Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

Abstract

FoxP3 is a key transcription factor for the development and function of natural CD4(+) regulatory T cells (Treg cells). Here we show that human FoxP3(+)CD4(+) T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA(+)FoxP3(lo) resting Treg cells (rTreg cells) and CD45RA(-)FoxP3(hi) activated Treg cells (aTreg cells), both of which were suppressive in vitro, and cytokine-secreting CD45RA(-)FoxP3(lo) nonsuppressive T cells. The proportion of the three subpopulations differed between cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTreg cells rapidly died whereas rTreg cells proliferated and converted into aTreg cells in vitro and in vivo. This was shown by the transfer of rTreg cells into NOD-scid-common gamma-chain-deficient mice and by TCR sequence-based T cell clonotype tracing in peripheral blood in a normal individual. Taken together, the dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3(+) subpopulations.

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

“…3c). Adult Tregs are now appreciated to have differential functionality that is characterized by the degree of FoxP3− and CD45RA expression 18. Subquantification of the FoxP3low and FoxP3hi fractions revealed a significant reduction in the FoxP3low, but not in the FoxP3hi fraction in cord blood from babies born to preeclamptic mothers (Fig.…”

“…Sakaguchi et al 18. developed a simple staining and gating strategy that allows for the identification of three Treg subtypes with distinct biological features distinguished by the surface expression of CD45RA in combination with the intranuclear expression of FoxP3 (Table 4).…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Naive CD4 + T cells expressing FoxP3 are produced by the thymus. These cells, which are termed natural CD4 + Treg cells (nTregs) (reviewed in 225), respond to antigenic stimulation by differentiating into effector Treg cells 226. There are nTreg cells with specificity for both self and foreign antigens, although the ratio of antigen‐specific FoxP3 + to FoxP3 − cells is higher for the former, enabling more stringent control of responses to autoantigens 227.…”

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

“…The gating strategy for characterizing nTregs and aTregs using CD45RA and FoxP3, as well as the differentiation status for CD4 and CD8 T cell subpopulations, using CD45RA and CCR7 to distinguish between naïve (CD45RA + CCR7 + ), central memory (CM; CD45RA − CCR7 + ), effector memory (EM; CD45RA − CCR7 − ) and effector (EMRA; CD45RA + CCR7 − ) was performed according Supplementary Figure S1 . 24

10.1080/2162402X.2018.1474318-F0001Figure 1.Schematic overview of the clinical trial. Scheme of clinical trial.

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“…Miyara et al . 24 have shown that the classically defined Treg population of FoxP3 + CD4 T cells, comprise three functionally different subpopulations: suppressive naïve Tregs (nTreg; CD45RA + FoxP3 med ), activated Tregs (aTreg; CD45RA − FoxP3 hi ) and the cytokine-secreting activated T cells (aTcell; CD45RA − FoxP3 med ). Santegoets et al .…”