A Structure-Guided Delineation of FOXP3 Regulation Mechanism in IPEX

The FOXP3 transcription factor acts as a master regulator in the development and function of regulatory T cells (Tregs). Insufficient expression or mutation of FOXP3 gene impairs Treg abundancy and function and causes fatal autoimmune lymphoproliferative diseases in mice and humans. The available crystal structures of FOXP3 protein fragments provide insights into understanding details of the FOXP3 work mechanism in Tregs. This chapter consists of four sections. First, we introduce some features of Treg cells indispensable for the establishment of immune tolerance; second, we describe the critical roles of FOXP3 in Treg development and function; third, we summarize the current available crystal structures of FOXP3 functional domains and related pathogenic mutations in autoimmune diseases; finally, we discuss the potential functional and pathological relevance of FOXP3 protein structure modulation, partner interaction, and posttranslation modification based on the clinical significance in IPEX disease. The information presented in this chapter will help to consider therapeutic strategies to enhance FOXP3 activity and Treg function in the settings of autoimmune disease. Targeting Treg suppression based on FOXP3 structure and interactions hold great promises for the therapy of autoimmune diseases.