DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated immune responses by inactivating a transcriptional repressor

Abstract

Abstract Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivorole of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO, DUSP8 f/f;CD4-Cre) mice, mass spectrometry, and chromatin-immunoprecipitation sequencing, we found that DUSP8 stimulated interleukin-9 (IL-9) gene expression and Th9 differentiation. TGF-β stimulated DUSP8 phosphatase activity in T cells. Mechanistically, DUSP8 dephosphorylated a transcriptional repressor upon TGF-β signaling, leading to the nuclear export of this transcriptional repressor and subsequent IL-9 transcriptional activation. Reduction of IL-9 mRNA levels in T cells of T-DUSP8 cKO mice was reversed by knocking out the transcriptional repressor in double knockout mice. Furthermore, IL-9 mRNA levels were induced in T cells lacking the transcriptional repressor. In addition, T-DUSP8 cKO mice displayed a reduction of IL-9 and Th9-mediated immune responses of allergy, autoimmune responses, and anti-tumor immunity in animal models. In contrast, the reduced allergy phenotype in T-DUSP8 cKO mice was reversed by knocking out the transcriptional repressor in double knockout mice. Collectively, DUSP8 induces TGF-β-stimulated IL-9 transcription and Th9-mediated immune responses by promoting the nuclear export of a transcriptional repressor.