TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells

Abstract

TNF-alpha (TNF) is a pleiotropic cytokine which can have proinflammatory or immunosuppressive effects, depending on the context, duration of exposure and disease state. The basis for the opposing actions of TNF remains elusive. The growing appreciation of CD4+FoxP3+ regulatory T cells (Tregs), which comprise approximately 10% of peripheral CD4 cells, as pivotal regulators of immune responses has provided a new framework to define the cellular and molecular basis underlying the contrasting action of TNF. TNF by itself can overcome the profound anergic state of T cell receptor-stimulated Tregs. Furthermore, in concert with IL-2, TNF selectively activates Tregs, resulting in proliferation, upregulation of FoxP3 expression and increases in their suppressive activity. Both human and mouse Tregs predominantly express TNFR2, making it possible for TNF to enhance Treg activity, which helps limit the collateral damage caused by excessive immune responses and eventually terminates immune response. TNFR2-expressing CD4+FoxP3+ Tregs comprise approximately 40% of peripheral Tregs in normal mice and present the maximally suppressive subset of Tregs. In this review, studies describing the action of TNF on Treg function will be discussed. The role of Tregs in the autoimmune disorders and cancer as well as the effect of anti-TNF therapy on Tregs, especially in rheumatoid arthritis, will also be considered.

Copyright (c) 2010 S. Karger AG, Basel.

Figures

Fig. 1.

Tregs predominately express TNFR2 and outcompete Teffs for TNF. TNFR2 is predominately expressed by both human and mouse Tregs. In the inflammatory responses, pathogenic Teffs and APCs are able to produce TNF. The chronic TNF exposure may favor the activation of Tregs by TNFR2 costimulation pathways. Accumulation of activated Tregs at the inflammatory site suppresses the activation of both innate immune cells as well as adaptive immune cells, and therefore may present an important negative feedback mechanism to limit the magnitude of the immune responses and avoid collateral damage.