The FOXP3 full-length isoform controls the lineage-stability of CD4⁺FOXP3⁺ regulatory T cells

The transcription factor FOXP3 is essential for CD4⁺FOXP3⁺ regulatory T (Treg) cell development and function. Human FOXP3 exists in distinct isoforms and alterations in isoform expression is associated with inflammatory disease progression, however, the exact functions of FOXP3 isoforms remain poorly understood. Herein we used flow cytometry and RNA-sequencing to analyze subsets of Treg cells from two IPEX patients, and a healthy carrier, of a recently described FOXP3 mutation (c.305delT). This mutation is located in exon 2 and results in the loss of the full-length FOXP3 isoform. Treg cells lacking full-length FOXP3 are found at lower-than-expected frequencies. This loss cannot be explained solely by altered thymic output, changes in proliferation, peripheral induction of Treg cells, or apoptosis. Instead, fulllength FOXP3 control a distinct genetic program, involving the previously identified FOXP3 regulators ID3, BCL6 and eIF4E, that upholds Treg cell lineage stability, while it appears nonessential for Treg cell activation.