SRSF3 determines T_reg cell fate in antitumor immunity and autoimmunity

Human FOXP3 shows two isoforms due to exon 2 skipping, and the exon 2 is critical for FOXP3 function in T_reg cells. However, the factor(s) regulating its splicing remain unknown. Here, we show that SRSF3 regulates FOXP3 exon 2 function and determines T_reg cell fate and function in autoimmunity and tumor immunity. Mechanistically, SRSF3 promoted FOXP3 exon 2 inclusion and protein expression and thus safeguarded T_reg cells, as deletion of Srsf3 gene specifically in T_reg cells resulted in profound deficiency of T_reg cells in mice, leading to lethal systemic inflammation. T_reg cells in human tumor showed high SRSF3 expression. SRSF3 was required for human T_reg cell-suppressive function. Humanized mice generated with human FOXP3 exon 2 and adjacent introns showed significantly reduced tumor formation with the decreased T_reg cell function and consequently increased intratumoral CD8⁺ T cell infiltration. We have thus revealed a previously unrecognized role of SRSF3 in controlling T_reg cell fate and function in antitumor immunity and autoimmunity by regulating FOXP3 exon 2 inclusion and protein expression.