Date: Monday, November 9, 2015
Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
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.
To cite this abstract in AMA style:Nishimoto T, Okazaki Y, Hanaoka H, Takeuchi T, Kuwana M. A Unique Naturally-Occurring Regulatory T Cell Subset Associated with Disease Activity in Patients with Systemic Lupus Erythematosus [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-unique-naturally-occurring-regulatory-t-cell-subset-associated-with-disease-activity-in-patients-with-systemic-lupus-erythematosus/. Accessed September 23, 2020.
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