TDRD3, a Tudor domain-containing protein, regulates Klf2 -dependent T reg 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.