A unique thymus-derived regulatory T cell subset associated with systemic lupus erythematosus

Background: Foxp3 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). Methods: We 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. Results: CD4⁺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. Conclusions: A 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.