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FOXO transcription factors throughout T cell biology

Nature Reviews Immunology volume 12, pages 649–661 (2012)Cite this article

Subjects

Key Points

  • Forkhead box O (FOXO) transcription factors can affect many aspects of organismal physiology, including immunity, longevity, metabolism and oncogenesis. They can activate or repress gene expression and affect chromatin accessibility; in each case, the effects are context dependent.

  • FOXO1 and FOXO3 are the major FOXO paralogues expressed in T cells, and they have distinct (but sometimes overlapping) functions in T cell survival and differentiation. Genetic experiments indicate that FOXO1 is the predominant factor.

  • Inhibition of FOXO transcription factors constitutes a major endpoint in phosphoinositide 3-kinase (PI3K) signalling that is accentuated by extracellular signal-regulated kinase (ERK) signalling or inflammatory signals mediated by IκB kinase. This activity may be opposed in some cells by oxidative stress or an energy deficiency.

  • FOXO1 and FOXO3 have overlapping but unique effects on the survival of T cells during primary and secondary population expansion. Attenuation of FOXO3 may lead to enhanced memory cell survival, as evidenced by increases in HIV-specific T cells in elite controller patients.

  • FOXO1 regulates CD4+ T cell differentiation, including the development and function of regulatory T cells and T helper 1 cells.

  • In CD8+ T cell differentiation, FOXO1 is required for diminished T-bet and enhanced eomesodermin expression in memory T cells. FOXO1 may also be required for the expansion of CD8+ memory T cell populations.

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.

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Figure 1: A signalling scheme regulating FOXO transcription factors.
Figure 2: Inhibitory and activating post-translational modifications of FOXO1 transcription factors mapped onto a schematic diagram of the functional domains.
Figure 3: Context-dependent FOXO transcriptional activity.
Figure 4: The Foxp3 locus.

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Acknowledgements

The authors would like to thank D. R. Beisner, A. S. Dejean, and Y. M. Kerdiles for contributing to this work with their many experimental and conceptual insights.

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  1. University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0377, California, USA

    Stephen M. Hedrick, Rodrigo Hess Michelini, Andrew L. Doedens, Ananda W. Goldrath & Erica L. Stone

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Glossary

Tumour suppressor proteins

Proteins that limit the generation of cancer. Many of these proteins regulate scheduled entry to the cell cycle or promote the apoptosis of damaged cells. Loss-of-function mutations in tumour suppressor genes increase susceptibility to cancer.

Reactive oxygen species

Highly reactive oxygen-containing molecules that can be produced by the mitochondria in eukaryotic cells. Examples include hydrogen peroxide, ions such as hypochlorite, and free radicals such as superoxide and nitric oxide. They can be inactivated by enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase.

mTORC2

(Mammalian target of rapamycin complex 2). A complex consisting of: mammalian target of rapamycin (mTOR); rapamycin-insensitive companion of mTOR (RICTOR); mammalian stress-activated MAP kinase-interacting protein 1 (mSIN1; also known as MAPKAP1); protein observed with RICTOR 1 (PROTOR1); PROTOR2; DEP domain-containing mTOR-interacting protein (DEPTOR); and mLST8 (also known as GβL).

MDM2

An E3 ubiquitin ligase that can cause the proteasomal degradation of p53 as well as of other tumour suppressor proteins such as FOXO3.

MicroRNAs

(miRNAs). Non-coding RNA molecules that provide recognition for the RNA-induced silencing complex (RISC), which has inhibitory effects on transcription and/or translation. This large, multisubunit, nucleoprotein complex includes DICER, which is essential for processing precursor RNA molecules, and Argonaute, which is central to silencing.

T follicular helper cells

(TFH cells). CD4+ T cells that migrate to the B cell-rich follicles in an active immune response and provide helper functions that promote the differentiation of B cells into antibody-producing cells. They are variously described as a separate T cell subset or a further differentiation of TH1, TH2 and TH17 cells.

