We report here a central role for polyamines in T cell differentiation and function. Deficiency in ornithine decarboxylase (ODC), a critical enzyme for polyamine synthesis, resulted in a profound failure of CD4 + T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineagedefining transcription factors across T H 1, T H 2, T H 17, and T reg polarizing conditions, and enhanced colitogenic potential. T cells deficient in deoxyhypusine synthase (DHPS) or deoxyhypusine hydroxylase (DOHH), which sequentially utilize polyamines to generate hypusine, phenocopied Odc-deficient T cells, and mice in which T cells lacked Dhps or Dohh developed colitis. Polyamine-hypusine pathway enzyme deficiency caused widespread chromatin and transcriptional dysregulation accompanied by alterations in histone methylation, histone acetylation, and TCA cycle metabolites. Epigenetic modulation by 2-hydroxyglutarate, or histone acetyltransferase inhibition, restored CD4 + T cell subset specification. Thus, polyamine synthesis via hypusine is critical for maintaining the epigenome to focus T H cell subset fidelity.