Expansion of regulatory GITR+CD25low/-CD4+ T cells in systemic lupus erythematosus patients

IntroductionCD4+CD25low/-GITR+ T lymphocytes expressing forkhead box protein P3 (FoxP3) and showing regulatory activity have been recently described in healthy donors. The objective of the study was to evaluate the proportion of CD4+CD25low/-GITR+ T lymphocytes within CD4+ T cells and compare their phenotypic and functional profile with that of CD4+CD25highGITR¿ T lymphocytes in systemic lupus erythematosus (SLE) patients.MethodsThe percentage of CD4+CD25low/-GITR+ cells circulating in the peripheral blood (PB) of 32 patients with SLE and 25 healthy controls was evaluated by flow cytometry. CD4+CD25low/-GITR+ cells were isolated by magnetic separation and their phenotype was compared with that of CD4+CD25highGITR¿ cells. Regulatory activity of both cell subsets was tested in autologous and heterologous co-cultures following purification through a negative sorting strategy.ResultsResults indicated that CD4+CD25low/-GITR+ cells are expanded in the PB of 50% of SLE patients. Expansion was observed only in patients with inactive disease. Phenotypic analysis demonstrated that CD4+CD25low/-GITR+ cells display regulatory T cell (Treg) markers, including FoxP3, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), transforming growth factor-beta (TGF-ß) and interleukin (IL)-10. In contrast, CD4+CD25highGITR¿ cells appear to be activated and express low levels of Treg markers. Functional experiments demonstrated that CD4+CD25low/-GITR+ cells exert a higher inhibitory activity against both autologous and heterologous cells as compared to CD4+CD25highGITR¿ cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-ß.ConclusionsPhenotypic and functional data demonstrate that in SLE patients CD4+CD25low/-GITR+ cells are fully active Treg possibly representing peripheral Treg (pTreg) that are expanded in patients with inactive disease. These data may suggest a key role of this T cell subset in the modulation of the abnormal immune response in SLE. Strategies aimed at expanding this Treg subset for therapeutic purpose deserve to be investigated.