Unexpected effects

Foxp3 is a transcription factor that has a key role in the differentiation and function of regulatory T (T_reg) cells. Two recent studies report that a commonly used reporter Foxp3 gene has unexpected effects in different mouse genetic backgrounds (Immunity 36, 717–730; Immunity 36, 731–741).

The Foxp3^tm2Ayr allele encodes Foxp3 joined to EGFP, allowing tracking of Foxp3-expressing T_reg cells in vivo. Jaime Darce et al. found that this allele reduced the severity of disease when expressed in a mouse model of inflammatory arthritis (the K/BxN model), but made the disease worse when expressed in a nonobese diabetes (NOD) mouse model. These effects seemed to be due to the increased binding of Foxp3-EGFP to insulin regulatory factor 4 (IRF4) and lowered binding to hypoxia-inducible factor 1α (HIF-1α), resulting in increased transcription of IRF4-regulated genes in T_reg cells and altered T_reg cell responses. The changes in T_reg cell responses may have differential effects on autoimmune diseases, depending on the underlying type of immunity, which may be different in diabetes and arthritis.

Similarly, Matthew Bettini et al. also observed acceleration of diabetes when Foxp3^tm2Ayr was expressed in a NOD model as well as impaired development of natural T_reg cells in the thymus and of induced T_reg cells in the periphery. They found that Foxp3-EGFP showed decreased binding to the histone acetyltransferase Tip60, histone deacetylase 7 and the transcription factor Eos. These changes altered the T_reg transcriptome, resulting in deficient T_reg cell responses.

These two studies show that the preservation of Foxp3 interactions with other regulatory proteins is necessary for the correct transcriptional program to be enacted in T_reg cells. Further investigations will be needed to examine whether disruption of interactions between Foxp3 and its binding partners may have affected the results of previous studies that used the Foxp3^tm2Ayr allele.