SRSF3 determines Treg 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 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.