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.
Highlights
FOXP3þ regulatory T cells (Tregs) are produced in the thymus asR.C
Analysis of the flow cytometry profile of patients with systemic autoimmunity as compared to healthy donors revealed that the frequency of FOXP3þ CD4þ T cells is highly increased in CD127low cells of some patients
We found that among systemic lupus erythematosus (SLE) and Combined immunodeficiency patients (CID) patients with increased CD127low FOXP3-expressing cells there is a notable loss of CD25 expression, which results in an extremely high frequency of CD127lowCD25lowFOXP3þ cells (Fig. 1A)
Summary
FOXP3þ regulatory T cells (Tregs) are produced in the thymus asR.C. Ferreira et al / Journal of Autoimmunity 84 (2017) 75e86 patients are more readily available, rather than the effector T cells and Tregs present in the inflamed tissue and associated lymph nodes. A subset of FOXP3þ CD4þ T cells with low expression of CD25 was reported to be increased in peripheral blood of autoimmune systemic lupus erythematosus (SLE) patients [5e9], a finding that was later expanded to the peripheral blood of multiple sclerosis [10] and rheumatoid arthritis [11] patients. The frequency of this cell subset has been demonstrated to be associated with increased SLE disease activity in one study [7] but not in another [5]. We suggest that these cells represent the last stage of the natural life-cycle of TSDR-demethylated Tregs in vivo and that chronic stimulation in the form of active autoimmunity increases their prevalence
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