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

Curr Dir Autoimmun. 2010;11:119-34. doi: 10.1159/000289201. Epub 2010 Feb 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology
  • Forkhead Transcription Factors / immunology
  • Humans
  • Inflammation / immunology
  • Interleukin-2 / pharmacology
  • Lymphocyte Activation
  • Mice
  • Models, Immunological
  • Pertussis Toxin / pharmacology
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / pharmacology


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Pertussis Toxin