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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 CD127^lowCD25^low CD4⁺ T cells (here defined as CD25^lowFOXP3⁺ 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 CD25^lowFOXP3⁺ T cells share phenotypic features resembling conventional CD127^lowCD25^highFOXP3⁺ 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 CD25^lowFOXP3⁺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 CD25^lowFOXP3⁺ T cells is correlated (P = 3.1 × 10^-⁷) with the proportion of CD25^highFOXP3⁺ T cells in cell cycle (Ki-67⁺). These findings suggest that CD25^lowFOXP3⁺ T cells represent a subset of Tregs that are derived from CD25^highFOXP3⁺ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.

SUBMITTER: Ferreira RC

PROVIDER: S-EPMC5656572 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Ferreira Ricardo C RC Simons Henry Z HZ Thompson Whitney S WS Rainbow Daniel B DB Yang Xin X Cutler Antony J AJ Oliveira Joao J Castro Dopico Xaquin X Smyth Deborah J DJ Savinykh Natalia N Mashar Meghavi M Vyse Tim J TJ Dunger David B DB Baxendale Helen H Chandra Anita A Wallace Chris C Todd John A JA Wicker Linda S LS Pekalski Marcin L ML

Journal of autoimmunity 20170723

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 C ...[more]

PMID: 28747257

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Project description:BackgroundNaturally occurring thymus derived regulatory T cells (Tregs) are central in the maintenance of self-tolerance. The transcription factor FOXP3 is crucial for the suppressive activity of Tregs and is considered the most specific marker for this population. However, human non regulatory T cells upregulate FOXP3 transiently upon activation which calls for other means to identify the Treg population. Since epigenetic mechanisms are involved in the establishment of stable gene expression patterns during cell differentiation, we hypothesized that the methylation profile of the FOXP3 promoter would allow the distinction of truly committed Tregs.Methodology/principal findingsHuman CD4(+)CD25(hi) Tregs displayed a demethylated FOXP3 promoter (1.4%+/-0.95% SEM methylated) in contrast to CD4(+)CD25(lo) T cells which were partially methylated (27.9%+/-7.1%). Furthermore, stimulated CD4(+)CD25(lo) T cells transiently expressed FOXP3 but remained partially methylated, suggesting promoter methylation as a mechanism for regulation of stable FOXP3 expression and Treg commitment. In addition, transient FOXP3 expressing cells exhibited suppressive abilities that correlate to the methylation status of the FOXP3 promoter. As an alternative to bisulphite sequencing, we present a restriction enzyme based screening method for the identification of committed Tregs and apply this method to evaluate the effect of various culturing conditions. We show that a partial demethylation occurs in long-term cultures after activation, whereas the addition of TGF-beta and/or IL-10 does not induce any additional change in methylation level.Conclusions/significanceThe unique FOXP3 promoter methylation profile in Tregs suggests that a demethylated pattern is a prerequisite for stable FOXP3 expression and suppressive phenotype. Presently, FOXP3 is used to identify Tregs in several human diseases and there are future implications for adoptive Treg transfer in immunotherapy. In these settings there is a need to distinguish true Tregs from transiently FOXP3(+) activated T cells. The screening method we present allows this distinction and enables the identification of cells suitable for in vitro expansions and clinical use.

Dataset Information

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

Publications

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

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