cAMP Response Element Modulator a Induces Dual Specificity Protein Phosphatase 4 to Promote Effector T Cells in Juvenile-Onset Lupus

摘要

Effector CD4(+) T cells with increased IL-17A and reduced IL-2 production contribute to tissue inflammation and organ damage in systemic lupus erythematosus (SLE). Increased expression of the transcription factor cAMP response element modulator (CREM) alpha promotes altered cytokine expression in SLE. The aim of this study was to investigate CREM alpha-mediated events favoring effector CD4(+) T cells in health and disease. Using CRISPR/Cas9 genome editing and lentiviral transduction, we generated CREM alpha-deficient and CREM alpha-overexpressing Jurkat T cells. Gene expression and regulatory events were assessed using luciferase reporter assays and chromatin immunoprecipitation. Interaction between CREM alpha and p300 was investigated using proximity ligation assays, coimmunoprecipitation, and knockdown of p300. Gene expression profiles of modified cells were compared with CD4(+) T cells from patients with juvenile-onset SLE. We show that CREM alpha induces dual specificity protein phosphatase (DUSP) 4 in effector CD4(+) T cells through corecruitment of p300. The transcriptional coactivator p300 mediates histone acetylation at DUSP4, prompting increased gene expression. Using DUSP4 transfection models and genetically modified CREM-deficient and CREM alpha-overexpressing T cells, we demonstrate the molecular underpinnings by which DUSP4 induces IL-17A while limiting IL-2 expression. We demonstrate that CD4(+) T cells from patients with juvenile-onset SLE share phenotypical features with CREM alpha-overexpressing CD4(+) T cells, including increased DUSP4 expression and imbalanced IL-17A and IL-2 production. Taken together, we describe CREM alpha-mediated mechanisms that involve the transcriptional upregulation of DUSP4, leading to imbalanced cytokine production by effector T cells. Our findings identify the CREM alpha/DUSP4 axis as a promising candidate in the search for biomarkers and therapeutic targets in SLE.