Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells

Abstract

Regulation of an immune response requires complex crosstalk between cells of the innate and adaptive immune systems, via both cell-cell contact and secretion of cytokines. An important cytokine with a broad regulatory role in the immune system is transforming growth factor-β (TGF-β). TGF-β is produced by and has effects on many different cells of the immune system, and plays fundamental roles in the regulation of immune responses during homeostasis, infection and disease. Although many cells can produce TGFβ, it is always produced as an inactive complex that must be activated to bind to the TGFβ receptor complex and promote downstream signalling. Thus, regulation of TGFβ activation is a crucial step in controlling TGFβ function. This review will discuss how TGFβ controls diverse immune responses and how TGFβ function is regulated, with a focus on recent work highlighting a critical role for the integrin αvβ8 expressed by dendritic cells in activating TGFβ.

Fig. 1

Activated TGFβ signals via Smad-dependent and independent pathways. Once the latent complex of TGFβ is activated, active TGFβ binds to TGFβRII, resulting in recruitment of a TGFβRI. Phosphorylation of TGFβRI by TGFβRII allows either SMAD2 or SMAD3 to bind. TGFβRI phosphorylates SMAD2/3, which dissociates from the receptor complex and binds SMAD4. SMAD7 is able to disrupt SMAD2/3 attachment to the receptor complex. SMAD4 in complex with SMAD2/3 translocates to the nucleus where they decorate SMAD-binding elements of gene promoter regions. Constitutive dephosphorylation of SMADs results in their export from the nucleus, ensuring tight regulation of TGFβ signalling. The complex is able to recruit coactivators or corepressors to either up- or down-regulate expression of a wide range of genes, dependent on the cell type. TGFβ can also signal through poorly understood SMAD-independent pathways including MAP kinase, PI3 kinase, Wnt and other pathways.

Fig. 2

Integrin αvβ8-mediated TGFβ activation is mediated by, and acts upon DCs to regulate pro- and anti-inflammatory immune responses. Latent TGFβ binds integrin αvβ8 integrin via an RGD motif in the LAP region of the latent complex, resulting in the release of active TGFβ which can orchestrate pro- or anti-inflammatory responses. Pro-inflammatory immunity is stimulated when (1) Th17 cells are induced from naive CD4+ T-cells DC-mediated TGFβ activation via integrin αvβ8, which can result in diseases such as EAE and AHR and (2) TGFβ is activated by lung fibroblast-expressed integrin αvβ8, with TGFβ acting in an autocrine manner to stimulate chemokine secretion and DC recruitment to the lung. Anti-inflammatory immunity is stimulated when TGFβ activated by DC-expressed integrin αvβ8: (3) induces Foxp3+ Tregs and (4) directly inhibits T-cell activation.