Foxp3-Deficient Regulatory T Cells Do Not Revert into Conventional Effector CD4+ T Cells but Constitute a Unique Cell Subset

Abstract

Homeostasis in the immune system is maintained by specialized regulatory CD4+ T cells (Treg) expressing transcription factor Foxp3. According to the current paradigm, high-affinity interactions between TCRs and class II MHC-peptide complexes in thymus “instruct” developing thymocytes to up-regulate Foxp3 and become Treg cells. However, the loss or down-regulation of Foxp3 does not disrupt the development of Treg cells but abrogates their suppressor function. In this study, we show that Foxp3-deficient Treg cells in scurfy mice harboring a null mutation of the Foxp3 gene retained cellular features of Treg cells including in vitro anergy, impaired production of inflammatory cytokines, and dependence on exogenous IL-2 for proliferation and homeostatic expansion. Foxp3-deficient Treg cells expressed a low level of activation markers, did not expand relative to other CD4+ T cells, and produced IL-4 and immunomodulatory cytokines IL-10 and TGF-β when stimulated. Global gene expression profiling revealed significant similarities between Treg cells expressing and lacking Foxp3. These results argue that Foxp3 deficiency alone does not convert Treg cells into conventional effector CD4+ T cells but rather these cells constitute a distinct cell subset with unique features.