Background/Purpose: Foxp3 is a lineage-specifying transcription factor for CD4⁺ regulatory T cells (Tregs), but recent studies have shown plasticity and heterogeneity within CD4⁺Foxp3⁺ cells, which include thymus-derived naturally-occurring Tregs (nTregs), peripherally-derived adaptive Tregs, and a subpopulation of activated effecter T cells. It has been reported that the number and function of Foxp3⁺ Tregs are altered in patients with systemic lupus erythematosus (SLE), although data reported are somewhat conflicting. In this study, we examined phenotype and function of circulating CD4⁺Foxp3⁺ T cells in association with disease activity in SLE patients.

Methods: We enrolled 47 patients with SLE, 31 with organ-specific autoimmune diseases (15 multiple sclerosis and 16 primary immune thrombocytopenia), and 19 healthy subjects. Peripheral blood samples were obtained, and phenotype of CD4⁺Foxp3⁺ T cells was assessed using multi-color flow cytometry. Serial samples were evaluated in some SLE patients. Treg-specific demethylated region of the Foxp3 gene (TSDR) was evaluated by methylation-specific polymerase-chain reaction using CD4⁺Foxp3⁺ T cells sorted by a flow cytometer. Immunoregulatory function of CD4⁺CD25⁺ T cells was examined by allogeneic mixed lymphocytes reaction. Finally, infiltration of IL-17-expressing CD4⁺Foxp3⁺ T cells was evaluated by immunohistochemistry of renal biopsy specimens obtained from 6 patients with active lupus nephritis (ISN/RPS-IV) and 5 with IgA nephropathy. Clinical information including SLE disease activity index (SLEDAI) at examination was retrospectively collected by review of clinical charts.

Results: CD4⁺Foxp3⁺ T cells were increased in circulation of SLE patients compared with organ-specific autoimmune disease controls or healthy subjects (P < 0.01 for all comparisons). Circulating CD4⁺Foxp3⁺ T cells were correlated positively with anti-double-strand DNA antibody levels or SLEDAI, and negatively with serum complement activity (r > 0.52, P < 0.01 for all correlations). Serial analysis in active SLE patients revealed reduction of CD4⁺Foxp3⁺ T cells after remission induction by immunosuppressive treatment. CD4⁺Foxp3⁺ T cells increased in peripheral blood of active SLE patients were nTregs, as determined by completely demethylated TSDR status. This SLE-specific nTreg subset represented unique phenotype; low expression of CD25, up-regulated expression of CD49d and CD127, expression of authentic Treg markers Helios and CD152, and expression of T helper 17 (Th17) markers CD161 and IL-17. The CD4⁺CD25⁺ T cells obtained from SLE patients exerted immunosuppressive ability comparable to those from healthy subjects. Finally, immunohistochemistry of renal specimens revealed that proportion of Foxp3⁺ cells in infiltrating CD4⁺IL-17⁺ T cells was significantly increased in patients with active lupus nephritis than in those with IgA nephropathy (54% ± 10% versus 21% ± 9%, P< 0.01).

Conclusion: A unique nTreg subset acquiring both immunoregulatory and Th17 phenotypes is increased in circulation of active SLE patients, and may be involved in pathogenic process of SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-unique-naturally-occurring-regulatory-t-cell-subset-associated-with-disease-activity-in-patients-with-systemic-lupus-erythematosus/