Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Shaw, J. P. et al. Identification of a putative regulator of early T cell activation genes. Science 241, 202–205 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. Rao, A., Luo, C. & Hogan, P. G. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15, 707–747 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Hogan, P. G., Chen, L., Nardone, J. & Rao, A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 17, 2205–2232 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Graef, I. A., Chen, F. & Crabtree, G. R. NFAT signaling in vertebrate development. Curr. Opin. Genet. Dev. 11, 505–512 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Crabtree, G. R. & Olson, E. N. NFAT signaling: choreographing the social lives of cells. Cell 109, S67–S79 (2002). References 3 and 5 provide an excellent overview of the regulation of NFAT proteins and their function in different organs and tissues.

    Article  CAS  PubMed  Google Scholar 

  6. Kiani, A. et al. Expression and regulation of NFAT (nuclear factors of activated T cells) in human CD34+ cells: down-regulation upon myeloid differentiation. J. Leukoc. Biol. 76, 1057–1065 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Lopez-Rodriguez, C., Aramburu, J., Rakeman, A. S. & Rao, A. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc. Natl Acad. Sci. USA 96, 7214–7219 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Miyakawa, H., Woo, S. K., Dahl, S. C., Handler, J. S. & Kwon, H. M. Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity. Proc. Natl Acad. Sci. USA 96, 2538–2542 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stroud, J. C., Lopez-Rodriguez, C., Rao, A. & Chen, L. Structure of a TonEBP–DNA complex reveals DNA encircled by a transcription factor. Nature Struct. Biol. 9, 90–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Lopez-Rodriguez, C. et al. Bridging the NFAT and NF-κB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress. Immunity 15, 47–58 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Go, W. Y., Liu, X., Roti, M. A., Liu, F. & Ho, S. N. NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment. Proc. Natl Acad. Sci. USA 101, 10673–10678 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Luo, C. et al. Recombinant NFAT1 (NFATp) is regulated by calcineurin in T cells and mediates transcription of several cytokine genes. Mol. Cell. Biol. 16, 3955–3966 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Imamura, R. et al. Carboxyl-terminal 15-amino acid sequence of NFATx1 is possibly created by tissue-specific splicing and is essential for transactivation activity in T cells. J. Immunol. 161, 3455–3463 (1998).

    CAS  PubMed  Google Scholar 

  14. Park, J., Takeuchi, A. & Sharma, S. Characterization of a new isoform of the NFAT (nuclear factor of activated T cells) gene family member NFATc. J. Biol. Chem. 271, 20914–20921 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Chuvpilo, S. et al. Multiple NF-ATc isoforms with individual transcriptional properties are synthesized in T lymphocytes. J. Immunol. 162, 7294–7301 (1999).

    CAS  PubMed  Google Scholar 

  16. Chen, L., Glover, J. N., Hogan, P. G., Rao, A. & Harrison, S. C. Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature 392, 42–48 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Feske, S., Okamura, H., Hogan, P. G. & Rao, A. Ca2+/calcineurin signalling in cells of the immune system. Biochem. Biophys. Res. Commun. 311, 1117–1132 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Garcia-Cozar, F. J. et al. Two-site interaction of nuclear factor of activated T cells with activated calcineurin. J. Biol. Chem. 273, 23877–23883 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Aramburu, J. et al. Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT. Mol. Cell 1, 627–637 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Aramburu, J. et al. Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285, 2129–2133 (1999). This paper describes the identification of a selective peptide that can specifically inhibit NFAT–calcineurin interactions and block cytokine expression by T cells.

    Article  CAS  PubMed  Google Scholar 

  21. Li, H., Rao, A. & Hogan, P. G. Structural delineation of the calcineurin–NFAT interaction and its parallels to PP1 targeting interactions. J. Mol. Biol. 342, 1659–1674 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Liu, J., Masuda, E. S., Tsuruta, L., Arai, N. & Arai, K. Two independent calcineurin-binding regions in the N-terminal domain of murine NF-ATx1 recruit calcineurin to murine NF-ATx1. J. Immunol. 162, 4755–4761 (1999).

