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-beta 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. The Journal of Immunology, 2009, 183: 3731-3741.