Foxp3-deficient regulatory T cells do not revert into conventional effector CD4⁺ T cells but constitute a unique cell subset

Homeostasis in the immune system is maintained by specialized regulatory CD4⁺ T cells (T^reg) 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 T^reg cells. However, the loss or down-regulation of Foxp3 does not disrupt the development of T ^reg cells but abrogates their suppressor function. In this study, we show that Foxp3-deficient T^reg cells in scurfy mice harboring a null mutation of the Foxp3 gene retained cellular features of T^reg cells including in vitro anergy, impaired production of inflammatory cytokines, and dependence on exogenous IL-2 for proliferation and homeostatic expansion. Foxp3-deficient T^reg 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 T ^reg cells expressing and lacking Foxp3. These results argue that Foxp3 deficiency alone does not convert T^reg cells into conventional effector CD4⁺ T cells but rather these cells constitute a distinct cell subset with unique features.