CTLL cell line

A T cell line that grows indefinitely in the presence of interleukin-2 (IL-2) with no requirement for stimulation through the T cell receptor (TCR). This is not a feature of freshly explanted T cells, which require a cycle of TCR and IL-2 stimulation followed by rest before re-stimulation.

Electrophoretic mobility shift assay

(EMSA). An assay used to measure DNA–protein interactions. Short stretches of double-stranded, radio-labelled DNA are mixed with nuclear extracts and subjected to sizing by gel electrophoresis. In the presence of bound proteins, the labelled DNA will migrate more slowly. To determine the identity of the bound proteins, specific antibodies can be added to see whether the migration of the complex is altered — either becoming even slower ('supershifted') or being prevented altogether.

Chromatin immunoprecipitation

(ChIP). An assay used to determine whether specific transcription factors are bound to chromatin. DNA–protein complexes are stabilized by reversible crosslinking, the DNA is sheared to an average size of about 500 bp, an antibody specific for a suspected chromatin-associated factor is used to carry out immunoprecipitation, and the complexes are isolated. Following dissolution of the crosslinks and protein digestion, PCR is used to determine whether specific DNA sequences were co-isolated. A positive signal using appropriate controls indicates that a given factor is within proximity (about 500 bp) of the primers used to amplify the DNA.

ChIP–seq

An assay similar to chromatin immunoprecipitation (ChIP) with the exception that the immunoprecipitated DNA is modified by the addition of coded oligonucleotides, and the resulting libraries of DNA are sequenced using massively parallel sequencing techniques.

mRNA sequencing

In this technique, poly(A)-containing mRNA isolated by hydridization to oligo-dT columns may be fragmented and is then converted to complementary DNA (cDNA) using the enzyme reverse transcriptase. The cDNA is then prepared for parallel sequencing. The number of sequencing reads specific for each gene correlates with mRNA abundance. Information can also be obtained pertaining to alternative splicing or transcriptional start isoforms of each gene. This technique yields accurate and abundant data, and is rapidly superseding microarray technologies.

3C techniques

Chromosome conformation capture (3C) is used to determine whether a distal enhancer sequence is in proximity to a promoter in a given state of a particular cell type. The basic concept is that DNA–protein and protein–protein interactions in the nucleus are reversibly crosslinked to stabilize interacting regions of DNA. The DNA is digested to completion with a restriction enzyme, and intramolecular ligation is carried out to link promoter and enhancer sequences. The resulting complex can be analysed by sequencing in several ways to identify known or unknown interacting regulatory elements.

mTORC1

(Mammalian target of rapamycin complex 1). A complex consisting of: mammalian target of rapamycin (mTOR), which is a serine/threonine kinase; regulatory-associated protein of mTOR (RAPTOR); proline-rich AKT substrate of 40 kDa (PRAS40), which is an mTORC1 inhibitor; mLST8 (also known as GβL), which is of unknown function; and DEP domain-containing mTOR-interacting protein (DEPTOR), which is an mTOR inhibitor.

CNS3 enhancer

One of four DNA regulatory regions in the Foxp3 gene (together with the promoter, CNS1 and CNS2) that was initially defined by histone modifications that are permissive for transcription. CNS1, CNS2 and CNS3 were then analysed for activity by generating mice with deletions spanning each region of the chromosome.

Cd4Cre Foxo1f/f mice

Mice in which both alleles of the Foxo1 gene are modified to include loxP sites flanking exon 2 and in which the Cre recombinase gene from the P1 bacteriophage is expressed from a transgene using control elements of the Cd4 gene. In such mice, the Foxo1 gene is inactivated in the T cell lineage during the CD4+CD8+ stage of thymic development.

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Hedrick, S., Michelini, R., Doedens, A. et al. FOXO transcription factors throughout T cell biology. Nat Rev Immunol 12, 649–661 (2012). https://doi.org/10.1038/nri3278

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