Feb 28, 2014 - on FOXA1 (also known as HNF3α) for its development and functions. These FOXA1+ TReg cells are induced in response to interferon-β (IFNβ).
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Nature Reviews Immunology | AOP, published online 28 February 2014; doi:10.1038/nri3643
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FOXA1+ TReg cell populations were expanded in patients who responded to IFNβ therapy
Commitment to the regulatory T (TReg) cell lineage is typically associated with the expression of the forkhead box P3 (FOXP3) transcription factor. Liu et al. now describe a novel TReg cell population, which does not express FOXP3 but instead depends on FOXA1 (also known as HNF3α) for its development and functions. These FOXA1+ TReg cells are induced in response to interferon-β (IFNβ) and inhibit inflammatory responses in the central nervous system (CNS) by killing activated T cells. Mice deficient in IFNβ or the receptor for this cytokine develop chronic and relapsing CNS inflammation in experimental autoimmune encephalomyelitis (EAE) — a mouse model of multiple sclerosis. This suggests a regulatory role for this cytokine in the CNS and,
in keeping with this, IFNβ can reduce relapse rates in patients with multiple sclerosis. It has remained unclear how IFNβ regulates CNS inflammation, so the authors explored its effects on TReg cells in the CNS. They found that wild-type and IFNβ-deficient mice with EAE had similar numbers of FOXP3+ TReg cells in the CNS. However, they identified a population of CD4+ T cells expressing the regulatory molecule programmed cell death ligand 1 (PDL1) that was present in the CNS of wild-type mice with EAE but absent from IFNβ-deficient mice with this disease. Further analyses showed that these cells expressed FOXA1, CD47 and CD69, and they suppressed effector T cell responses in vitro and in in vivo adoptive transfer models of EAE.
NATURE REVIEWS | IMMUNOLOGY
The absence of the FOXA1+ TReg cell population in IFNβ-deficient mice suggested that this cytokine was necessary for their induction. In keeping with this, treatment with IFNβ promoted the development of FOXA1+ TReg cells in IFNβ-deficient mice with EAE. IFNβ was also shown to drive the development of FOXA1+PDL1hi T cells in mouse or human CD4+ T cell cultures. FOXA1 was required for both the development and functions of the IFNβ-induced TReg cells, and was found to bind to the Pdl1 promoter and promote the upregulation of PDL1 expression. PDL1 itself was shown to mediate the regulatory activity of the FOXA1+ TReg cells by inducing apoptosis in activated T cells. Finally, the authors assessed whether clinical responsiveness to IFNβ therapy in patients with multiple sclerosis might be mediated by FOXA1+ TReg cells. In support of this, they found that FOXA1+ TReg cell populations were expanded in patients who responded to IFNβ therapy, whereas no expansion of these populations was seen in patients who did not respond to therapy. Notably, FOXA1+ TReg cells from the IFNβ responders showed suppressive activity ex vivo. These results suggest that IFNβ may have a beneficial effect on CNS inflammation by promoting the expansion of a novel population of FOXA1+ TReg cells. A better understanding of these cells may help improve the efficacy of IFNβ therapies. Yvonne Bordon ORIGINAL RESEARCH PAPER Liu, Y. et al. FoxA1 directs the lineage and immunosuppressive properties of a novel regulatory T cell population in EAE and MS. Nature Med. http://dx.doi. org/10.1038/nm.3485 (2014)
