FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

The defective generation or function of regulatory T (T reg) 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 T reg cell population, herein called FoxA1 + T reg cells. FoxA1 bound to the Pdl1 promoter, inducing programmed cell death ligand 1 (Pd-l1) expression, which was essential for the FoxA1 + T reg cells to kill activated T cells. FoxA1 + T reg 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 + T reg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-l1-dependent manner. The development of FoxA1 + T reg cells is induced by interferon-β (IFN-β) and requires T cell-intrinsic IFN-α/β receptor (Ifnar) signaling, as the frequency of FoxA1 + T reg 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 + T reg 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 + T reg cells.

Detaljer

Författare
  • Yawei Liu
  • Robert Carlsson
  • Manuel Comabella
  • Jun Yang Wang
  • Michael Kosicki
  • Belinda Carrion
  • Maruf Hasan
  • Xudong Wu
  • Xavier Montalban
  • Morten Hanefeld Dziegiel
  • Finn Sellebjerg
  • Per Soelberg Sørensen
  • Kristian Helin
  • Shohreh Issazadeh-Navikas
Externa organisationer
  • University of Copenhagen
  • Vall d'Hebron University Hospital
  • Copenhagen University Hospital
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Immunologi inom det medicinska området
Originalspråkengelska
Sidor (från-till)272-282
Antal sidor11
TidskriftNature Medicine
Volym20
Utgåva nummer3
StatusPublished - 2014 jan 1
PublikationskategoriForskning
Peer review utfördJa
Externt publiceradJa