Foxp3: shades of tolerance

Abstract

In this issue of Immunity, Darce et al. (2012) and Bettini et al. (2012) demonstrate that seemingly subtle alterations in the interaction of Foxp3 with its transcriptional partners have a ripple effect on the outcome of autoimmune phenotypes, worsening some while ameliorating others.

Figure 1

Altered Functions of EGFP-Foxp3 Fusion Protein Interactions of the N-terminal domain of the native Foxp3 protein with different cofactors (top). Dimeric Foxp3 proteins interact at their N-termini with a number of transcriptional factors and regulators, including among others the transcription factors Hif1α, IRF4, and Eos, the histone acetyltransferases (HATs) Tip60 and p300, and the histone deacetylase HDAC7. These interactions enable a number of cofactor dependent transcriptional circuitries and help regulate the levels of Foxp3 protein. Altered N-terminal domain interactions and Treg cell responses induced by the EGFP-Foxp3 fusion protein (bottom). The introduction of an N-terminal EGFP alters the interaction of the EGFP-Foxp3 fusion protein with the different co-factors, invigorating some interactions (e.g., with IRF4) while weakening or abolishing others (e.g., those with HATs, Eos, and Hif1α). These alterations impact the transcriptional landscape of Treg cells, potentiating their capacity to enforce tolerance against some autoimmune responses (e.g., autoantibody production in the K/BxN arthritis model) while weakening their response to others (e.g., Th1-driven type 1 diabetes in the NOD mouse).