    CAS  PubMed  Google Scholar 

  23. Park, S., Uesugi, M. & Verdine, G. L. A second calcineurin binding site on the NFAT regulatory domain. Proc. Natl Acad. Sci. USA 97, 7130–7135 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu, J., Arai, K. & Arai, N. Inhibition of NFATx activation by an oligopeptide: disrupting the interaction of NFATx with calcineurin. J. Immunol. 167, 2677–2687 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Coghlan, V. M. et al. Association of protein kinase A and protein phosphatase 2B with a common anchoring protein. Science 267, 108–111 (1995).

    Article  CAS  PubMed  Google Scholar 

  26. Sun, L. et al. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 8, 703–711 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Kashishian, A. et al. AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region. J. Biol. Chem. 273, 27412–27419 (1998).

    Article  CAS  PubMed  Google Scholar 

  28. Klauck, T. M. et al. Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein. Science 271, 1589–1592 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Rothermel, B. et al. A protein encoded within the Down syndrome critical region is enriched in striated muscles and inhibits calcineurin signaling. J. Biol. Chem. 275, 8719–8725 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Esau, C. et al. Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabin1 results in enhanced cytokine gene expression in T cells. J. Exp. Med. 194, 1449–1459 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ryeom, S., Greenwald, R. J., Sharpe, A. H. & McKeon, F. The threshold pattern of calcineurin-dependent gene expression is altered by loss of the endogenous inhibitor calcipressin. Nature Immunol. 4, 874–881 (2003).

    Article  CAS  Google Scholar 

  32. Okamura, H. et al. Concerted dephosphorylation of the transcription factor NFAT1 induces a conformational switch that regulates transcriptional activity. Mol. Cell 6, 539–550 (2000). This study describes the mechanism of NFAT1 activation by the concerted dephosphorylation of several serines, which induce a conformational switch that exposes a nuclear-localization signal.

    Article  CAS  PubMed  Google Scholar 

  33. Beals, C. R., Sheridan, C. M., Turck, C. W., Gardner, P. & Crabtree, G. R. Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3. Science 275, 1930–1934 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Chow, C. W., Rincon, M., Cavanagh, J., Dickens, M. & Davis, R. J. Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science 278, 1638–1641 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Chow, C. W., Dong, C., Flavell, R. A. & Davis, R. J. c-Jun NH2-terminal kinase inhibits targeting of the protein phosphatase calcineurin to NFATc1. Mol. Cell. Biol. 20, 5227–5234 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Okamura, H. et al. A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol. Cell. Biol. 24, 4184–4195 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gomez del Arco, P., Martinez-Martinez, S., Maldonado, J. L., Ortega-Perez, I. & Redondo, J. M. A role for the p38 MAP kinase pathway in the nuclear shuttling of NFATp. J. Biol. Chem. 275, 13872–13878 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Zhu, J. et al. Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell 93, 851–861 (1998). References 33, 36 and 38 identify GSK3 and CK1 as NFAT kinases that regulate nuclear import and/or export of NFAT proteins.

    Article  CAS  PubMed  Google Scholar 

  39. Yang, T. T., Xiong, Q., Enslen, H., Davis, R. J. & Chow, C. W. Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Mol. Cell. Biol. 22, 3892–3904 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Beals, C. R., Clipstone, N. A., Ho, S. N. & Crabtree, G. R. Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction. Genes Dev. 11, 824–834 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Chuvpilo, S. et al. Alternative polyadenylation events contribute to the induction of NF-ATc in effector T cells. Immunity 10, 261–269 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Zhou, B. et al. Regulation of the murine Nfatc1 gene by NFATc2. J. Biol. Chem. 277, 10704–10711 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002). This study shows that, in the absence of AP1, calcium–calcineurin–NFAT signals control the activation of a programme of gene expression that induces T-cell inactivation.

