Abstract
The peripheral Foxp3+ Treg pool consists of naturally arising Treg (nTreg) and adaptive Treg cells (iTreg). It is well known that naive CD4+ T cells can be readily converted to Foxp3+ iTreg in vitro, and memory CD4+ T cells are resistant to conversion. In this study, we investigated the induction of Foxp3+ T cells from various CD4+ T-cell subsets in human peripheral blood. Though naive CD4+ T cells were readily converted to Foxp3+ T cells with TGF-β and IL-2 treatment in vitro, such Foxp3+ T cells did not express the memory marker CD45RO as do Foxp3+ T cells induced in the peripheral blood of Hepatitis B Virus (HBV) patients. Interestingly, a subset of human memory CD4+ T cells, defined as CD62L+ central memory T cells, could be induced by TGF-β to differentiate into Foxp3+ T cells. It is well known that Foxp3+ T cells derived from human CD4+CD25- T cells in vitro are lack suppressive functions. Our data about the suppressive functions of CD4+CD62L+ central memory T cell-derived Foxp3+ T cells support this conception, and an epigenetic analysis of these cells showed a similar methylation pattern in the FOXP3 Treg-specific demethylated region as the naive CD4+ T cell-derived Foxp3+ T cells. But further research showed that mouse CD4+ central memory T cells also could be induced to differentiate into Foxp3+ T cells, such Foxp3+ T cells could suppress the proliferation of effector T cells. Thus, our study identified CD4+CD62L+ central memory T cells as a novel potential source of iTreg.
Highlights
Regulatory T cells play an important role in self-tolerance, acquired tolerance, and immunological homeostasis [1,2]
Treg, which are defined by their expression of Foxp3, are broadly subdivided into naturally arising Treg (nTreg) and iTreg [4]. nTreg are generated by the interactions between thymic T cell receptors (TCRs) with a high affinity for MHC class II ligands in the thymus
We gated on CD4+Foxp3+ cells from the Peripheral blood mononuclear cells (PBMCs) (Figure 1C) and further confirmed a significantly higher proportion of CD45RO+ cells in the CD4+Foxp3+ cells of chronic HBVinfected women compared to the healthy controls (67.49±1.117 vs. 48.27±1.857; P
Summary
Regulatory T cells play an important role in self-tolerance, acquired tolerance, and immunological homeostasis [1,2]. There are multiple types of immune regulatory T cells, including Tr1 cells, natural killer T cells, CD8+ T cells and CD4+CD25+Foxp3+ cells [3]. CD4+CD25+Foxp3+ cells (referred to as Treg) are the predominant regulatory T cells. NTreg are generated by the interactions between thymic T cell receptors (TCRs) with a high affinity for MHC class II ligands in the thymus. Treg, which are defined by their expression of Foxp, are broadly subdivided into nTreg and iTreg [4]. These cells help to maintain tolerance to self-antigens to prevent autoimmunity and to regulate immune responses by raising activation thresholds. Induced Treg cells are potentially derived from various conditions outside the thymus, a phenomenon that has been supported by numerous in vivo studies [4]
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