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

Introduction: CD4(+)CD25(low/-)GITR(+) T lymphocytes expressing forkheod 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(+)CD25(low/-)GITR(+) T lymphocytes within CD4(+) T cells and compare their phenotypic and functional profile with that of CD4(+)CD25(low/-)GITR(+) T lymphocytes in systemic lupus erythematosus (SLE) patients. Methods: The percentage of CD4(+)CD25(low/-)GITR(+) cells circulating in the peripheral blood (PB) of 32 patients with SLE and 25 healthy controls was evaluated with flow cytometry. CD4(+)CD25(low/-)GITR(+) T cells were isolated with magnetic separation, and their phenotype was compared with that of CD4(+)CD25(low/-)GITR(+) T cells. Regulatory activity of both cell subsets was tested in autologous and heterologous co cultures after purification through a negative sorting strategy. Results: Results indicated that CD4(+)CD25(low/-)GITR(+) T cells are expanded in the PB of 50% of SLE patients. Expansion vvas observed only in patients with inactive disease. Phenotypic analysis demonstiated that CD4(+)CD25(low/-)GITR(+) T cells display regulatory T--cell (Treg) markers, including FoxP3, cytotoxic Tlymphocyte-associated protein 4 (CTLA-4), transforming growth factor beta (TGE 13), and interleukin (IL) 10. In contrast, CD4(+)CD25(low/-)GITR(+) T cells appear to be activated and express low levels of Treg markers. Functional experiments demonstrated that CD4(+)CD25(low/-)GITR(+) T cells exert a higher inhibitory activity against both autologous and heterologous cells as compared with CD4(+)CD25(low/-)GITR(+) T cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-beta. Conclusions: Phenotypic and functional data demonstrate that in SLE patients, CD4(+)CD25(low/-)GITR(+) T cells are fully active Treg cells, 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.