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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.

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References
1.
Josefowicz S, Lu L, Rudensky A . Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-64. PMC: 6066374. DOI: 10.1146/annurev.immunol.25.022106.141623. View

2.
Frank S, Schroeder M, Fernandez P, Taubert S, Amati B . Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev. 2001; 15(16):2069-82. PMC: 312758. DOI: 10.1101/gad.906601. View

3.
Hesse D, Krakauer M, Lund H, Sondergaard H, Limborg S, Soelberg Sorensen P . Disease protection and interleukin-10 induction by endogenous interferon-β in multiple sclerosis?. Eur J Neurol. 2010; 18(2):266-272. DOI: 10.1111/j.1468-1331.2010.03116.x. View

4.
Collison L, Chaturvedi V, Henderson A, Giacomin P, Guy C, Bankoti J . IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol. 2010; 11(12):1093-101. PMC: 3008395. DOI: 10.1038/ni.1952. View

5.
Kumar V, Stellrecht K, Sercarz E . Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE). J Exp Med. 1996; 184(5):1609-17. PMC: 2192866. DOI: 10.1084/jem.184.5.1609. View