CD4+CD25+Foxp3+ regulatory T cells (Treg) that specialize in the suppression of immune responses might be critically involved in the pathogenesis of autoimmune diseases. Recent studies have described increased proportions of CD4+Foxp3+ T cells that lacked expression of CD25 in systemic lupus erythematosus (SLE) patients but the suppressive capacity of these cells has not been analyzed so far. We therefore performed combined phenotypic and functional analyses of CD4+CD25−Foxp3+ T cells in patients with autoimmune diseases and healthy controls (HC). Phenotypic analysis revealed increased proportions of CD4+CD25−Foxp3+ T cells in SLE patients as compared with patients with systemic sclerosis, rheumatoid arthritis, (RA), or HC. In addition, increased proportions of CD4+CD25−Foxp3+ T cells correlated with the clinical disease activity and the daily cortisone dose. According to phenotypic analysis, CD4+CD25−Foxp3+ T cells resembled regulatory T cells rather than activated T cells. For functional analysis, a surrogate surface marker combination to substitute for intracellular Foxp3 was defined: CD4+CD25−CD127− T cells from SLE patients were isolated by FACS sorting and analyzed for their suppressive capacity in vitro. CD4+CD25−CD127− T cells, that contained up to 53% Foxp3+ T cells, were found to suppress T cell proliferation but not IFN-γ production in vitro. In summary, CD4+CD25−Foxp3+ T cells phenotypically and to a certain extent also functionally resemble conventional Treg. Despite increased proportions, however, their selective functional defects might contribute to the failure of Treg to control autoimmune dysregulation in SLE patients.

The objective of the study was that the regulatory T cells (Treg) that specialize in the suppression of immune responses might be critically involved in the pathogenesis of autoimmune disease. As for systemic lupus erythematosus (SLE), however, published data concerning Treg phenotype and function are partly conflicting. We therefore performed quantitative and qualitative analyses of naturally occurring CD4(+)CD25(+) Treg from SLE patients as compared with healthy controls (HC) in order to further elucidate the role of Treg in this systemic autoimmune disease. The phenotype of peripheral blood CD4(+)CD25(+) Treg was determined by flow cytometry (FACS) in SLE patients and HC. Treg were isolated from SLE patients and HC and their functional capacity was analyzed in suppression assays. Phenotypic and functional data were correlated with clinical data. Decreased proportions of CD4(+) Treg with high-level expression of CD25 (CD4(+)CD25(hi)) were observed in active and inactive SLE patients (0.96 +/- 0.08 and 1.17 +/- 0.08%, respectively) as compared with HC (2 +/- 0.1%). In contrast to HC, Treg from SLE patients displayed an activated phenotype as determined by the expression of CD69, CD71 and HLA-DR. The suppressive capacity of isolated Treg from SLE patients, however, was significantly reduced as compared with HC. Proportions of CD4(+)CD25(hi) T cells and the suppressive capacity of Treg were inversely correlated with the clinical disease activity in SLE patients. Our data describe quantitative and qualitative defects of Treg in SLE patients. These deficiencies might contribute to the breakdown of self-tolerance and the development of the autoimmune response in SLE patients.

Our data suggest that the expression of Foxp3 on CD4(+) T cells in patients with SLE, at least to some extent, reflects the activation of CD4(+) T cells due to underlying disease activity and does not necessarily indicate a functional regulatory T cell capacity.