1 activation. "
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    ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPARγ ligands have demonstrated its regulatory functions in inflammation and adaptive immunity, its intrinsic role in T cells and autoimmunity has yet to be fully elucidated. Here we used CD4-PPARγKO mice to investigate PPARγ-deficient T cells, which were hyper-reactive to produce higher levels of cytokines and exhibited greater proliferation than wild type T cells with increased ERK and AKT phosphorylation. Diminished expression of IκBα, Sirt1, and Foxo1, which are inhibitors of NF-κB, was observed in PPARγ-deficient T cells that were prone to produce all the signature cytokines under Th1, Th2, Th17, and Th9 skewing condition. Interestingly, 1-year-old CD4-PPARγKO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (TFH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4-PPARγKO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPARγ has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity.
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    • "FOXO1 controls T cell tolerance and naive T cell homeostasis through the induction of IL-7R expression. It binds to the promoter of IL7r gene and may promote expression by interacting with other nuclear factors (e.g., GABP and Gfi-1) [91]. FOXO1 also regulates the homing of peripheral B cells through upregulation of L-selectin and regulates class-switch recombination in peripheral B cells [92]. "
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    ABSTRACT: Members of the class O of forkhead box transcription factors (FOXO) have important roles in metabolism, cellular proliferation, stress resistance, and apoptosis. The activity of FOXOs is tightly regulated by posttranslational modification, including phosphorylation, acetylation, and ubiquitylation. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase phosphorylates FOXOs at different sites which regulate FOXOs nuclear localization or degradation. FOXO transcription factors are upregulated in a number of cell types including hepatocytes, fibroblasts, osteoblasts, keratinocytes, endothelial cells, pericytes, and cardiac myocytes. They are involved in a number of pathologic and physiologic processes that include proliferation, apoptosis, autophagy, metabolism, inflammation, cytokine expression, immunity, differentiation, and resistance to oxidative stress. These processes impact a number of clinical conditions such as carcinogenesis, diabetes, diabetic complications, cardiovascular disease, host response, and wound healing. In this paper, we focus on the potential role of FOXOs in different disease models and the regulation of FOXOs by various stimuli.
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    • "Expression of the CD62L and CCR7 homing receptors allow T cells to follow gradients of CCL19 and CCL21 chemokines made by the LN stromal cells, and thus access IL-7. Interestingly, the transcription factor Foxo1 regulates expressions of IL-7R, CD62L, and CCR7 in naïve T cells (Freitas and Rocha, 2009; Kerdiles et al., 2009; Ouyang et al., 2009), establishing a close link between lymphocyte migration and survival. Migration ensures the distribution of lymphocytes between different environments and allows the cells to find the appropriate niche for survival. "
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