title: NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis.
abstract: NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic calcium influx where calmodulin, a calcium sensor protein, activates the phosphatase calcineurin that dephosphorylates NFAT proteins and results in NFAT nuclear import. Here, we show the analysis of conditional NFATc1-deficient mice bearing a deletion of NFATc1 in CD4(+) and CD8(+) T cells. NFATc1-deficient CD4(+) T cells polarized under Th17 conditions express reduced levels of the Th17-associated transcription factor RORγT (where ROR is RAR-related orphan receptor) as well as the Th17-associated cytokines IL-17A, IL-17F, IL-21, and IL-10. In the murine model of experimental EAE, we found a strong reduction of the disease outcome in conditional NFATc1-deficient mice, as compared with control littermates. This was accompanied by a diminished inflammation in the brain and spinal cord and reduced IL-17A and IFN-γ expression by antigen-specific spleen, spinal cord, and brain cells. Altogether, these results reveal an important role of NFATc1 in inducing Th17-cell responses and IFN-γ, both being relevant for the EAE development.
authors.affiliation: Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Reppert
authors.affiliation: Department of Immune Modulation, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zinser
authors.affiliation: Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Holzinger
authors.affiliation: Department of Immune Modulation, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Sandrock
authors.affiliation: Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Koch
authors.affiliation: Department of Molecular Pneumology, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Susetta
authors.initials: S
authors.lastname: Finotto
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050778:NFATC Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; D018123:Receptors, Interleukin; C539901:Rorc protein, mouse; D053773:Transforming Growth Factor beta1; C528688:interleukin-23 receptor, mouse; D016753:Interleukin-10; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: CD4+ T cells; EAE; NFAT; RORγT; Th17