biostudies-literatureUnknown12(4)Shi YTudor 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 <i>Tdrd3</i> 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 <i>Tdrd3</i>-deficient mice also show spontaneous autoinflammation. MechaScience advanceseaea3960https://www.ebi.ac.uk/biostudies/studies/S-EPMC12829583biostudies-literatureTDRD3, a Tudor domain-containing protein, regulates &lt;i&gt;Klf2&lt;/i&gt;-dependent T&lt;sub&gt;reg&lt;/sub&gt; differentiation and function to modulate immune tolerance.PMC12829583Eurmsirilerd EShen LYang YChang RTao XYuan YCWang GShang WSun ZShi YJia ZfalseTDRD3, a Tudor domain-containing protein, regulates &lt;i&gt;Klf2&lt;/i&gt;-dependent T&lt;sub&gt;reg&lt;/sub&gt; 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 <i>Tdrd3</i> 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 <i>Tdrd3</i>-deficient mice also show spontaneous autoinflammation. Mecha2026-01-01T00:00:00Z2026 Jan2026-06-06T21:49:41.829Z2026-06-05T03:11:30.658ZS-EPMC128295834157615410.1126/sciadv.aea3960