Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression

Polyamines produced by both prokaryotes and eukaryotes are bioactive substances with pleiotropic effects. Accumulating evidence has demonstrated that polyamines contribute to anti-inflammatory responses by suppressing the expression of proinflammatory cytokines in mononuclear cells and macrophages. However, the effects of polyamines on CD4⁺ T cell responses remain to be elucidated. Here, we investigated the effect of polyamines on cell fate decisions of naïve CD4⁺ T cells in vitro. We found that endogenously generated polyamines are essential for the development of T helper 2 (Th2) cells. Treatment with DL-2-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, diminished GATA3 expression in CD4⁺ T cells under Th2-skewed conditions. Supplementation of exogenous polyamines rescued GATA3 downregulation caused by DFMO treatment in CD4⁺ T cells. Transcriptome analysis revealed that deprivation of endogenous polyamines resulted in upregulated Th9-related genes, such as Il9, Irf4, and Batf3, even under the Th2-skewing conditions. Depletion of intracellular polyamines reduced GATA3 expression but increased IL-9-producing CD4⁺ T cells under both Th2 and Th9-skewing conditions. Furthermore, oral administration of DFMO increased IL-9-producing CD4⁺ T cells in small intestine in mice. Thus, our data indicate that polyamines play a critical role in the regulation of the Th2/Th9 balance.