METTL8 orchestrates TFH cell differentiation through m³C-mediated TCF1 regulation in infection and cancer models

ABSTRACT: Follicular helper T (TFH) cells are critical for humoral immunity against infections and correlate with immunotherapy efficacy, whereas immune checkpoint inhibitor (ICI) therapy can drive their aberrant expansion, underscoring the need to understand the regulators controlling TFH cell fate. However, the epitranscriptomic regulation of their differentiation remains poorly understood. Here we identify the m³C methyltransferase METTL8 as a key regulator of TFH cell differentiation in both viral infection and cancer. METTL8 is preferentially expressed in CXCL13hi TFH cells, and its deficiency impairs TFH differentiation and germinal center responses in the LCMV infection model and following anti-PD-1 immunotherapy tumor models. Mechanistically, METTL8 exerts dual functions: it binds and stabilizes Tcf7 mRNA through m³C modification; and it interacts with TCF1 protein to regulate chromatin accessibility and three-dimensional genome organization at key TFH-associated loci, including Cxcr5 and Il6ra. Notably, pharmacological inhibition of METTL8 by ginkgolic acid suppresses TFH responses without compromising the antitumor efficacy of anti-PD-1 therapy. Collectively, our findings identify METTL8 as an epitranscriptomic regulator linked to RNA modification, TCF1-associated transcriptional control, and chromatin architecture during TFH differentiation, and suggest that modulation of this pathway may provide a strategy to tune TFH-driven immune responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE249068 | GEO | 2026/03/07

REPOSITORIES: GEO