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.

Point mutants of forkhead box P3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked have diverse abilities to reprogram T cells into regulatory T cells

“…Furthermore, F324L, which causes a mild form of IPEX, did not display any significant defect in the best characterized cellular and molecular functions of FOXP3. The hypothesis that IPEX is not caused by a numerical deficit in Treg cells is supported by a recent study 64 in Scurfy mice finding that Foxp3-deficient Treg cells share many characteristics with WT Treg cells including in vitro anergy, decreased cytokine production, and gene expression profiles. Therefore, it seems likely that the immune deficiencies in patients with IPEX can be caused by changes in the function of FOXP3 outside its currently recognized role in regulation of Treg cell development and function.…”

CD8+Foxp3+ T cells in peripheral blood of relapsing-remitting multiple sclerosis patients

“…CD4 ϩ Treg cells that lose Foxp3 function become unable to suppress immune responses [22]. Recently, Cosmi et al demonstrated the existence of a subset of human CD8 ϩ CD25 ϩ thymocytes, which expressed high levels of Foxp3 and shared phenotype, functional features and mechanism of action with CD4 ϩ CD25 ϩ Treg cells [23].…”

Altered Connexin 43 Expression Underlies Age-Dependent Decrease of Regulatory T Cell Suppressor Function in Nonobese Diabetic Mice

“…NOD mice expressing Foxp3 GFP reporter (NOD GFP mice) were constructed as reported previously (27). A fragment of Foxp3 locus (located on BAC clone RP23-446O15) was modified to express GFP controlled by the Foxp3 regulatory sequences.…”

“…Membranes were probed with antibody specific for Foxp3 (1 μg/ml, eBio7979, eBioscience) as described (27). For Smad2 and phospho-Smad2 detection membranes were probed overnight (4°C) with the corresponding antibodies (Cell Signaling Technology).…”