title: NFAT1 deficit and NFAT2 deficit attenuate EAE via different mechanisms.
abstract: EAE serves as an animal model for multiple sclerosis and is initiated by autoreactive T cells that infiltrate the CNS. Recognition of myelin-associated Ags within the CNS leads to activation of the transcription factor family NFAT. Here, we demonstrate an essential role for NFAT in disease induction, as the combined lack of NFAT1 (NFATc2) and NFAT2 (NFATc1) completely protected mice. Single deficiency of either NFAT1 or NFAT2 ameliorated the course of EAE, and NFAT2 ablation resulted in an obstructed proinflammatory reaction. However, NFAT1 deficit led to an anti-inflammatory response with nonpathogenic Th17 and Th2 cells concurrently secreting IL-17, IL-4, and IL-10. Both IL-4 and IL-10 contributed to disease protection. In Nfat1(-/-) CD4(+) T cells, the expression of anti-inflammatory lymphokines was mediated by NFAT2, thus directly enabling protective IL expression. Consequently, blocking NFAT in toto may be an option for immunosuppressive therapy. More importantly, selective NFAT1 blockade could represent a safe long-term immunomodulatory treatment approach for multiple sclerosis patients, potentially avoiding the adverse effects of global immunosuppression.
authors: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Lena
authors: L
authors: Dietz
authors: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.|Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany.
authors: Friederike
authors: F
authors: Frommer
authors: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Anna-Lena
authors: AL
authors: Vogel
authors: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Martin
authors: M
authors: Vaeth
authors: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Edgar
authors: E
authors: Serfling
authors: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University of Mainz, Mainz, Germany.
authors: Ari
authors: A
authors: Waisman
authors: Department of Neurology, University of Wuerzburg, Wuerzburg, Germany.
authors: Mathias
authors: M
authors: Buttmann
authors: Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Wuerzburg, Germany.
authors: Friederike
authors: F
authors: Berberich-Siebelt
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D056747:Immunomodulation; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage / Q000276:immunology; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D016207:Cytokines; C556062:IL10 protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C494007:Nfatc2 protein, mouse; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; D015847:Interleukin-4
keywords: Autoimmunity; Immunomodulation; Multiple sclerosis; Nonpathogenic Th17; Signal transduction