Hyperactivation of nuclear factor of activated T cells 1 (NFAT1) in T cells attenuates severity of murine autoimmune encephalomyelitis.
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.
Ghosh
Srimoyee
S
Department of Pathology, Harvard Medical School and Immune Disease Institute, Children's Hospital, Boston, MA 02115, USA.
Koralov
Sergei B
SB
Stevanovic
Irena
I
Sundrud
Mark S
MS
Sasaki
Yoshiteru
Y
Rajewsky
Klaus
K
Rao
Anjana
A
Müller
Martin R
MR
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D019703:Calcineurin / Q000378:metabolism; D020013:Calcium Signaling; D047389:Casein Kinase I / Q000378:metabolism; D002454:Cell Differentiation; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D011994:Recombinant Proteins; D016753:Interleukin-10; D047389:Casein Kinase I; D019703:Calcineurin