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TDRD3, a Tudor Domain-Containing Protein, Regulates Klf2-Dependent Treg differentiation and function to Modulate Immune Tolerance

ABSTRACT: Tudor domain-containing protein 3 (TDRD3) functions as a methylarginine reader that relays post-translational arginine methylation signals to the transcriptional machinery, thereby regulating cellular functions through modulation of gene expression. Regulatory T cells (Tregs) are pivotal for establishing and maintaining immune tolerance. In this study, we demonstrate that while TDRD3 is dispensable for thymic Tregs, it is essential for the differentiation of induced Tregs (iTregs) from naïve CD4⁺ T cells and for their immunosuppressive function. Mice with Treg-specific deletion of TDRD3 (Tdrd3fl/fl/Foxp3YFP-Cre) exhibit severely impaired iTreg, but not thymic Treg, differentiation and develop exacerbated experimental autoimmune encephalomyelitis (EAE), correlating with reduced Treg populations. Moreover, iTregs, but not thymic Tregs, derived from these mice fail to suppress colitis in adoptive transfer models, indicating compromised inhibitory capacity. Aged TDRD3-deficient mice also show spontaneous autoinflammation, characterized by splenomegaly and inflammatory infiltration in the lungs and liver, accompanied by increased IFN-γ–producing CD4⁺ T cells. Mechanistically, TDRD3 is recruited by the transcription factor FOXO1, presumably in a methylation-dependent manner, to activate Klf2 expression, which is essential for Treg differentiation. Notably, the enforced expression of Klf2 in TDRD3-deficient CD4⁺ T cells rescue both iTreg development and suppressive function. Collectively, our findings identify TDRD3 as a central transcriptional regulator of iTreg differentiation and immune homeostasis, highlighting it as a potential therapeutic target for modulating immune tolerance.

ORGANISM(S): Mus musculus

PROVIDER: GSE307870 | GEO | 2025/09/12

REPOSITORIES: GEO

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Project description:Treg dysfunction is associated with a variety of inflammatory diseases. Treg populations are defined by expression of the oligomeric transcription factor FOXP3 and inability to produce IL-2, a cytokine required for T cell maintenance and survival. FOXP3 activity is regulated post-translationally by histone/protein acetyltransferases and histone/protein deacetylases (HDACs). Here, we determined that HDAC3 mediates both the development and function of the two main Treg subsets, thymus-derived Tregs and induced Tregs (iTregs). We determined that HDAC3 and FOXP3 physically interact and that HDAC3 expression markedly reduces Il2 promoter activity. In murine models, conditional deletion of Hdac3 during thymic Treg development restored Treg production of IL-2 and blocked the suppressive function of Tregs. HDAC3-deficient mice died from autoimmunity by 4-6 weeks of age; however, injection of WT FOXP3+ Tregs prolonged survival. Adoptive transfer of Hdac3-deficient Tregs, unlike WT Tregs, did not control T cell proliferation in naive mice and did not prevent allograft rejection or colitis. HDAC3 also regulated the development of iTregs, as HDAC3-deficient conventional T cells were not converted into iTregs under polarizing conditions and produced large amounts of IL-2, IL-6, and IL-17. We conclude that HDAC3 is essential for the normal development and suppressive functions of thymic and peripheral FOXP3+ Tregs. RNA was isolated using RNeasy kits (QIAGEN), and RNA integrity and quantity were analyzed by NanoDrop ND-1000 and Nanochip 2100 Bioanalyzer (Agilent Technologies). Microarray experiments were performed using whole mouse genome oligoarrays (Mouse430a, Affymetrix) and array data analyzed using MAYDAY 2.12 software. Array data were subjected to robust multiarray average (RMA) normalization and analyzed using Student’s t test. Only data with a false discovery rate-adjusted P value of less than 0.05 and at least 2× differential expression were included in the analysis. Data underwent z-score transformation for display.

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TDRD3, a Tudor Domain-Containing Protein, Regulates Klf2-Dependent Treg differentiation and function to Modulate Immune Tolerance

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