    Article  CAS  PubMed  Google Scholar 

  44. Barlic, J. et al. Interleukin (IL)-15 and IL-2 reciprocally regulate expression of the chemokine receptor CX3CR1 through selective NFAT1- and NFAT2-dependent mechanisms. J. Biol. Chem. 279, 48520–48534 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Diehl, S. et al. Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation. J. Exp. Med. 196, 39–49 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Terui, Y., Saad, N., Jia, S., McKeon, F. & Yuan, J. Dual role of sumoylation in the nuclear localization and transcriptional activation of NFAT1. J. Biol. Chem. 279, 28257–28265 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Stroud, J. C. & Chen, L. Structure of NFAT bound to DNA as a monomer. J. Mol. Biol. 334, 1009–1022 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Macian, F., Lopez-Rodriguez, C. & Rao, A. Partners in transcription: NFAT and AP-1. Oncogene 20, 2476–2489 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Jain, J., McCaffrey, P. G., Valge-Archer, V. E. & Rao, A. Nuclear factor of activated T cells contains Fos and Jun. Nature 356, 801–804 (1992). This paper reports, for the first time, that the nuclear component that interacts with NFAT proteins in activated T cells is AP1.

    Article  CAS  PubMed  Google Scholar 

  50. Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Macian, F., Garcia-Rodriguez, C. & Rao, A. Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. EMBO J. 19, 4783–4795 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Palacios, E. H. & Weiss, A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 23, 7990–8000 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Wulfing, C., Sjaastad, M. D. & Davis, M. M. Visualizing the dynamics of T cell activation: intracellular adhesion molecule 1 migrates rapidly to the T cell/B cell interface and acts to sustain calcium levels. Proc. Natl Acad. Sci. USA 95, 6302–6307 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Perez, O. D. et al. Leukocyte functional antigen 1 lowers T cell activation thresholds and signaling through cytohesin-1 and Jun-activating binding protein 1. Nature Immunol. 4, 1083–1092 (2003).

    Article  CAS  Google Scholar 

  55. Acuto, O. & Michel, F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nature Rev. Immunol. 3, 939–951 (2003).

    Article  CAS  Google Scholar 

  56. Diehn, M. et al. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc. Natl Acad. Sci. USA 99, 11796–11801 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Appleman, L. J., van Puijenbroek, A. A., Shu, K. M., Nadler, L. M. & Boussiotis, V. A. CD28 costimulation mediates down-regulation of p27kip1 and cell cycle progression by activation of the PI3K/PKB signaling pathway in primary human T cells. J. Immunol. 168, 2729–2736 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Wang, D. et al. CD3/CD28 costimulation-induced NF-κB activation is mediated by recruitment of protein kinase C-q, Bcl10, and IκB kinase β to the immunological synapse through CARMA1. Mol. Cell. Biol. 24, 164–171 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jun, J. E. et al. Identifying the MAGUK protein Carma-1 as a central regulator of humoral immune responses and atopy by genome-wide mouse mutagenesis. Immunity 18, 751–762 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Bodor, J. & Habener, J. F. Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of cytokine gene expression in human thymocytes. J. Biol. Chem. 273, 9544–9551 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nature Immunol. 3, 643–651 (2002). This study shows that NFAT1 binds specifically to the Ifn-γ promoter in T H 1 cells and to the Il-4 promoter in T H 2 cells, where it cooperates with lineage-specific factors.

    Article  CAS  Google Scholar 

  62. Decker, E. L. et al. Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression. Nucleic Acids Res. 31, 911–921 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Duncliffe, K. N., Bert, A. G., Vadas, M. A. & Cockerill, P. N. A T cell-specific enhancer in the interleukin-3 locus is activated cooperatively by Oct and NFAT elements within a DNase I-hypersensitive site. Immunity 6, 175–185 (1997).

    Article  CAS  PubMed  Google Scholar 

  64. Ho, I. C., Hodge, M. R., Rooney, J. W. & Glimcher, L. H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85, 973–983 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Iacobelli, M., Wachsman, W. & McGuire, K. L. Repression of IL-2 promoter activity by the novel basic leucine zipper p21SNFT protein. J. Immunol. 165, 860–868 (2000).

