Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells

Abstract

CD4(+) regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 have a pivotal role in maintaining immunological tolerance. Here we show that mice with T cell-specific deletion of both the Foxo1 and Foxo3 transcription factors (collectively called 'Foxo proteins' here) developed a fatal multifocal inflammatory disorder due in part to T(reg) cell defects. Foxo proteins functioned in a T(reg) cell-intrinsic manner to regulate thymic and transforming growth factor-beta (TGF-beta)-induced Foxp3 expression, in line with the ability of Foxo proteins to bind to Foxp3 locus and control Foxp3 promoter activity. Transcriptome analyses showed that Foxo proteins regulated the expression of additional T(reg) cell-associated genes and were essential for inhibiting the acquisition of effector T cell characteristics by T(reg) cells. Thus, Foxo proteins have crucial roles in specifying the T(reg) cell lineage.

Fox family ties

“…However, there is little effect of T cell-specific Foxo1 deficiency on thymic development, and the frequency of Foxp3 + cells in the thymus, spleen, and lymph nodes of these mice is similar to controls. Importantly, mice with a compound deletion of Foxo1 and Foxo3 in T cells develop a lethal autoimmune inflammatory disease associated with reductions in Treg cell frequency, number, and function [9]. The cumulative data support the hypothesis that Foxo1 and Foxo3 act early in Treg cell lineage specification, while Foxp3 is a late-acting differentiation factor that maintains and stabilizes the Treg cell phenotype.…”

KLF2 is a rate-limiting transcription factor that can be targeted to enhance regulatory T-cell production

“…At the same time, robust antigen receptor and cytokine receptor stimulation activates PI3K, which negatively regulates FoxP3 expression (3,4). This occurs when PI3K activates protein kinase B (PKB), which in turn phosphorylates and inactivates forkhead-box O (Foxo) transcription factors that promote FoxP3 expression (5)(6)(7). Consistent with this model, conditional deletion of Foxo1 and Foxo3 results in reduced numbers of thymic-and peripheral-derived Tregs (7,8).…”

PKB/Akt-dependent regulation of inflammation in cancer

“…For instance, PKB directly phosphorylates FoxO1 and FoxO3 [37,38], leading to their cytoplasmic retention thus inhibiting its nuclear transcriptional activity [45]. This further dampens FoxO-dependent transcriptional regulation of T-bet [46,47] and FoxP3 [47][48][49][50][51]. Helper T cell differentiation is accompanied by the activation of unique metabolic programs.…”