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

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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-L1hiFoxP3. 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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Figure 1: CD4hiPd-l1hi T cells are absent in the inflamed CNS of Ifnb−/− mice.
Figure 2: FoxA1+ Treg cells have a distinct transcriptional profile and suppress skin and CNS inflammation.
Figure 3: FoxA1+ Treg cells are induced by IFN-β.
Figure 4: FoxA1 is essential for the development and function of suppressive FoxA1+ Treg cells.
Figure 5: Ectopic FoxA1 expression generates suppressive FoxA1+ Treg cells that induce activated T cell apoptosis.
Figure 6: IFN-β responsiveness in patients with RRMS is associated with increased numbers of suppressive FoxA1+ Treg cells.

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Acknowledgements

This work was supported by grants from The Lundbeck Foundation in Denmark, The Danish Multiple Sclerosis Society, The Danish Council for Independent Research–Medical Sciences, The Danish Cancer Society, The Swedish Research Council–Medicine and the Bibi and Nils Jensen Foundation to S.I.-N. We thank H. Wekerle, U. Grohmann and M. Prinz for valuable discussion and suggestions.

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Y.L. performed experiments, analyzed and prepared data for presentation and contributed to the writing of the manuscript. R.C. performed experiments and analyzed data and contributed to the writing of the manuscript. J.W., M.K., B.C., M.H. and X.W. performed experiments. M.K., B.C., M.H., X.W., M.C., X.M., M.H.D., F.S. and P.S.S. contributed to collection of patients' blood and clinical studies. K.H. contributed to discussions and final revision of the manuscript. S.I.-N. planned the study design, supervised the overall project, analyzed data and wrote the manuscript.

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Correspondence to Shohreh Issazadeh-Navikas.

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The University of Copenhagen holds the rights to a submitted patent application in which S.I.-N., Y.L. and R.C. are the co-inventors.

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Liu, Y., Carlsson, R., Comabella, M. et al. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nat Med 20, 272–282 (2014). https://doi.org/10.1038/nm.3485

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