    Article  CAS  PubMed  Google Scholar 

  66. Lee, D. U., Avni, O., Chen, L. & Rao, A. A distal enhancer in the interferon-γ (IFN-γ) locus revealed by genome sequence comparison. J. Biol. Chem. 279, 4802–4810 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Molkentin, J. D. et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell 93, 215–228 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rengarajan, J. et al. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med. 195, 1003–1012 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang, T. T. & Chow, C. W. Transcription cooperation by NFAT•C/EBP composite enhancer complex. J. Biol. Chem. 278, 15874–15885 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Yang, X. Y. et al. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor γ (PPARγ) agonists. PPARγ co-association with transcription factor NFAT. J. Biol. Chem. 275, 4541–4544 (2000).

    Article  CAS  PubMed  Google Scholar 

  71. Youn, H. D., Chatila, T. A. & Liu, J. O. Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J. 19, 4323–4331 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Giffin, M. J. et al. Structure of NFAT1 bound as a dimer to the HIV-1 LTRκB element. Nature Struct. Biol. 10, 800–806 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Jin, L. et al. An asymmetric NFAT1 dimer on a pseudo-palindromic κB-like DNA site. Nature Struct. Biol. 10, 807–811 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Chang, C. P. et al. A field of myocardial–endocardial NFAT signaling underlies heart valve morphogenesis. Cell 118, 649–663 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Muller, C. W. & Harrison, S. C. The structure of the NF-κB p50:DNA-complex: a starting point for analyzing the Rel family. FEBS Lett. 369, 113–117 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Timmerman, L. A. et al. Redundant expression but selective utilization of nuclear factor of activated T cells family members. J. Immunol. 159, 2735–2740 (1997).

    CAS  PubMed  Google Scholar 

  77. Lyakh, L., Ghosh, P. & Rice, N. R. Expression of NFAT-family proteins in normal human T cells. Mol. Cell. Biol. 17, 2475–2484 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chuvpilo, S. et al. Autoregulation of NFATc1/A expression facilitates effector T cells to escape from rapid apoptosis. Immunity 16, 881–895 (2002). This paper describes a property of NFAT2A, the only autoregulated NFAT isoform, in T cells.

    Article  CAS  PubMed  Google Scholar 

  79. Hodge, M. R. et al. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity 4, 397–405 (1996).

    Article  CAS  PubMed  Google Scholar 

  80. Xanthoudakis, S. et al. An enhanced immune response in mice lacking the transcription factor NFAT1. Science 272, 892–895 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Yoshida, H. et al. The transcription factor NF-ATc1 regulates lymphocyte proliferation and TH2 cytokine production. Immunity 8, 115–124 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Ranger, A. M. et al. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc. Immunity 8, 125–134 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. von Boehmer, H. et al. Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Aifantis, I., Gounari, F., Scorrano, L., Borowski, C. & von Boehmer, H. Constitutive pre-TCR signaling promotes differentiation through Ca2+ mobilization and activation of NF-κB and NFAT. Nature Immunol. 2, 403–409 (2001).

    Article  CAS  Google Scholar 

  86. Jenkins, M. K., Schwartz, R. H. & Pardoll, D. M. Effects of cyclosporine A on T cell development and clonal deletion. Science 241, 1655–1658 (1988).

    Article  CAS  PubMed  Google Scholar 

  87. Gao, E. K., Lo, D., Cheney, R., Kanagawa, O. & Sprent, J. Abnormal differentiation of thymocytes in mice treated with cyclosporin A. Nature 336, 176–179 (1988).

    Article  CAS  PubMed  Google Scholar 

  88. Bueno, O. F., Brandt, E. B., Rothenberg, M. E. & Molkentin, J. D. Defective T cell development and function in calcineurin Aβ-deficient mice. Proc. Natl Acad. Sci. USA 99, 9398–9403 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Neilson, J. R., Winslow, M. M., Hur, E. M. & Crabtree, G. R. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20, 255–266 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Hayden-Martinez, K., Kane, L. P. & Hedrick, S. M. Effects of a constitutively active form of calcineurin on T cell activation and thymic selection. J. Immunol. 165, 3713–3721 (2000).

