Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity

Abstract

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+; P = 1.3 × 10−9) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 × 10−18), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells is correlated (P = 3.1 × 10−7) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.

IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging

“…Supporting this tenet, reduced CD25 expression in aged Foxp3 + cells ( Figure 8D , X-axis, Figure 10A , X-axis) and their likely inability to regulate IL-2 is likely associated with their dysfunction and immunopathology during infection in aged mice ( 26 , 57 – 59 ). These data are also in accord with previous reports showing an association of CD25 low Foxp3 + cells with tissue autoimmunity ( 60 ). The contribution of IL-17A in the immunomodulatory role of T reg 17 cells is currently unclear.…”

Distinct microbial and immune niches of the human colon

“…T reg cell subpopulations within the mLN and colon tissue are analogous to those we have recently described in mouse 22 . We also identify an additional population, termed T reg -like cells, reminiscent of a CD25 − FOXP3 lo PD1 hi T reg population in the peripheral blood, although the latter was described to also express Ki67 34 . This population could represent uncommitted T reg cells experiencing transient loss of FOXP3 while retaining regulatory potential 23 or permanent loss of FOXP3 and adoption of a more pro-inflammatory phenotype after repeated stimulation 35 .…”

FOXP3+ Regulatory T Cell Compartment Is Altered in Children With Newly Diagnosed Type 1 Diabetes but Not in Autoantibody-Positive at-Risk Children

“…Multiple studies have set out to address the potential dysregulation of Tregs in patients with T1D by analyzing whether the frequency of Tregs is altered in peripheral blood. Although some have reported both increased (10, 11) and decreased (12) frequencies of Tregs, the majority of studies have concluded that no differences in peripheral blood Treg frequencies exist (13–19). It is, however, noteworthy that several of these studies have used variable markers to define Tregs, and only some have used the most specific markers, CD25 in combination with CD127, FOXP3, and HELIOS (20–23), to define peripheral blood Tregs.…”