Transcription factor Foxp1 regulates Foxp3 chromatin binding and coordinates regulatory T cell function

Regulatory T cells (T_reg cells), whose differentiation and function are controlled by transcription factor Foxp3, express the closely related family member Foxp1. Here we explored Foxp1 function in T_reg cells. We found that a large number of Foxp3-bound genomic sites in T_reg cells were occupied by Foxp1 in both T_reg cells and conventional T cells (T_conv cells). In T_reg cells, Foxp1 markedly increased Foxp3 binding to these sites. Foxp1 deficiency in T_reg cells resulted in their impaired function and competitive fitness, associated with markedly reduced CD25 expression and interleukin-2 (IL-2) responsiveness, diminished CTLA-4 expression and increased SATB1 expression. The characteristic expression patterns of CD25, Foxp3 and CTLA-4 in T_reg cells were fully or partially rescued by strong IL-2 signaling. Our studies suggest that Foxp1 serves an essential non-redundant function in T_reg cells by enforcing Foxp3-mediated regulation of gene expression and enabling efficient IL-2 signaling in these cells.