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  • Review Article
  • Published:

Immunoregulation by members of the TGFβ superfamily

Nature Reviews Immunology volume 16, pages 723–740 (2016)Cite this article

Subjects

Key Points

  • Activins and bone morphogenetic proteins (BMPs), which are part of transforming growth factor-β (TGFβ) superfamily, regulate a diverse range of immune responses through their effects on both immune and non-immune cell populations.

  • TGFβ, activins and BMPs have distinct receptors and use both different and some shared signalling mediators. Similarly to TGFβ, activins signal through their receptors to activate SMAD2 and SMAD3; by contrast, signalling by BMPs activates SMAD1, SMAD5 and SMAD8.

  • Activin A is the best characterized of the activins, and innate and adaptive immune cell populations both produce and respond to this cytokine.

  • Activin A can synergize with TGFβ to promote FOXP3+ regulatory T (Treg) cell generation from naive CD4+ T cells in vitro, but activin A alone fails to induce Treg cells.

  • Activin A can have pro-inflammatory or anti-inflammatory effects depending on the target cell type, the activation status of the targeted immune cells and the tissue microenvironment.

  • Similarly, BMPs have been found to both positively and negatively regulate innate and adaptive immune responses; their effects are dependent on the target cells and the type of BMP.

  • BMPs have been shown to have both tumour-promoting and tumour-suppressing effects in cancer.

Abstract

The transforming growth factor-β (TGFβ) superfamily is encoded by 33 genes and includes TGFβ, bone morphogenetic proteins (BMPs) and activins. Although TGFβ is well recognized as a crucial regulator of immune responses, the immunoregulatory functions of other TGFβ family members are less clear. However, recent evidence suggests that BMPs and activins have important roles in regulating immune responses. In this Review, we briefly outline the signalling pathways of the TGFβ superfamily and discuss new insights into the immunoregulatory functions of BMPs and activins in the context of infection, inflammation and cancer.

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Figure 1: Signal transduction by the TGFβ superfamily.
Figure 2: TGFβ regulates immune cells in the thymus and periphery.
Figure 3: Immunoregulation by BMPs and activins in the thymus and peripheral tissues.
Figure 4: Effects of TGFβ, activins and BMPs on immune responses in cancer.

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Acknowledgements

The authors thank all of the members in the Mucosal Immunology Section, National Institute for Dental and Craniofacial Research, for their help preparing the tables and figures. We also thank Y. Wu and V. Chen for critically reading the manuscript. This research was supported by The Intramural Research Program of the US National Institutes of Health (W.J.C.).

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  1. Mucosal Immunology Section, National Institute for Dental and Craniofacial Research, National Iinstitutes of Health, Bethesda, Maryland, USA

    WanJun Chen

  2. Department of Molecular Cell Biology, Cancer Genomics Centre Netherlands, Leiden University Medical Center, Leiden, Netherlands

    Peter ten Dijke

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Glossary

SMAD transcription factors

A family of proteins that act as intracellular effectors of TGFβ superfamily members. This family was named for their similarity to the Drosophila gene product mothers against decapentaplegic (Mad) and the Caenorhabditis elegans SMA protein.

M2-like macrophage

Macrophages that develop in response to interleukin-4 (IL-4) or IL-13 and produce high levels of IL-10 and TGF, and low levels of IL-12. They are generally involved in type 2 immunity and tissue repair.

Remyelination

The process of propagating oligodendrocyte precursor cells to form oligodendrocytes to create new myelin sheaths on demyelinated axons in the central nervous system.

β-Selection process

A process during T cell development in the thymus to produce mature T cells with a diverse array of functional T cell receptors. It eliminates thymocytes with gross defects introduced into the T cell receptor by gene rearrangement.

Nuclear factor of activated T cells

(NFAT). A family of transcription factors in lymphocytes that is crucial for regulating early gene transcription in response to T cell receptor-mediated signals.

Langerhans cell

A group of dendritic cells that are mainly resident in the basal and suprabasal layers of the skin and mucosa, such as the mucosa of the mouth, foreskin and vagina, as well as in the epidermis and in the epithelia of the respiratory, digestive and urogenital tracts.

Cyclin-dependent kinases

(CDKs). A family of protein kinases that phosphorylate various proteins involved in cell cycle progression on serine and threonine residues. CDKs require the presence of cyclins to become active.

Innate lymphoid cells

(ILCs). A group of innate-like lymphocytes that do not express antigen receptors but produce effector cytokines and other immune mediators in response to stimulation.

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Chen, W., ten Dijke, P. Immunoregulation by members of the TGFβ superfamily. Nat Rev Immunol 16, 723–740 (2016). https://doi.org/10.1038/nri.2016.112

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