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

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

Publication date: Oct 15, 2021

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.

Concepts Keywords
Cd4 Branches of biology
Forkhead T cells
Mice Forkhead transcription factors
Neuroimmunol Medical specialties
Sclerosis Immune system
Regulatory T cell
Immunology
FOXP3
Immune checkpoint

Semantics

Type Source Name
disease MESH autoimmunity
disease MESH experimental autoimmune encephalomyelitis
disease MESH multiple sclerosis
drug DRUGBANK Isoxaflutole
disease MESH development

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *