Anti–TNF-α therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-β

Abstract

The induction of regulatory T (T reg) cells holds considerable potential as a treatment for autoimmune diseases. We have previously shown that CD4+CD25hi T reg cells isolated from patients with active rheumatoid arthritis (RA) have a defect in their ability to suppress proinflammatory cytokine production by CD4+CD25− T cells. This defect, however, was overcome after anti–tumor necrosis factor (TNF)-α antibody (infliximab) therapy. Here, we demonstrate that infliximab therapy gives rise to a CD4+CD25hiFoxP3+ T reg cell population, which mediates suppression via transforming growth factor (TGF)-β and interleukin 10, and lacks CD62L expression, thereby distinguishing this T reg cell subset from natural T reg cells present in healthy individuals and patients with active RA. In vitro, infliximab induced the differentiation of CD62L− T reg cells from CD4+CD25− T cells isolated from active RA patients, a process dependent on TGF-β. In spite of the potent suppressor capacity displayed by this CD62L− T reg cell population, the natural CD62L+ T reg cells remained defective in infliximab-treated patients. These results suggest that anti–TNF-α therapy in RA patients generates a newly differentiated population of T reg cells, which compensates for the defective natural T reg cells. Therefore, manipulation of a proinflammatory environment could represent a therapeutic strategy for the induction of T reg cells and the restoration of tolerance.

Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial

“…25 In patients with rheumatoid arthritis, treatment with infl iximab has been shown to increase survival of CD4+/CD25+ regulatory T cells, expand peripherally induced regulatory T cells, and reduce the severity of illness in patients resistant to disease-modifying antirheumatic drugs. 26 Thus, infl iximab treatment in acute Kawasaki disease could be benefi cial by lowering concentrations of this pro-infl ammatory cytokine and stimulating the expansion of regulatory T cells.…”

Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis

“…Similarly, another study showed resistance of CD4ϩ T cells to Treg cell-mediated suppression in the peripheral blood of RA patients (22). Moreover, TNF␣ compromises Treg cell function in RA (19,23).…”

“…Our objective in the present study was to elucidate the consequences of anti-IL-6R treatment in terms of its effects on the Treg cell phenotype and the activation of Treg cells in both a mouse model of RA (CIA) and in human patients with RA (23), in order to determine whether Treg cells are involved in the mode of action of this targeted therapy.…”

Role of regulatory T cells in rheumatoid arthritis: facts and hypothesis

“…They also argued that anti-TNF therapy may generate a new Treg cell population in RA patients by converting effector T cells into Treg cells following unknown processes. This hypothesis has been confirmed in further studies which have demonstrated the induction of an adaptative Treg cell subset able to exert a suppressive effect via TGFβ in a cohort of infliximabtreated RA patients [49].…”

“…As summarized in Table 2, recent studies by Ehrenstein et al represent a milestone in this field [48][49][50]. They showed that infliximab is able to restore the ability of PB Treg cells from RA patients to inhibit proinflammatory cytokine secretion, including TNFα, in in vitro culture supernatants [48].…”