Metabolic control of T_FH cells and humoral immunity by phosphatidylethanolamine

T follicular helper (T_FH) cells are crucial for B cell-mediated humoral immunity¹. Although transcription factors such as BCL6 drive the differentiation of T_FH cells^2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce T_FH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of T_FH cells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of T_FH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. T_FH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of T_FH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for T_FH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs.