DUSP2 Suppresses the Chromatin Remodeling BAF Complex to Orchestrate CD8+ T Cell Effector Programming [ATAC-seq]

Effector gene expression in CD8⁺ T cells is tightly controlled at epigenetic and transcriptional levels; however, crucial regulatory signals remain incompletely understood. In this study, we identify Dual Specificity Phosphatase 2 (DUSP2) as a key epigenetic modulator of effector CD8⁺ T cell state, by elucidating inhibition of BAF-mediated chromatin opening by DUSP2. Induced downregulation of DUSP2 in human CD8+ T cells enhanced cytotoxicity and effector phenotypes by increasing chromatin accessibility through upregulation of BAF subunits, such as SMARCA4, and permitting binding of ETS1 to BAF subunit gene loci and those essential for effector programs. Conversely, during chronic activation, DUSP2 knockout in murine CD8+ T cells predisposed terminally differentiated effector cells to exhaustion. These findings uncover a previously unrecognized role of DUSP2 in the management of the chromatin landscape in CD8+ T cells and the epigenetic fine-tuning of their functionality, highlighting DUSP2 as a promising therapeutic target for T cell-based immunotherapy.