Prox1 represses IL-2 gene expression by interacting with NFAT2

Interleukin-2 (IL-2) is critical for T lymphocyte activation and regulated by many transcriptional factors. Prospero-related homeobox 1 (Prox1) is a multifunctional transcription factor, which can work as either a transcriptional activator or repressor depending on the cellular and developmental environment. We previously reported the Prox1 expression in T cells, raising the possibility of Prox1 involvement in the regulation of T cell function and IL-2 production. Here we demonstrated that the Prox1 expression in CD4+ T cells was downregulated by T cell receptor (TCR) activation. Overexpression of Prox1 attenuated IL-2 production, while knockdown of endogenous Prox1 by small interfering RNA increased IL-2 expression. Mechanistically, we showed that Prox1 inhibited the IL-2 promoter activity, and associated with the minimal IL-2 promoter. Prox1 repressed the nuclear factor of activated T cells 2 (NFAT2)-dependent transactivation of IL-2 gene by physically binding to NFAT2. The N-terminal region of Prox1 was essential for the binding and repression. In summary, our findings established Prox1 as a negative regulator in IL-2 gene expression through the direct interaction with NFAT2.