TNFα: Activator or inhibitor of regulatory T cells?

TNFα is a cytokine that is central to the pathogenesis of several autoimmune diseases. More specifically, the deleterious effects of TNFα in rheumatoid arthritis (RA) are well established. The proinflammatory influence of TNFα in RA is related both to direct effects mediated by the induction of other proinflammatory cytokines, metalloproteinases, and free radicals; and to modulation of the regulatory T cells (Tregs). Furthermore, the TNFα antagonists used to treat RA can induce the emergence of a distinctive Treg subpopulation. Nevertheless, a recent body of data suggests that TNFα may also exert anti-inflammatory effects, which may be mediated in part via Tregs. TNFα binds to the TNF receptor 2 expressed preferentially at the Treg surface, thereby activating and promoting the development of Tregs. Data from patients with RA and more recent evidence obtained in the absence of disease are consistent with a paradoxical effect of TNFα on Tregs. TNFα may have different effects on naturally occurring Tregs and induced Tregs.