Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T cell responses during pulmonary viral infection

The generation of regulatory T (Treg) cells is driven by Foxp3 and is responsible for dampening inflammation and reducing autoimmunity. In this study the epigenetic regulation of iTreg cells was examined and identified a H3K4 histone methyltransferase, SMYD3, which regulates expression of Foxp3 by a TGFβ1/Smad3 dependent mechanism. Using ChIP assays, SMYD3 depletion led to reduction in H3K4me3 in the promoter region and CNS-1 of the foxp3 locus. SMYD3 abrogation affected iTreg cell formation while allowing dysregulated IL-17 production. In a mouse model of respiratory syncytial virus infection (RSV), a model where iTreg cells play a critical role in regulating lung pathogenesis, SMYD3(−/−) mice demonstrated exacerbation of RSV-induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung. Our data highlight a novel activation role for the TGFβ-inducible SMYD3 in regulating iTreg cell formation leading to increased severity of virus-related disease.