    Article  CAS  PubMed  Google Scholar 

  91. Oukka, M. et al. The transcription factor NFAT4 is involved in the generation and survival of T cells. Immunity 9, 295–304 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Amasaki, Y. et al. A constitutively nuclear form of NFATx shows efficient transactivation activity and induces differentiation of CD4+CD8+ T cells. J. Biol. Chem. 277, 25640–25648 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Amasaki, Y., Masuda, E. S., Imamura, R., Arai, K. & Arai, N. Distinct NFAT family proteins are involved in the nuclear NFAT–DNA binding complexes from human thymocyte subsets. J. Immunol. 160, 2324–2333 (1998).

    CAS  PubMed  Google Scholar 

  94. Ranger, A. M., Oukka, M., Rengarajan, J. & Glimcher, L. H. Inhibitory function of two NFAT family members in lymphoid homeostasis and TH2 development. Immunity 9, 627–635 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Rengarajan, J., Tang, B. & Glimcher, L. H. NFATc2 and NFATc3 regulate TH2 differentiation and modulate TCR-responsiveness of naive TH2 cells. Nature Immunol. 3, 48–54 (2002).

    Article  CAS  Google Scholar 

  96. Schuh, K. et al. Retarded thymic involution and massive germinal center formation in NF-ATp-deficient mice. Eur. J. Immunol. 28, 2456–2466 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Murphy, K. M. & Reiner, S. L. The lineage decisions of helper T cells. Nature Rev. Immunol. 2, 933–944 (2002).

    Article  CAS  Google Scholar 

  98. Agarwal, S. & Rao, A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9, 765–775 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Ansel, K. M., Lee, D. U. & Rao, A. An epigenetic view of helper T cell differentiation. Nature Immunol. 4, 616–623 (2003).

    Article  CAS  Google Scholar 

  100. Szabo, S. J., Sullivan, B. M., Peng, S. L. & Glimcher, L. H. Molecular mechanisms regulating TH1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Agarwal, S., Avni, O. & Rao, A. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo. Immunity 12, 643–652 (2000). This study identifies T H 2-cell-specific binding of NFAT1 to sites in the 3′ enhancer of the Il-4 gene.

    Article  CAS  PubMed  Google Scholar 

  102. Ansel, K. M. et al. Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity. Nature Immunol. 5, 1251–1259 (2004).

    Article  CAS  Google Scholar 

  103. Im, S. H., Hueber, A., Monticelli, S., Kang, K. H. & Rao, A. Chromatin-level regulation of the IL10 gene in T cells. J. Biol. Chem. 279, 46818–46825 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Kiani, A., Viola, J. P., Lichtman, A. H. & Rao, A. Down-regulation of IL-4 gene transcription and control of TH2 cell differentiation by a mechanism involving NFAT1. Immunity 7, 849–860 (1997).

    Article  CAS  PubMed  Google Scholar 

  105. Kiani, A. et al. Regulation of interferon-γ gene expression by nuclear factor of activated T cells. Blood 98, 1480–1488 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Monticelli, S. & Rao, A. NFAT1 and NFAT2 are positive regulators of IL-4 gene transcription. Eur. J. Immunol. 32, 2971–2978 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Porter, C. M. & Clipstone, N. A. Sustained NFAT signaling promotes a TH1-like pattern of gene expression in primary murine CD4+ T cells. J. Immunol. 168, 4936–4945 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Nurieva, R. I. et al. Transcriptional regulation of TH2 differentiation by inducible costimulator. Immunity 18, 801–811 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Riley, J. L. et al. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc. Natl Acad. Sci. USA 99, 11790–11795 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Teague, T. K. et al. Activation changes the spectrum but not the diversity of genes expressed by T cells. Proc. Natl Acad. Sci. USA 96, 12691–12696 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Feske, S., Draeger, R., Peter, H. H., Eichmann, K. & Rao, A. The duration of nuclear residence of NFAT determines the pattern of cytokine expression in human SCID T cells. J. Immunol. 165, 297–305 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Peng, S. L., Gerth, A. J., Ranger, A. M. & Glimcher, L. H. NFATc1 and NFATc2 together control both T and B cell activation and differentiation. Immunity 14, 13–20 (2001). This study shows that NFAT1 and NFAT2 are necessary for T-cell activation and cytokine production.

