Targeting NAT10 suppresses T _FH responses and alleviates allergic asthma via an ac4C-TOX2 axis

Chemical modifications of RNA, such as N4-acetylcytidine (ac⁴C), fine-tune gene expression, but their roles in cell fate determination within the immune system remain poorly understood. Here, we identify the RNA cytidine acetyltransferase NAT10 as a pivotal regulator of T follicular helper (T _FH ) cell differentiation and the germinal centre response. T cell-specific ablation of Nat10 in mice severely impaired T _FH cell development, germinal centre formation, and antibody production following viral infection. Integrated epitranscriptomic and transcriptional profiling revealed that NAT10 deposits ac⁴C modifications on a cohort of mRNAs critical for immune function. We pinpointed the transcription factor TOX2 as a key downstream target, showing that ac⁴C modification within its mRNA coding sequence enhances both transcript stability and translation efficiency, thereby promoting TOX2 protein expression. Enforced TOX2 expression fully rescued the T _FH differentiation defect in NAT10-deficient cells. This NAT10-ac⁴C-TOX2 axis is conserved in humans, where its activity correlates with the magnitude of vaccine-elicited T _FH responses. Furthermore, we identified R428 as a potent NAT10 inhibitor and demonstrated that its administration could suppress pathogenic T _FH responses and alleviate symptoms in a mouse model of allergic asthma. Our work elucidates a central epitranscriptomic mechanism controlling T helper cell fate and humoral immunity, and nominates NAT10 as a potential therapeutic target for T _FH -driven diseases.