- (1) University of Copenhagen, grid.5254.6, KU
- (2) Centre d'Esclerosi Múltiple de Catalunya (CEM-Cat), Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d´Hebron (HUVH)–Universitat Autònoma de Barcelona, Barcelona, Spain
- (3) Blood Bank, Copenhagen University Hospital, Copenhagen, Denmark
- (4) Danish Multiple Sclerosis Center, grid.488278.9
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.