Abstract
Introduction: CD4+
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.
Methods: The percentage of CD4+
CD25low/-GITR+ cells circulating in the peripheral blood (PB) of 32 patients with
SLE and 25 healthy controls was evaluated with flow cytometry. CD4+
CD25low/-GITR+ cells were isolated with
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 after purification through a negative
sorting strategy.
Results: Results 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-β), 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 with CD4+
CD25highGITR−
cells. Suppression is independent of cell contact and is mediated by IL-10 and TGF-β.
Conclusions: Phenotypic and functional data demonstrate that in SLE patients, CD4+
CD25low/-GITR+ 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.