TET2 Regulates 5-Hydroxymethylcytosine Signature and CD4(+) T-Cell Balance in Allergic Rhinitis

PURPOSE: Previous studies have shown the role of ten-eleven translocation 2 (TET2) in CD4(+) T cells. However, its function in CD4(+) T cells under allergic inflammation is unclear. We aimed to investigate the epigenomic distribution of DNA 5-hydroxymethylcytosine (5hmC) and the role of TET2 in CD4(+) T cells of allergic rhinitis (AR). METHODS: The hMeDIP-seq was performed to identify sequences with 5hmC deposition in CD4(+) T cells of AR patients. Tet2-deficient or wild type mice were stimulated with ovalbumin (OVA) to develop an AR mouse model. The histopathology in nasal mucosae, Th1/Th2/Treg/Th17 cell percentage, concentrations of Th-related cytokines, expression of Tet and differential hydroxymethylated genes (DhMG), and the global deposition of 5hmC in sorted CD4(+) T cells were detected. RESULTS: Epigenome-wide 5hmC landscape and DhMG in the CD4(+) T cells of AR patients were identified. Tet2 depletion did not led to spontaneous inflammation. However, under the stimulation of allergen, OVA, loss of Tet2 resulted in the exacerbation of allergic inflammation, which was characterized by severer allergic symptoms, more inflammatory cells infiltrating the nasal lamina propria, sharper imbalances between Th1/Th2 and Treg/Th17 cells, and excessive secretion of OVA-specific IgE and Th2-related cytokines. Moreover, altered mRNA production of several DhMG and sharp decrease in 5hmC deposition were also observed in Tet2-deficient OVA-exposed mice. CONCLUSIONS: TET2 may regulate DNA 5hmC, DhMG expressions, and CD4(+) T cell balance in AR.