Metabolic control of T

T follicular helper (Tfh) cells are crucial for B cell-mediated humoral immunity(1). Although transcription factors, such as Bcl6, drive Tfh cell differentiation(2,3), whether and how posttranscriptional and metabolic programs enforce Tfh cell programming are unclear. Here, we show that the cytidine diphosphate (CDP)-ethanolamine pathway coordinates the expression and localization of CXCR5 with Tfh responses and humoral immunity. Using in vivo CRISPR-Cas9 screening and functional validation, we uncover Etnk1, Pcyt2 and Selenoi – enzymes in the CDP-ethanolamine pathway for de novo phosphatidylethanolamine (PE) synthesis – as selective posttranscriptional regulators of Tfh cell differentiation, by promoting CXCR5 surface expression and functional effects. Tfh cells show unique lipid metabolic programs and PE distribution to the plasma membrane outer layer where it co-localizes with CXCR5. De novo PE synthesis via the CDP-ethanolamine pathway coordinates these events to prevent CXCR5 internalization and degradation. Genetic deletion of Pcyt2, but not the CDP-choline pathway enzyme Pcyt1a, in activated T cells impairs Tfh cell differentiation, associated with reduced humoral immune responses. Surface PE levels and CXCR5 expression on B cells also depend upon Pcyt2. Our results reveal that phospholipid metabolism coordinates posttranscriptional mechanisms for Tfh cell differentiation and humoral immunity, highlighting metabolic control of context-dependent immune signaling and effector programs.