NFAT proteins: key regulators of T-cell development and function (original) (raw)

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Zhou, B. et al. Regulation of the murine Nfatc1 gene by NFATc2. J. Biol. Chem. 277, 10704–10711 (2002).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Macian, F., Lopez-Rodriguez, C. & Rao, A. Partners in transcription: NFAT and AP-1. Oncogene 20, 2476–2489 (2001).
  Article CAS PubMed Google Scholar
• 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
• Chang, L. & Karin, M. Mammalian MAP kinase signalling cascades. Nature 410, 37–40 (2001).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• Appleman, L. J., van Puijenbroek, A. A., Shu, K. M., Nadler, L. M. & Boussiotis, V. A. CD28 costimulation mediates down-regulation of p27_kip1_ 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• von Boehmer, H. et al. Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Murphy, K. M. & Reiner, S. L. The lineage decisions of helper T cells. Nature Rev. Immunol. 2, 933–944 (2002).
  Article CAS Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Nurieva, R. I. et al. Transcriptional regulation of TH2 differentiation by inducible costimulator. Immunity 18, 801–811 (2003).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Baksh, S. et al. NFATc2-mediated repression of cyclin-dependent kinase 4 expression. Mol. Cell 10, 1071–1081 (2002).
  Article CAS PubMed Google Scholar
• 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
• 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
• Schwartz, R. H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Gremese, E. & Ferraccioli, G. F. Benefit/risk of cyclosporine in rheumatoid arthritis. Clin. Exp. Rheumatol. 22, S101–S107 (2004).
  CAS PubMed Google Scholar
• Ponticelli, C. et al. From cyclosporine to the future. Transplant. Proc. 36, 557S–560S (2004).
  Article CAS PubMed Google Scholar
• Kaufman, D. B. et al. Immunosuppression: practice and trends. Am. J. Transplant. 4, 38–53 (2004).
  Article PubMed Google Scholar
• Griffiths, B. & Emery, P. The treatment of lupus with cyclosporin A. Lupus 10, 165–170 (2001).
  Article CAS PubMed Google Scholar
• 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
• Bechstein, W. O. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl. Int. 13, 313–326 (2000).
  Article CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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