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Forkhead-box transcription factors and their role in the immune system

Nature Reviews Immunology volume 4, pages 889–899 (2004)Cite this article

Key Points

  • More than 100 forkhead transcription factors have been identified, and they are known as FOX (forkhead box) proteins. These proteins are classified in terms of structure, not function, and mutation of various FOX proteins leads to immune dysfunction.

  • FOXP3 regulates the production of CD4+CD25+ regulatory T cells, which are crucial for the maintenance of self-tolerance. Deletion of the gene encoding FOXP3 results in overproliferation of activated T cells and development of both autoimmune disease and allergy.

  • FOXN1 is crucial for the growth and differentiation of thymic epithelial cells. Deletion or mutation of the gene encoding this transcription factor, as found in the nude mouse, results in athymia.

  • FOXJ1 is a transcriptional activator, and its expression levels are downregulated by lymphocytes from mice prone to systemic lupus erythematosus. FOXJ1 regulates T-cell activation, probably through inhibiting the activation of nuclear factor-κB (NF-κB).

  • FOXO-subfamily members have central roles in the regulation of proliferation and apoptosis of various cell types. In the immune system, FOXO activity tends to be inversely correlated with cellular activation.

  • Deletion of the gene encoding FOXO3A results in lymphoproliferation and multi-organ inflammation. Similar to FOXJ1, this might also occur through modulation of NF-κB activity.

Abstract

It is more than a decade since the discovery of the first forkhead-box (FOX) transcription factor in the fruit fly Drosophila melanogaster. In the intervening time, there has been an explosion in the identification and characterization of members of this family of proteins. Importantly, in the past few years, it has become clear that members of the FOX family have crucial roles in various aspects of immune regulation, from lymphocyte survival to thymic development. This review focuses on FOXP3, FOXN1, FOXJ1 and members of the FOXO subfamily and their function in the immune system.

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Figure 1: The FOX protein winged-helix DNA-binding domain.
Figure 2: FOXP3 is a master regulator of regulatory T cells.
Figure 3: Thymic development and FOXN1.
Figure 4: Regulation of TH1-cell activation by FOXJ1 and FOXO3A.
Figure 5: Regulation and function of FOXO transcription factors.

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Authors and Affiliations

  1. Department of Pulmonary Diseases, University Medical Centre, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

    Paul J. Coffer

  2. Department of Physiological Chemistry, University Medical Centre, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands

    Boudewijn M. T. Burgering

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Correspondence to Paul J. Coffer.

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DATABASES

Entrez Gene

FOXJ1

FOXN1

FOXO3A

FOXP3

IKK

PKB

PI3K

SMAD7

TGF-β

FURTHER INFORMATION

Paul Coffer's laboratory

Boudewijn Burgering's laboratory

Glossary

REGULATORY T (TReg) CELLS

A subset of CD4+ suppressor T cells that express high levels of CD25 (the interleukin-2 receptor α-chain), the role of which is to maintain self-tolerance.

RECOMBINATION-ACTIVATING-GENE-KNOCKOUT MICE

Recombination-activating genes (Rag1 and Rag2) are expressed by developing lymphocytes. Mice that are deficient in either RAG protein fail to produce B and T cells owing to a developmental block in the gene rearrangement that is required for receptor expression.

ARREST

Any process by which progression through the cell cycle is halted during one of the normal phases — G1 (gap 1), S (synthesis), G2 (gap 2) or M (mitosis).

WNT PROTEINS

WNTs are glycoproteins related to the Drosophila melanogaster protein Wingless, a ligand that regulates the temporal and spatial development of the embryo. WNT-mediated signalling has been shown to regulate cell-fate determination, proliferation, adhesion, migration and polarity during development. In addition to their crucial role in embryogenesis, WNTs and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colon cancers.

BONE MORPHOGENETIC PROTEINS

(BMPs). The genes encoding BMPs constitute a subfamily of the transforming growth factor-β gene superfamily. BMPs have a crucial role in the modulation of mesenchymal differentiation and the induction of cartilage and bone formation.

ANERGY

A state of T cells that have been stimulated through their T-cell receptors in the absence of ligation of CD28. On restimulation, these T cells are unable to produce interleukin-2 or to proliferate, even in the presence of co-stimulatory signals.

PROGRAMMED CELL DEATH

A common form of cell death, which is also known as apoptosis. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation. Apoptosis involves cell shrinkage, chromatin condensation in the periphery of the nucleus, plasma-membrane blebbing and DNA fragmentation into segments of about 180 base pairs. Eventually, the cell breaks up into many membrane-bound 'apoptotic bodies', which are phagocytosed by neighbouring cells.

HYPERMORPHIC

A type of mutation in which the altered gene product has an increased level of activity or in which the wild-type gene product is expressed at an increased level.

BCR-ABL

A tyrosine-kinase oncogene. The Abelson leukaemia-virus protein (ABL) is fused with the breakpoint-cluster region (BCR) in the Philadelphia-chromosome translocation found in chronic myeloid leukaemia.

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Coffer, P., Burgering, B. Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4, 889–899 (2004). https://doi.org/10.1038/nri1488

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