The m6A demethylase FTO controls Th1 differentiation and immunity against infections

Abstract

Antigen-specific effector CD4⁺ T cells are critical for defense against exogenous pathogens. However, the epigenetic mechanisms underlying CD4⁺ T cell immune responses, particularly RNA modifications, remain incompletely understood. In this study, we employed a T cell-specific deletion of the fat mass and obesity-associated protein (FTO), a key N6-methyladenosine (m⁶A) demethylase, to elucidate its role in CD4⁺ T cell mediated immunity. Our findings demonstrate that FTO is essential for maintaining CD4⁺ T cell immune responses and protective functions. Specifically, FTO deficiency restricts the expansion of CD4⁺ T helper (Th)1 effector cells following antigen challenge and results in decreased expression of T-bet and IFN-γ in Th1 cells. Additionally, FTO deficient CD4⁺ T cells exhibit impaired pathogen elimination. Collectively, our study reveals a novel epigenetic regulatory mechanism in supporting CD4⁺ T cell differentiation, providing new insights into the post-transcriptional regulation of CD4⁺ T cell immunity and highlighting the potential for therapeutic strategies.