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  • Review Article
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NFAT proteins: key regulators of T-cell development and function

Nature Reviews Immunology volume 5, pages 472–484 (2005)Cite this article

Key Points

  • The nuclear factor of activated T cells (NFAT) family of transcription factors consists of five members, NFAT1–NFAT5, which share a conserved DNA-binding domain that is structurally related to the REL-homology domain of REL and nuclear factor-κB family members.

  • T cells express three of the four calcium-regulated NFAT proteins: NFAT1, NFAT2 and NFAT4. These proteins are key regulators of T-cell activation, differentiation and development.

  • In T cells, NFAT proteins are activated following T-cell receptor (TCR) ligation. Increases in calcium that are induced by TCR engagement activate calcineurin, which causes NFAT dephosphorylation and nuclear translocation.

  • Several kinases, including casein kinase 1 (CK1) and glycogen-synthase kinase 3 (GSK3), are also involved in the regulation of NFAT nuclear import and export.

  • In activated T cells, NFAT proteins synergize with activator protein 1 (AP1) transcription factors at composite sites that are located in the promoters and enhancers of many cytokine genes.

  • Interactions of NFAT proteins with transcription factors other than AP1 have been described for different gene promoters in T cells and can induce the activation or inhibition of NFAT activity. NFAT1 can also bind as a homodimer to NF-κB-binding motifs.

  • The results obtained from the analysis of single and double gene-knockout mice indicate that, although there is a certain level of redundancy in the NFAT family of transcription factors, some specific T-cell functions might be regulated by specific NFAT proteins.

  • Experimental evidence indicates that, during T-cell development, calcium–calcineurin–NFAT signalling is a key regulator of positive selection. NFAT2 and NFAT4 might also control thymocyte proliferation and survival.

  • NFAT proteins cooperate with lineage-specific transcription factors to determine pathways of T helper (TH)-cell differentiation into TH1- or TH2-cell populations.

  • Programmes of gene expression that lead to T-cell inactivation and are crucial to maintain T-cell tolerance are also regulated by NFAT proteins in the absence of AP1 cooperation.

  • Disrupting function-specific NFAT interactions with other transcription factors might provide new targets for the development of more specific therapeutic approaches to control immune responses during autoimmunity or graft rejection.

Abstract

Since the discovery of the first nuclear factor of activated T cells (NFAT) protein more than a decade ago, the NFAT family of transcription factors has grown to include five members. It has also become clear that NFAT proteins have crucial roles in the development and function of the immune system. In T cells, NFAT proteins not only regulate activation but also are involved in the control of thymocyte development, T-cell differentiation and self-tolerance. The functional versatility of NFAT proteins can be explained by their complex mechanism of regulation and their ability to integrate calcium signalling with other signalling pathways. This Review focuses on the recent advances in our understanding of the regulation, mechanism of action and functions of NFAT proteins in T cells.

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Figure 1: The NFAT family of transcription factors.
Figure 2: Regulation of NFAT activation.
Figure 3: NFAT and T-helper-cell differentiation.
Figure 4: NFAT-activated programmes of gene expression: T-cell activation versusT-cell anergy.

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Acknowledgements

I thank A. M. Cuervo for critical reading of this manuscript. I give special thanks to A. Rao for stimulating discussions and many useful suggestions. I apologize to those colleagues whose work I could not cite owing to space limitations. This work was supported by grants from the National Institutes of Health (United States) and the Irene Diamond Fund (United States).

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  1. Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Fernando Macian

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DATABASES

Entrez Gene

AKAP79

BCL-2

CABIN1

CDK4

GATA3

IL-2

IL-4

IL-5

IL-10

IL-13

IL-15

LCK

NFAT1

NFAT2

NFAT3

NFAT4

NFAT5

STAT1

STAT4

STAT6

FURTHER INFORMATION

Macian's laboratory

Glossary

REL-FAMILY TRANSCRIPTION FACTORS

Also known as the nuclear factor-κB (NF-κB) family of transcription factors. These factors share an amino-terminal REL-homology domain that contains sequences that are responsible for nuclear localization, dimerization and DNA binding. Homo- or heterodimers of NF-κB proteins modulate the expression of genes that control immune, inflammatory and acute-phase responses, as well as cell growth, apoptosis and oncogenesis. In vertebrates, this family includes NF-κB1 (also known as p50), NF-κB2 (also known as p52), REL (also known as cREL), REL-A (also known as p65) and REL-B.

TRANSACTIVATION DOMAIN

The domain of a transcription factor that binds the promoter region of a gene and induces its transcription.

CALMODULIN

A small calcium-binding protein. Calmodulin is the most important transducer of intracellular calcium signals. It interacts with, and regulates the activity of, a range of proteins that control many cellular processes, including protein phosphorylation and dephosphorylation, cyclic-nucleotide formation and breakdown, cytoskeletal rearrangement, gene transcription and membrane potential.

GREEN FLUORESCENT PROTEIN FUSION PROTEIN

(GFP fusion protein). A hybrid protein that is created by the fusion of the GFP from Aequorea victoria and another protein. This construct allows the tracking of the behaviour of the fused protein using the fluorescence that is emitted by GFP.

SUMOYLATION

The post-translational modification of proteins that involves the covalent attachment of small ubiquitin-like modifier (SUMO) and regulates the interactions of those proteins with other macromolecules.

NF-κB-BINDING MOTIF

(Nuclear factor-κB-binding motif). A DNA-binding sequence that is recognized by NF-κB proteins. Nuclear factor of activated T cells (NFAT)-dimer complexes can form on motifs that are similar to these.

THYMIC INVOLUTION

An age-dependent decrease of thymic epithelial volume that results in the decreased production of T cells.

T-BOX-FAMILY TRANSCRIPTION FACTORS

A family of transcription factors that contain a DNA-binding domain of 200 amino acids, which is known as the T box. These factors are usually involved in developmental programmes. The founding member of this family was Brachyury, and T-bet and eomesodermin are also members.

CHROMATIN-REMODELLING COMPLEXES

Enzymatic complexes that achieve the remodelling of DNA–nucleosomal architecture and determine transcriptional activity. The SWI–SNF (switching-defective–sucrose non-fermenting) ATPases are an example of complexes that remodel chromatin.

HISTONE DEACETYLASE

An enzyme that removes the acetyl groups from lysine residues located at the amino termini of histones. In general, decreased levels of histone acetylation are associated with the repression of gene expression. The balance of histone acetylation is maintained by the interplay between histone deacetylases and histone acetyltransferases.

ANERGY

A state of T cells that have been stimulated through their T-cell receptor 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.

E3 UBIQUITIN LIGASE

An enzyme that attaches the molecular tag ubiquitin to proteins. Depending on the position and number of ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation by the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

CD4+CD25+ REGULATORY T CELLS

(TReg cells). A specialized subset of CD4+ T cells that can suppress the responses of other T cells. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance, and they are characterized by the expression of the α-chain ofthe interleukin-2 receptor(also known as CD25) and the transcription factor FOXP3 (forkhead box P3).

FLUORESCENCE-POLARIZATION ASSAY

A method that can be usedto evaluate the strength of a protein–protein interaction.A fluorescent tag is attachedto one of the protein partners. The formation of a complex is then deduced from an increase in fluorescence polarization, and the equilibrium dissociation constant of the complex can be determined.

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Macian, F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5, 472–484 (2005). https://doi.org/10.1038/nri1632

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  • DOI: https://doi.org/10.1038/nri1632

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