TGF‐β in the Immune Response

Abstract

Transforming growth factor‐β (TGF‐β) is a highly evolutionally conserved cytokine that is critical for embryogenesis, cancer and matrix formation and immune responses. Three distinct isoforms, TGF‐β1, 2 and 3, are found in mammals. TGF‐β is secreted by immune and nonhematopoietic cells and acts on virtually all cell types through ubiquitously expressed receptors, which transduce the TGF‐β signal through canonical Smad‐dependent pathway and noncanonical Smad‐independent pathways. In particular, TGF‐β plays a crucial role in immune tolerance and maintains immune homeostasis by inhibiting proliferation, differentiation, activation and effector function of immune cells. On the other side of the coin, TGF‐β can display proinflammatory properties, depending on the context. The more complete understanding of the various functions of TGF‐β in the immune system, especially in tolerance, will enable us to design more specific and effective therapies for immune disorders.

Key Concepts

  • TGF‐β is a multifunctional cytokine that mainly suppresses immune responses to maintain immune homeostasis.
  • TGF‐β signalling is transduced via not only its unique protein, Smad, but also via Smad‐independent pathways.
  • T cells are the major targets of TGF‐β in immune system and its activation/proliferation, apoptosis and differentiation are regulated by TGF‐β.
  • TGF‐β is a key mediator for the regulation of autoimmune diseases.

Keywords: TGF‐β; immune tolerance; autoimmune disease; helper T cell differentiation; regulatory T cell

Figure 1. TGF‐β signalling. Latent TGF‐β consists of TGF‐β, latent TGF‐β‐binding protein (LTBP) and latency‐associated protein (LAP), and requires activation in order to bind to its receptor. Bioactive TGF‐β binds TβRIIs, which are constitutively phosphorylated, and subsequently recruit and phosphorylate TβRIs. In the Smad‐dependent pathway, activated TβRs phosphorylate Smad2 and/or Smad3 and subsequently interact with Smad4 that enables Smad2/3 to translocate into the nucleus. Binding of the Smad complex to the Smad‐binding element (SBE) regulates target gene expression. In Smad‐independent pathways, mitogen‐activated protein kinases (MAPK), phosphatidylinositol‐3 kinase (PI3K)‐Akt‐mTOR, TNF receptor‐associated factor 6 (TRAF6)/TGF‐β‐activated kinase 1 (TAK1)‐MAP kinase kinases (MKKs)‐p38 MAPK and small GTPases can be activated downstream of TGF‐β/TβR interaction.
Figure 2. The role of TGF‐β in helper T cell differentiation. In the periphery, naïve CD4+ T cells differentiate into subpopulations of helper T cells upon activation. TGF‐β promotes differentiation of Treg, Th17 and Th9 cells, whereas the differentiation of Th1, Th2 and Th22 cells is inhibited by TGF‐β. The role of TGF‐β in Tfh cell differentiation is still unknown. TGF‐β appears to be involved in the tTreg differentiation in the thymus.
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Nakatsukasa, Hiroko, Tu, Eric, Chia, Cheryl Pei Zhi, and Chen, WanJun(Sep 2015) TGF‐β in the Immune Response. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021546]