Deficient CD4+CD25high T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus

Abstract

CD4+CD25+ T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4+CD25high Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4+CD25high Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4+CD25high Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4+ effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4+ effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4+CD25high Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4+CD25high Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease.

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…Although we found a substantial increase in the number of CD4 1 FOXP3 1 T cells from lupus patients in agreement with some recent reports [33], this could be a further indicator of abnormal T-cell activation. Indeed a number of groups have noted a reduction of CD4 1 CD25 hi Treg in SLE [54,55]. FOXP3 expression is known to be increased upon activation of human T cells [56][57][58].…”

Is FOXP3 a bona fide marker for human regulatory T cells?

“…Interestingly, in vitro activation of these cells, which promoted sustained high expression of FOXP3, restored the ability of nTreg to suppress [26]. It is therefore possible that, in IPEX patients or in patients affected by autoimmune diseases, impairment of the cytokinemediated mechanisms responsible for maintaining stable high expression of FOXP3 leads to the defective function of nTreg and to the break of self tolerance.…”

Customising an antibody leukocyte capture microarray for systemic lupus erythematosus: Beyond biomarker discovery

“…Th17 cells themselves express a number of chemokine receptors including a secondary lymphoid tissue homing receptor (CCR7), the B follicle homing receptor (CXCR5), and nonlymphoid tissue homing receptors (CCR4, CCR5, and CXCR6) [32]. The role of Tregs in SLE has not been elucidated, but there are a large number of observations that indicate that Tregs are decreased in number and function in SLE [33,34]. The surface markers that identify Tregs include CD4, CD25, CD127, CD152, CD62L and glucocorticoid-induced tumour necrosis factor receptor and glucocorticoid-induced tumour necrosis factor receptor ligand where the last five markers are not included in the current generation of the array and should therefore be included in the proposed SLE-specific array.…”