Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 34; pp. 15169 - 15174
• Main Authors: Ghosh, Srimoyee, Koralov, Sergei B., Stevanovic, Irena, Sundrud, Mark S., Sasaki, Yoshiteru, Rajewsky, Klaus, Rao, Anjana, Müller, Martin R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24-08-2010; National Acad Sciences
• Subjects: Animals; Autoimmune diseases; Base Sequence; Binding Sites - genetics; Biochemistry; Biological Sciences; Calcineurin - metabolism; Calcium; Calcium Signaling; Casein Kinase I - metabolism; Cell Differentiation; Cells; Cellular differentiation; Cellular immunity; Central Nervous System - immunology; Central Nervous System - metabolism; Central Nervous System - pathology; Cytokines; DNA Primers - genetics; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Female; Forkhead Transcription Factors - metabolism; Genetic loci; Interleukin-10 - biosynthesis; Interleukin-10 - genetics; Interleukin-17 - biosynthesis; Interleukin-17 - genetics; Lymphocytes; Messenger RNA; Mice; Mice, Transgenic; Molecular Sequence Data; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Protein Engineering; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1009193107

Nuclear factor of activated T cells (NFAT) proteins are a group of Ca 2+ -regulated transcription factors residing in the cytoplasm of resting cells. Dephosphorylation by calcineurin results in nuclear translocation of NFAT and subsequent expression of target genes; rephosphorylation by kinases, including casein kinase 1 (CK1), restores NFAT to its latent state in the cytoplasm. We engineered a hyperactivable version of NFAT1 with increased affinity for calcineurin and decreased affinity for casein kinase 1. Mice expressing hyperactivable NFAT1 in their T-cell compartment exhibited a dramatically increased frequency of both IL-17– and IL-10–producing cells after differentiation under Th17 conditions—this was associated with direct binding of NFAT1 to distal regulatory regions of Il-17 and Il-10 gene loci in Th17 cells. Despite higher IL-17 production in culture, the mice were significantly less prone to myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis than controls, correlating with increased production of the immunomodulatory cytokine IL-10 and enhanced accumulation of regulatory T cells within the CNS. Thus, NFAT hyperactivation paradoxically leads to decreased susceptibility to experimental autoimmune encephalomyelitis, supporting previous observations linking defects in Ca 2+ /NFAT signaling to lymphoproliferation and autoimmune disease.