Preserved suppressive function despite loss of Foxp3: insights into the identity of regulatory T cells

Abstract

Regulatory T (Treg) cells are essential for maintaining immune homeostasis, with Foxp3 acting as the master transcription factor governing their differentiation and function. The acquisition of effector signatures in Treg cells is closely tied to the surrounding tissue-specific immune environment and typically occurs alongside Foxp3 expression. In this study, we investigated the transcriptomic and functional consequences of Treg-mediated regulation in a Th2-driven disease setting. The application of both in vitro systems and in vivo disease models allowed us to mimic Th2-mediated environments. We could demonstrate Th2-driven loss of Foxp3 expression in Treg cells in vitro and in vivo. Transcriptomic analysis revealed a maintained Treg signature despite the loss of active Foxp3 expression. Functional characterization of Tregs both in vitro and in vivo uncovered a preserved suppressive capacity even in the absence of Foxp3. Our findings unveil that, despite loss of Foxp3, a preserved Treg signature remains intact enabling the regulation of Th2-mediated diseases. The persistence of this regulatory transcriptome highlights the importance for developing Treg-cell therapy strategies in cancer and autoimmune diseases independent of Foxp3 expression.