Increased CD45RA+FoxP3low Regulatory T Cells with Impaired Suppressive Function in Patients with Systemic Lupus Erythematosus

Abstract

BackgroundThe role of naturally occurring regulatory T cells (Treg) in the control of the development of systemic lupus erythematosus (SLE) has not been well defined. Therefore, we dissect the phenotypically heterogeneous CD4+FoxP3+ T cells into subpopulations during the dynamic SLE development.Methodlogy/Principal FindingsTo evaluate the proliferative and suppressive capacities of different CD4+ T cell subgroups between active SLE patients and healthy donors, we employed CD45RA and CD25 as surface markers and carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay. In addition, multiplex cytokines expression in active SLE patients was assessed using Luminex assay. Here, we showed a significant increase in the frequency of CD45RA+FoxP3low naive Treg cells (nTreg cells) and CD45RA−FoxP3low (non-Treg) cells in patients with active SLE. In active SLE patients, the increased proportions of CD45RA+FoxP3low nTreg cells were positively correlated with the disease based on SLE disease activity index (SLEDAI) and the status of serum anti-dsDNA antibodies. We found that the surface marker combination of CD25+CD45RA+ can be used to defined CD45RA+FoxP3low nTreg cells for functional assays, wherein nTreg cells from active SLE patients demonstrated defective suppression function. A significant correlation was observed between inflammatory cytokines, such as IL-6, IL-12 and TNFα, and the frequency of nTreg cells. Furthermore, the CD45RA+FoxP3low nTreg cell subset increased when cultured with SLE serum compared to healthy donor serum, suggesting that the elevated inflammatory cytokines of SLE serum may promote nTreg cell proliferation/expansion.Conclusions/SignificanceOur results indicate that impaired numbers of functional CD45RA+FoxP3low naive Treg cell and CD45RA−FoxP3low non-suppressive T cell subsets in inflammatory conditions may contribute to SLE development. Therefore, analysis of subsets of FoxP3+ T cells, using a combination of FoxP3, CD25 and CD45RA, rather than whole FoxP3+ T cells, will help us to better understand the pathogenesis of SLE and may lead to the development of new therapeutic strategies.

STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity

“…The greatest expression of the CD39 molecule in an aT reg subset was consistent with the results of previous studies, which have shown enrichment of suppressive cells in the aT reg compartment not only in HCs but also in patients with SLE [18,53]. In contrast to an intact, suppressive function of the aT reg , an impaired suppressive function of rT regs was previously demonstrated in patients with SLE [53].…”

Regulatory T Cells Compensation Failure Cause the Dysregulation of Immune Response in Pristane Induced Lupus Mice Model

“…Similar results were also observed in other studies, where there is a decrease of suppressive ability of Tregs in SLE patients in modulating other Th cell subsets (13,17). The composition of the local milieu, including the types of cytokines, can influence Treg function (18).…”

The Disease-Ameliorating Function of Autoregulatory CD8 T Cells Is Mediated by Targeting of Encephalitogenic CD4 T Cells in Experimental Autoimmune Encephalomyelitis

“…By corollary, peripheral control of potentially pathogenic autoreactive T-cells is important in controlling immune-mediated disease. It is becoming clearer that several immune-mediated diseases, such as MS, are characterized by perturbation of immune regulation (27, 32–38). In the murine model of MS (EAE), there is ample evidence that neuroantigen-specific CD4 T-cells can initiate and sustain neuroinflammation and pathology.…”