Abstract:

Foxo1 is a key transcription factor in T-cell biology, playing a crucial role in their survival, migration, and the formation of immune memory. It also prevents exhaustion and senescence of effector T cells. However, its involvement in the differentiation of naive CD4 T cells into effector cells remains complex and less well understood. While Foxo1 is essential for the generation of induced regulatory T cells (iTreg) and Th9 cells, and inhibits the formation of Th17 and Tfh cells, its role in Th1 and Th2 cell differentiation is less documented. Our research has revealed an increased proportion of Th1 and Th2 cells in the periphery of Foxo1-deficient mice compared to wild-type mice. Interestingly, Foxo1 deficiency, unlike a chemical inhibitor targeting Foxo1, allows naive CD4 T cells to differentiate into Th1 and Th2 effector cells in vitro, even in the absence of polarizing cytokines. Our analyses show that Foxo1-deficient cells rapidly produce large amounts of Type 1 and Type 2 cytokines upon activation, suggesting that Foxo1 intrinsically inhibits the expression of many genes involved in their production. Additionally, complementary studies on IL-2 and epigenetic marks suggest that Foxo1 may also regulate CD4 T-cell differentiation through these mechanisms, by modulating IL-2 receptor expression and repressive histone marks (H3K27me3 and H3K9me3). In summary, these findings offer new insights into how Foxo1 orchestrates CD4 T-cell differentiation.