4.8 Article

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

Journal

NATURE MEDICINE
Volume 20, Issue 3, Pages 272-282

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3485

Keywords

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Funding

  1. Lundbeck Foundation in Denmark
  2. Danish Multiple Sclerosis Society
  3. Danish Council for Independent Research-Medical Sciences
  4. Danish Cancer Society
  5. Swedish Research Council-Medicine
  6. Bibi and Nils Jensen Foundation
  7. Lundbeck Foundation [R108-2012-10312] Funding Source: researchfish

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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-I1) 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(h1)FoxP3(-). Adoptive transfer of stable FoxA1(+) T-reg cells inhibited experimental autoimmune encephalomyelitis in a FoxA1-and Pd-I1-dependent manner. The development of FoxA1(+) T-reg cells is induced by interferon-beta (IFN-beta) and requires T cell-intrinsic IFN-alpha/beta 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-beta 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-beta and supports the differentiation and suppressive function of FoxA1(+) T-reg cells.

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