Phenotypic and Functional Analysis of CD4+CD25−Foxp3+ T Cells in Patients with Systemic Lupus Erythematosus

Abstract

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.

Imbalance of different types of CD4+forkhead box protein 3 (FoxP3)+ T cells in patients with new-onset systemic lupus erythematosus

“…+ T cells lacked inhibitory function [16][17][18][19]. However, little is known about the frequency of CD4…”

“…+ T cells are induced peripherally by environmental antigens presented by dendritic cells (DCs) [18,20]. The function of CD4…”

Abnormal phenotypic distribution of regulatory and effector T cells in octogenarian and nonagenarian women

“…However, in previous studies the authors and others have shown these cells to be increased in patients with active systemic lupus erythematosus. 34 36 In view of this, we hypothesize that these cells may represent intermediate or incomplete phenotypes towards Treg or effector T cells. It is possible that the increased frequency of these incomplete phenotypes in elderly people would be a consequence of counteracting mechanisms in a senescent immune system.…”

Regulatory T Cell Deficiency in Systemic Autoimmune Disorders – Causal Relationship and Underlying Immunological Mechanisms

“…These studies provided thus a plausible explanation for the systemic nature of the disease. A lack of Treg-mediated immune regulation in lupus is now a general consensus, although there have been differences in the findings as to whether a reduced Treg frequency [40-46, 49-53, 58-61, 68, 71-75, 82-84, 88, 90], defective Treg functions [44,48,53,57,59,60,66,70,76,80,89,90] or both, or alternatively an insensitivity of the Treg target cells [66,67,70,89,99], are truly accountable. By using CD25 as the marker, an early study by Crispin and colleagues first showed that, in lupus patients with active disease, the frequencies of Treg (CD4+CD25 +/bright ) were significantly decreased, while T cells with an activated T helper (Th) effector phenotype (CD4 + CD69 + ) increased [40].…”

“…However, there have also been controversial findings from other studies showing that the frequency of Treg cells, either defined as CD4 + CD25 bright or CD4 + Foxp3 + , could be normal www.intechopen.com [48,66,67,70,85,86] or even increased [47, 54-56, 58, 62-65, 69, 74, 76-79, 81] in lupus disease. Instead, some of these studies suggested that Treg were functionally defective and less capable of suppressing those potentially auto-reactive lymphocytes in lupus patients [44,48,53,57,59,60,66,76,80], and the mouse models [70,89,90]. Again, alternative findings demonstrating lupus Treg being functionally normal [49,50,62,67,85], or at least normal in majority of patients tested [48,64], or even enhanced in some way [68,80,87] added further confusion as well as interest to the matter.…”