    Article  CAS  PubMed  Google Scholar 

  113. Feske, S., Giltnane, J., Dolmetsch, R., Staudt, L. M. & Rao, A. Gene regulation mediated by calcium signals in T lymphocytes. Nature Immunol. 2, 316–324 (2001).

    Article  CAS  Google Scholar 

  114. Baksh, S. et al. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol. Cell 10, 1071–1081 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Caetano, M. S. et al. NFATC2 transcription factor regulates cell cycle progression during lymphocyte activation: evidence of its involvement in the control of cyclin gene expression. FASEB J. 16, 1940–1942 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Macian, F., Im, S. H., Garcia-Cozar, F. J. & Rao, A. T-cell anergy. Curr. Opin. Immunol. 16, 209–216 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Heissmeyer, V. et al. Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nature Immunol. 5, 255–265 (2004).

    Article  CAS  Google Scholar 

  119. Jeon, M. S. et al. Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21, 167–177 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Seroogy, C. M. et al. The gene related to anergy in lymphocytes, an E3 ubiquitin ligase, is necessary for anergy induction in CD4 T cells. J. Immunol. 173, 79–85 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Anandasabapathy, N. et al. GRAIL: an E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4+ T cells. Immunity 18, 535–547 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Bopp, T. et al. NFATc2 and NFATc3 transcription factors play a crucial role in suppression of CD4+ T lymphocytes by CD4+ CD25+ regulatory T cells. J. Exp. Med. 201, 181–187 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Gremese, E. & Ferraccioli, G. F. Benefit/risk of cyclosporine in rheumatoid arthritis. Clin. Exp. Rheumatol. 22, S101–S107 (2004).

    CAS  PubMed  Google Scholar 

  124. Ponticelli, C. et al. From cyclosporine to the future. Transplant. Proc. 36, 557S–560S (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Kaufman, D. B. et al. Immunosuppression: practice and trends. Am. J. Transplant. 4, 38–53 (2004).

    Article  PubMed  Google Scholar 

  126. Griffiths, B. & Emery, P. The treatment of lupus with cyclosporin A. Lupus 10, 165–170 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Kiani, A., Rao, A. & Aramburu, J. Manipulating immune responses with immunosuppressive agents that target NFAT. Immunity 12, 359–372 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Bechstein, W. O. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl. Int. 13, 313–326 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Olyaei, A. J., de Mattos, A. M. & Bennett, W. M. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr. Opin. Crit. Care 7, 384–389 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Noguchi, H. et al. A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nature Med. 10, 305–309 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Li, H., Rao, A., Hogan. P. G. Structural delineation of the calcineurin–NFAT interactions and its parallels to PP1 targeting interactions. J. Mol. Biol. 342, 1659–1674 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Rodriguez, A., Martinez-Martinez, S., Lopez-Maderuelo, M. D., Ortega-Perez, I. & Redondo, J. M. The linker region joining the catalytic and the regulatory domains of CnA is essential for binding to NFAT. J. Biol. Chem. 280, 9980–9984 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Roehrl, M. H. et al. Selective inhibition of calcineurin–NFAT signaling by blocking protein–protein interaction with small organic molecules. Proc. Natl Acad. Sci. USA 101, 7554–7559 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Venkatesh, N. et al. Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression. Proc. Natl Acad. Sci. USA 101, 8969–8974 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Issue Date:

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

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing