Abstract
BackgroundFoxp3 is a marker for regulatory T cells (Treg cells), but recent studies have shown the plasticity and heterogeneity of CD4+Foxp3+ T cells. This study aimed to examine the phenotype and function of circulating CD4+Foxp3+ T cells in patients with systemic lupus erythematosus (SLE).MethodsWe enrolled 47 patients with SLE, 31 with organ-specific autoimmune diseases (15 with multiple sclerosis and 16 with primary immune thrombocytopenia), and 19 healthy subjects. Peripheral blood mononuclear cells were used to evaluate the proportion and phenotype of CD4+Foxp3+ cells using multicolor flow cytometry, the status of the Treg-specific demethylated region (TSDR) of the foxp3 gene by methylation-specific polymerase chain reaction, and the immunoregulatory function of CD4+CD25+ cells by allogeneic mixed lymphocyte reaction. Immunohistochemistry of renal biopsy specimens obtained from 6 patients with lupus nephritis and 5 with IgA nephropathy was conducted to detect IL-17A-expressing CD4+Foxp3+ cells.ResultsCD4+Foxp3+ T cells were increased in SLE patients compared with organ-specific autoimmune disease controls or healthy controls. Circulating CD4+Foxp3+ T cells were correlated with the disease activity of SLE. The increased CD4+Foxp3+ T cells in active SLE patients were mainly derived from thymus-derived Treg (tTreg) cells, as determined by a demethylated TSDR status, and represented a unique phenotype, upregulated expression of CD49d, CD161, and IL-17A, with immunosuppressive ability comparable to that of healthy controls. Finally, CD4+Foxp3+IL-17A+ cells were infiltrated into the renal biopsy specimens of patients with active lupus nephritis.ConclusionsA unique tTreg subset with dichotomic immunoregulatory and T helper 17 phenotypes is increased in the circulation of SLE patients and may be involved in the pathogenic process of SLE.
Highlights
Forkhead box P3 (Foxp3) is a marker for regulatory T cells (Treg cells), but recent studies have shown the plasticity and heterogeneity of CD4+Foxp3+ T cells
The expression of Foxp3, considered a master regulator of Treg cell development and function, is essential for the role of Treg cells in the maintenance of immune tolerance, but recent studies have shown plasticity and heterogeneity within CD4+Foxp3+ T cells, which include thymus-derived Treg cells, which are directly developed from CD4 single-positive cells in the thymus, peripherally derived Treg cells, which are differentiated from naïve CD4+ T cells in the periphery, and a subpopulation of activated effector T cells [3, 4]
It is known that numeric abnormalities and functional impairment of Treg cells potentially contribute to the pathogenesis of various autoimmune diseases, including rheumatoid arthritis (RA) and organ-specific autoimmune diseases such as myasthenia gravis (MG), immune thrombocytopenia (ITP), and multiple sclerosis (MS) [6,7,8,9,10,11]
Summary
Foxp is a marker for regulatory T cells (Treg cells), but recent studies have shown the plasticity and heterogeneity of CD4+Foxp3+ T cells. Since Treg cells play a major role in maintaining immune tolerance in the periphery, the numbers and function of CD4+Foxp3+ T cells in SLE patients have been extensively studied in recent years [16,17,18,19,20,21,22,23]. These studies have demonstrated quite contradictory results: some reported a reduced frequency and/or impaired regulatory function of circulating Foxp3+ Treg cells [19,20,21] in SLE patients in comparison to healthy controls, but others found an increased or comparable frequency of circulating Foxp3+ Treg cells [22, 23]. In this study, we investigated CD4+Foxp3+ T cell subsets associated with SLE by focusing on the heterogeneity of phenotypes and function of CD4+Foxp3+ T cells
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