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.