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

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

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82 Citations (Scopus)

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. © 2014 Nature America, Inc.
Original languageEnglish
Pages (from-to)272-282
JournalNature Medicine
Volume20
Issue number3
DOIs
Publication statusPublished - 1 Jan 2014

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    Liu, Y., Carlsson, R., Comabella, M., Wang, J. Y., Kosicki, M., Carrion, B., Hasan, M., Wu, X., Montalban, X., Dziegiel, M. H., Sellebjerg, F., Sørensen, P. S., Helin, K., & Issazadeh-Navikas, S. (2014). FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nature Medicine, 20(3), 272-282. https://doi.org/10.1038/nm.3485