Foxo1 drives the TGFβ1-dependent dichotomy of Th17 cell fates.

Abstract

T-helper 17 cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens while also contributing to proinflammatory conditions and autoimmunity. While transforming growth factor β1 is pivotal for the differentiation of nonpathogenic T-helper 17 cells, the role of transforming growth factor β3 and activin in steering T-helper 17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a transforming growth factor β1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic T-helper 17 cells. Analyses in both patients with uveitis and an experimental autoimmune uveitis mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates T-helper 17A production under pathogenic T-helper 17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by transforming growth factor β1 signaling, is implicated in fatty acid metabolism pathways that favor nonpathogenic T-helper 17 differentiation. Our drug screening identifies several US Food and Drug Administration-approved compounds can upregulate Foxo1. Collectively, our findings offer evidence that Foxo1 serves as a molecular switch to specifically control pathogenic vs nonpathogenic T-helper 17 differentiation in a transforming growth factor β1-dependent manner. Targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases.