Comparative lipidomic and transcriptomic profiling reveals distinct fatty acid utilization in T and B cells across mouse and human

Lipid metabolism is increasingly recognized as a critical determinant of immune cell differentiation and function, yet the metabolic programs that distinguish closely related adaptive immune cell subsets remain incompletely defined. Here we demonstrate that T and B cells employ distinct fatty acid utilization strategies across species. Integrated lipidomic and transcriptomic analyses of mouse and human lymphocytes revealed enrichment of long-chain phospholipid species in T cells, including prominent increases in arachidonic acid–containing lipids, accompanied by elevated expression of fatty acid elongation–associated genes including Elovl5. In contrast, B cells preferentially accumulated phospholipids with shorter and/or more unsaturated acyl chains, notably with consistent enrichment of eicosapentaenoic acid–containing lipids, together with increased expression of genes involved in fatty acid uptake, desaturation, and phospholipid remodeling, including Cd36, Scd1, and Lpgat1. Acyl-chain pairing analyses further uncovered distinct organizational patterns in lipid assembly, and cross-species comparisons revealed both conserved features and marked species-specific divergence, highlighting shared metabolic principles in mouse and human lymphocytes. Our data indicate that differential fatty acid elongation, uptake, and remodeling programs shape lineage-specific lipid architectures and contribute to metabolic specialization in adaptive immune cells.