title: FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS.
abstract: The defective generation or function of regulatory T (Treg) cells in autoimmune disease contributes to chronic inflammation and tissue injury. We report the identification of FoxA1 as a transcription factor in T cells that, after ectopic expression, confers suppressive properties in a newly identified Treg cell population, herein called FoxA1(+) Treg cells. FoxA1 bound to the Pdl1 promoter, inducing programmed cell death ligand 1 (Pd-l1) expression, which was essential for the FoxA1(+) Treg cells to kill activated T cells. FoxA1(+) Treg cells develop primarily in the central nervous system in response to autoimmune inflammation, have a distinct transcriptional profile and are CD4(+)FoxA1(+)CD47(+)CD69(+)PD-L1(hi)FoxP3(-). Adoptive transfer of stable FoxA1(+) Treg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-l1-dependent manner. The development of FoxA1(+) Treg cells is induced by interferon-β (IFN-β) and requires T cell-intrinsic IFN-α/β receptor (Ifnar) signaling, as the frequency of FoxA1(+) Treg cells was reduced in Ifnb(-/-) and Ifnar(-/-) mice. In individuals with relapsing-remitting multiple sclerosis, clinical response to treatment with IFN-β was associated with an increased frequency of suppressive FoxA1(+) Treg cells in the blood. These findings suggest that FoxA1 is a lineage-specification factor that is induced by IFN-β and supports the differentiation and suppressive function of FoxA1(+) Treg cells.
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Yawei
authors: Y
authors: Liu
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Robert
authors: R
authors: Carlsson
authors: Centre d'Esclerosi Múltiple de Catalunya (CEM-Cat), Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d´Hebron (HUVH)-Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Manuel
authors: M
authors: Comabella
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Junyang
authors: J
authors: Wang
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Michael
authors: M
authors: Kosicki
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Belinda
authors: B
authors: Carrion
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Maruf
authors: M
authors: Hasan
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Xudong
authors: X
authors: Wu
authors: Centre d'Esclerosi Múltiple de Catalunya (CEM-Cat), Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d´Hebron (HUVH)-Universitat Autònoma de Barcelona, Barcelona, Spain.
authors: Xavier
authors: X
authors: Montalban
authors: Blood Bank, Copenhagen University Hospital, Copenhagen, Denmark.
authors: Morten Hanefeld
authors: MH
authors: Dziegiel
authors: Danish Multiple Sclerosis Center, University of Copenhagen and Department of Neurology, Rigshospitalet, Copenhagen, Denmark.
authors: Finn
authors: F
authors: Sellebjerg
authors: Danish Multiple Sclerosis Center, University of Copenhagen and Department of Neurology, Rigshospitalet, Copenhagen, Denmark.
authors: Per Soelberg
authors: PS
authors: Sørensen
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Kristian
authors: K
authors: Helin
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Shohreh
authors: S
authors: Issazadeh-Navikas
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002490:Central Nervous System / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D016899:Interferon-beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C498919:Cd274 protein, mouse; C496499:FOXA1 protein, human; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D014157:Transcription Factors; D016899:Interferon-beta