title: NAD+ protects against EAE by regulating CD4+ T-cell differentiation.
abstract: CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNγ(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD(+), the frequency of T-bet(-/-) CD4(+)IFNγ(+) T cells was twofold higher than wild-type CD4(+) T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4(+) T-cell differentiation and demonstrate that NAD(+) may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases.
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Tullius
authors.affiliation: 1] Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Clinic for Cardiovascular Surgery, University Hospital Zurich, Zurich 8091, Switzerland.
authors.forename: Hector Rodriguez Cetina
authors.initials: HR
authors.lastname: Biefer
authors.affiliation: Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts 02478, USA.
authors.forename: Suyan
authors.initials: S
authors.lastname: Li
authors.affiliation: Harvard Catalyst-Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Trachtenberg
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Karoline
authors.initials: K
authors.lastname: Edtinger
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Quante
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Krenzien
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Haydn T
authors.initials: HT
authors.lastname: Kissick
authors.affiliation: Harvard Catalyst-Laboratory for Innovative Translational Technologies, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Winston P
authors.initials: WP
authors.lastname: Kuo
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ionita
authors.initials: I
authors.lastname: Ghiran
authors.affiliation: Instituto de Biología y Genética Molecular, University of Valladolid, Valladolid 47003, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: de la Fuente
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Arredouani
authors.affiliation: Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Camacho
authors.affiliation: Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Tigges
authors.affiliation: Flow Cytometry Core Facility, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors.forename: Vasilis
authors.initials: V
authors.lastname: Toxavidis
authors.affiliation: Center for Neurological Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Rachid
authors.initials: R
authors.lastname: El Fatimy
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Angiogenesis and Brain Development Laboratory, Division of Basic Neuroscience, McLean Hospital/Harvard Medical School, Belmont, Massachusetts 02478, USA.
authors.forename: Anju
authors.initials: A
authors.lastname: Vasudevan
authors.affiliation: Division of Transplant Surgery and Transplantation Surgery Research Laboratory, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Abdallah
authors.initials: A
authors.lastname: ElKhal
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology*; D009186:Myelin Sheath / Q000187:drug effects*; D009243:NAD / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects*; D014365:Tryptophan Hydroxylase / Q000187:drug effects / Q000378:metabolism
chemical_list: D009243:NAD; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase