Regulation of autoreactive CD4 T cells by FoxO1 signaling in CNS autoimmunity

• Published in: Journal of neuroimmunology 2021-10, Vol.359, p.577675-577675, Article 577675
• Main Authors: Kraus, Emma E., Kakuk-Atkins, Laura, Farinas, Marissa F., Jeffers, Matthew, Lovett-Racke, Amy E., Yang, Yuhong
• Format: Article
• Language: English
• Subjects: Adult; Animals; AS1842856; Autoimmunity - drug effects; Autoimmunity - physiology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Central Nervous System (CNS); Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Experimental autoimmune encephalomyelitis (EAE); Female; Forkhead box O 1 (FoxO1); Forkhead Box Protein O1 - immunology; Forkhead Box Protein O1 - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Multiple Sclerosis (MS); Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Quinolones - pharmacology; T effector cells; T regulatory cells
• ISSN: 0165-5728; 1872-8421
• DOI: 10.1016/j.jneuroim.2021.577675

Myelin-specific CD4 T effector cells (Teffs), Th1 and Th17 cells, are encephalitogenic in experimental autoimmune encephalomyelitis (EAE), a well-defined murine model of multiple sclerosis (MS) and implicated in MS pathogenesis. Forkhead box O 1 (FoxO1) is a conserved effector molecule in PI3K/Akt signaling and critical in the differentiation of CD4 T cells into T helper subsets. However, it is unclear whether FoxO1 may be a target for redirecting CD4 T cell differentiation and benefit CNS autoimmunity. Using a selective FoxO1 inhibitor AS1842856, we show that inhibition of FoxO1 suppressed the differentiation and expansion of Th1 cells. The transdifferentiation of Th17 cells into encephalitogenic Th1-like cells was suppressed by FoxO1 inhibition upon reactivation of myelin-specific CD4 T cells from EAE mice. The transcriptional balance skewed from the Th1 transcription factor T-bet toward the Treg transcription factor Foxp3. Myelin-specific CD4 T cells treated with the FoxO1 inhibitor were less encephalitogenic in adoptive transfer EAE studies. Inhibition of FoxO1 in T cells from MS patients significantly suppressed the expansion of Th1 cells. Furthermore, FoxO1 inhibition with AS1842856 promoted the development of functional iTreg cells. The immune checkpoint programmed cell death protein-1 (PD-1)-induced Foxp3 expression in CD4 T cells was impaired by FoxO1 inhibition. These data illustrate an important role of FoxO1 signaling in CNS autoimmunity via regulating autoreactive Teff and Treg balance. [Display omitted] •FoxO1 inhibition with AS1842856 suppresses Th1 development and Th17 transdifferentiation.•FoxO1 inhibition shifts transcriptional balance of T-bet and Foxp3 in autoreactive CD4 T cells.•FoxO1 inhibition suppresses T cell encephalitogenicity and the expansion of Th1 cells of MS patients.•FoxO1 inhibition promotes the development of functional iTreg cells.