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Published on: January 3, 2025
SRSF3 determines Treg cell fate in antitumor immunity and autoimmunity
Rong Jia1, Jihua Guo1,2, Linyan Yan1
1State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Abstract:
Human FOXP3 shows two isoforms due to exon 2 skipping, and the exon 2 is critical for FOXP3 function in Treg cells. However, the factor(s) regulating its splicing remain unknown. Here, we show that SRSF3 regulates FOXP3 exon 2 function and determines Treg cell fate and function in autoimmunity and tumor immunity. Mechanistically, SRSF3 promoted FOXP3 exon 2 inclusion and protein expression and thus safeguarded Treg cells, as deletion of Srsf3 gene specifically in Treg cells resulted in profound deficiency of Treg cells in mice, leading to lethal systemic inflammation. Treg cells in human tumor showed high SRSF3 expression. SRSF3 was required for human Treg cell-suppressive function. Humanized mice generated with human FOXP3 exon 2 and adjacent introns showed significantly reduced tumor formation with the decreased Treg cell function and consequently increased intratumoral CD8+ T cell infiltration. We have thus revealed a previously unrecognized role of SRSF3 in controlling Treg cell fate and function in antitumor immunity and autoimmunity by regulating FOXP3 exon 2 inclusion and protein expression.
Insights
SRSF3 protein controls regulatory T (Treg) cell function by regulating FOXP3 splicing. This finding is crucial for understanding autoimmunity and tumor immunity, impacting Treg cell fate and function.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Human FOXP3 exhibits two isoforms due to alternative splicing of exon 2, which is essential for regulatory T (Treg) cell function.
- The specific factors governing FOXP3 alternative splicing remain largely unidentified.
Purpose of the Study:
- To investigate the role of SRSF3 in regulating FOXP3 splicing and its impact on Treg cell function in autoimmunity and tumor immunity.
Main Methods:
- Investigated SRSF3's effect on FOXP3 exon 2 splicing and protein expression.
- Utilized gene deletion models in mice to assess Treg cell deficiency and systemic inflammation.
- Analyzed SRSF3 expression in human tumors and its role in human Treg cell function.
- Employed humanized mouse models to evaluate tumor formation and immune cell infiltration.
Main Results:
- SRSF3 promotes FOXP3 exon 2 inclusion and protein expression, thereby safeguarding Treg cells.
- Deletion of SRSF3 in mouse Treg cells leads to severe Treg cell deficiency and lethal systemic inflammation.
- Human tumor-infiltrating Treg cells exhibit high SRSF3 expression and depend on SRSF3 for their suppressive function.
- Humanized mice with modified human FOXP3 splicing showed reduced tumor formation, impaired Treg cell function, and increased CD8+ T cell infiltration.
Conclusions:
- SRSF3 plays a critical, previously unrecognized role in controlling Treg cell fate and function.
- SRSF3 regulates FOXP3 exon 2 inclusion, impacting both autoimmunity and antitumor immunity.
- Targeting SRSF3 may offer therapeutic strategies for autoimmune diseases and cancer immunotherapy.
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