FOXO transcription factors throughout T cell biology

Abstract

The outcome of an infection with any given pathogen varies according to the dosage and route of infection, but, in addition, the physiological state of the host can determine the efficacy of clearance, the severity of infection and the extent of immunopathology. Here we propose that the forkhead box O (FOXO) transcription factor family--which is central to the integration of growth factor signalling, oxidative stress and inflammation--provides connections between physical well-being and the form and magnitude of an immune response. We present a case that FOXO transcription factors guide T cell differentiation and function in a context-driven manner, and might provide a link between metabolism and immunity.

Figure 1. A signalling scheme regulating FOXO transcription factors

Forkhead box O (FOXO) transcription factors make multiple connections with the cellular signalling network. Examples of connecting proteins include: phosphoinositide 3-kinase (PI3K) and AKT^,,–; ataxia telangiectasia mutated (ATM)^,; tuberous sclerosis protein 2 (TSC2); extracellular signal-regulated kinase (ERK); JUN N-terminal kinase (JNK); mammalian STE20-like kinase 1 (MST1)^,; IκB kinase (IKK)^,; mammalian target of rapamycin (mTOR); and CREB-binding protein (CBP). The mTOR pathway is inhibited in T cells by metformin, 5-aminoimidazole-4-carboxamide riboside (AICAR) and rapamycin. FOXO transcription factors also affect glycolysis. γ_c, γ-chain; 4EBP, EIF4E-binding protein 1; AMPK, AMP-activated protein kinase; BCL-6, B cell lymphoma 6; CTLA4, cytotoxic T lymphocyte antigen 4; EOMES, eomesodermin; IL-7Rα, interleukin-7 receptor subunit-α; KLF2, Krüppel-like factor 2; mTORC, mTOR complex; PDK1, 3-phosphoinositide-dependent kinase 1; ROS, reactive oxygen species; S1P₁, sphingosine-1-phosphate receptor 1; S6K1, S6 kinase 1; SIRT1, sirtuin 1; TCR, T cell receptor.

Figure 2. Inhibitory and activating post-translational modifications of FOXO1 transcription factors mapped onto a schematic diagram of the functional domains

Unless indicated the post-translational modifications were demonstrated for forkhead box O1 (FOXO1). See the FIG. 1 legend for references with the exception of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). AMPK, AMP-activated protein kinase; CDK2, cyclin-dependent kinase 2; ERK, extracellular signal-regulated kinase; FKH, forkhead domain; IKK, IκB kinase; JNK, JUN N-terminal kinase; MST1, mammalian STE20-like kinase 1; NES, nuclear export signal; NLS, nuclear localization signal; PRMT1, protein arginine N-methyltransferase 1; transactivation, transcriptional activation domain. *Shown for FOXO3. _‡Shown for FOXO4.

Figure 3. Context-dependent FOXO transcriptional activity

The figure shows a schematic representation of the forkhead box O1 (FOXO1) DNA-binding domain (amino acids 150–249) bound to the FOXO consensus DNA sequence (the structural data were obtained from Protein Data Bank entry 3C06 (REF. 71)). The transcriptional activity depends on recruited cofactors, post-translational modifications and cooperative binding, which can have positive (green) or negative (red) effects. FOXO transcription factors bind with differing affinities to DNA sequences related to the consensus site. FOXO factors can also affect chromatin conformation, thereby acting as gateway factors to make gene loci accessible for further regulation. The expectation is that FOXO factors offer unique programmes of gene expression in each distinct cell type.

Figure 4. The Foxp3 locus

The forkhead box P3 (Foxp3) promoter and enhancers may be controlled by activator protein 1 (AP1), forkhead box O1 (FOXO1), nuclear factor of activated T cells (NFAT), SMAD3 and signal transducer and activator of transcription 5 (STAT5), as well as by other factors identified through evolutionarily conserved consensus sites. The enhancer nomenclature for Foxp3 is from REF. . CBFβ, core-binding factor-β; CREB, cAMP-responsive element-binding protein; NF-κB, nuclear factor-κB. *Evolutionarily conserved DAF-16 binding elements.