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.