Abstract

Inflammatory bowel disease (IBD) is characterized by dysregulated T cell responses. RNA helicases, including DExD-box helicase 21 (DDX21), are pivotal in RNA metabolism, but their role in T cell-mediated pathology during IBD remains unclear. Here, we demonstrate that DDX21 expression in CD4 + T cells correlates with cell cycle and translation pathways in IBD-affected tissues. Conditional deletion of Ddx21 in mouse T cells disrupts T cell homeostasis and impairs cell proliferation. Consequently, Ddx21 –deficient CD4 + T cells exhibit resistance to inducing adoptive transfer colitis, with recipients showing reduced T cell infiltration compared to wild-type (WT) counterparts. Mechanistically, DDX21 ensures ribosome biogenesis after T cell activation and facilitates mRNA translation of Transcription factor dp-1 (TFDP1), a transcription factor critical for cell cycle progression. Given this dependence on ribosome biogenesis, pharmacological targeting of this pathway via KU55933—an inhibitor of ribosome synthesis-related signaling—recapitulated the protective effects of DDX21 loss: KU55933 alleviated dextran sulfate sodium (DSS)-induced colitis in mice and attenuated pathogenic CD4 + T cell expansion. Our findings establish DDX21 as a key regulator of T cell proliferation and highlight its potential as a therapeutic target for IBD and other autoimmune disorders.