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.

Enhanced in Vivo Efficacy of a Type I Interferon Superagonist with Extended Plasma Half-life in a Mouse Model of Multiple Sclerosis

“…In particular, a study using cell lineage specific IFNAR1 knock-out mice has identified the myeloid cells as critical for disseminating the IFN-therapeutic potential in EAE (56). How these myeloid cells interact with infiltrating CD4 ϩ subsets in particular will be a subject of future studies, complementing important findings made in this field (41,59).…”

“…In accordance with our original hypothesis, we further consider that CD274 may not only be acting as a marker of IFN response to in EAE and MS but is by itself an effector molecule that modulates the immune phenotype. This notion is strengthened by a recent study showing that a novel suppressive regulatory T-cell population expressing the transcription factor FoxA1 is instrumental in driving the IFN therapeutic response in EAE and MS (41). These FoxA1-positive T-reg cells were also shown to co-express high levels of CD274 (PD-L1).…”

“…These FoxA1-positive T-reg cells were also shown to co-express high levels of CD274 (PD-L1). The number of these FoxA1 ϩ PD-L1 cells was significantly reduced in IFNAR1 knock-out mice (41), indicating that the IFN-I signaling axis plays a major role in delineation of this novel T-Reg cell population. Our gene expression study with CD274 shown herein complements these findings.…”

“…It has recently been reported that a novel regulatory T-cell population expressing high levels of PD-L1 (CD274) plays a central role in the IFNmediated therapeutic activity upon treatment of EAE and MS (41). We have identified this gene as one that is differentially up-regulated in human WISH cells by IFN␤ but not by IFN␣ (31) and thus hypothesized that CD274 may act as a mediator of the IFN effect in this disease.…”

Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

“…These findings suggest that type I IFNs support a negative regulatory role of neonatal B cells in TLR-induced inflammation. Immunoregulatory effects of type I IFNs have also been reported in various animal models, including experimental colitis, experimental allergic encephalomyelitis and murine CMV infection [29][30][31]. In these studies, inhibition of the IFNAR-STAT1 inflammatory pathway by STAT3 and induction of the Treg cells were demonstrated as possible mechanisms for the immune regulatory function of IFN-α/β.…”