RNA Helicase DDX21 Controls CD4 ⁺ T Cell Proliferation and Promotes Inflammatory Bowel Disease via Translational Control

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.