Dual-specificity phosphatase 8 (DUSP8) is a member of the DUSP family. DUSP8 dephosphorylates and inactivates the kinase JNK. DUSP8 protein levels are predominantly expressed in CD4+ T cells and platelets. DUSP8 dephosphorylates and inactivates specifically JNK in Jurkat T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T-cell-specific DUSP8 conditional knockout (T-DUSP8 cKO, DUSP8f/f;CD4-Cre) mice, mass spectrometry, and chromatin-immunoprecipitation sequencing, we found that DUSP8 stimulated IL-9 gene expression and Th9 differentiation. TGF-β stimulated DUSP8 phosphatase activity in T cells. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels in murine T cells were induced in Pur-α knockout. Reduction of IL-9 levels in T cells of T-DUSP8 cKO mice was reversed by Pur-α heterozygous knockout. Consistently, T-DUSP8 cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in allergy, autoimmune responses, and anti-tumor immunity. Remarkably, DUSP8 overexpression and DUSP8-Pur-α interaction indeed occurred in the peripheral blood T cells of patients with asthma or atopic dermatitis, contributing to IL-9 overproduction in patients’ T cells. Thus, DUSP8 plays a critical role in the pathogenesis of asthma and atopic dermatitis, as well as autoimmune disease and cancer.
日期:
2024-05-01
關聯:
Journal of Immunology. 2024 May 01;212(1, Suppl.):Meeting Abstract 0608_4827.
