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

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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.