Abstract
BackgroundHelios is important for functional and phenotype stability of regulatory T cells (Tregs). However, the role of Helios in autoimmune diseases and its regulation remains unclear. This study aimed to investigate the role of Helios+ Tregs in myasthenia gravis (MG) and glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) in the modulation of Helios.MethodMulticolor flow cytometry was performed to analyze Helios+ Tregs in peripheral blood from MG patients and healthy donors (HDs). Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of soluble GITRL/GITR in plasma. Tregs were isolated via magnetic separation and treated with recombinant GITRL and GITR-Fc. Membrane GITRL on Tregs and expression of Helios and other markers (FOXP3, CD25, CD39, CTLA-4, PD-L1 and IL-10) involved in immunosuppressive activity were determined by flow cytometry.ResultBoth Helios+ Tregs and soluble GITR were decreased in generalized MG (GMG) patients (n = 14), compared with HDs (n = 14) and ocular MG (OMG) patients (n = 16). Helios+ Tregs possessed greater immunosuppressive capacity compared to Helios− Tregs. Further analysis indicates soluble GITR was negatively correlated with quantitative MG score and promoted Helios expression and enhanced function of Tregs independently of membrane GITRL.ConclusionThis work demonstrates abnormal changes in Helios+ Tregs and soluble GITR in MG, as well as direct regulation of Helios by GITR in the context of Tregs. This work provides new insight into the role of GITR in the regulatory pathway of Helios and pathogenesis of MG.
Highlights
Helios is important for functional and phenotype stability of regulatory T cells (Tregs)
We analyzed the frequencies of Helios+ Treg in peripheral blood from the ocular MG (OMG) and generalized MG (GMG) patients and healthy donors (HD) by flow cytometry
glucocorticoid-induced tumor necrosis factor receptor (GITR) regulated Helios expression independent of membrane glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) in Tregs we demonstrate that sGITR regulates Helios expression, the underlying mechanism remains unclear
Summary
Helios is important for functional and phenotype stability of regulatory T cells (Tregs). The role of Helios in autoimmune diseases and its regulation remains unclear. This study aimed to investigate the role of Helios+ Tregs in myasthenia gravis (MG) and glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand (GITRL) in the modulation of Helios. Recent studies have suggested that Helios is involved in Treg function and phenotype stability. Helios expression in Tregs ensures a suppressive and anergic phenotype in intense inflammatory responses [7]. Overexpression of Helios enhances Treg function in cooperation with FOXP3 [7]. Selective Helios deficiency within Tregs led to induction of an unstable phenotype and conversion of Tregs into T effector cells within the tumor
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