TDRD3, a Tudor domain-containing protein, regulates Klf2-dependent Treg differentiation and function to modulate immune tolerance

Tudor domain-containing protein 3 (TDRD3) functions as a methylarginine reader that relays posttranslational arginine methylation signals to the transcriptional machinery, thereby regulating cellular functions through modulation of gene expression. Regulatory T cells (T_regs) are pivotal for establishing and maintaining immune tolerance. In this study, we demonstrate that mice with T_reg-specific deletion of Tdrd3 exhibit severely impaired iT_reg, but not thymic T_reg, differentiation. Moreover, iT_regs, but not thymic T_regs, derived from these mice fail to suppress colitis in adoptive transfer models, indicating compromised inhibitory capacity. Aged Tdrd3-deficient mice also show spontaneous autoinflammation. Mechanistically, TDRD3 is recruited by the transcription factor FOXO1, presumably in a methylation-dependent manner, to activate Klf2 expression, which is essential for T_reg differentiation. Notably, the enforced expression of Klf2 in Tdrd3-deficient CD4⁺ T cells rescue both iT_reg development and suppressive function. Collectively, our findings identify TDRD3 as a central transcriptional regulator of iT_reg differentiation and immune homeostasis, highlighting it as a potential therapeutic target for modulating immune tolerance.