TGF-β activation and function in immunity

Abstract

The cytokine TGF-β plays an integral role in regulating immune responses. TGF-β has pleiotropic effects on adaptive immunity, especially in the regulation of effector and regulatory CD4(+) T cell responses. Many immune and nonimmune cells can produce TGF-β, but it is always produced as an inactive complex that must be activated to exert functional effects. Thus, activation of latent TGF-β provides a crucial layer of regulation that controls TGF-β function. In this review, we highlight some of the important functional roles for TGF-β in immunity, focusing on its context-specific roles in either dampening or promoting T cell responses. We also describe how activation of TGF-β controls its function in the immune system, with a focus on the key roles for members of the integrin family in this process.

Figure 1

Synthesis and processing of TGF-β isoforms into small and large latent complexes. TGF-β genes encode an N-terminal latency-associated peptide (LAP) and a C-terminal mature cytokine that form dimeric structures. The LAP and the mature TGF-β cytokine are cleaved from each other by the enzyme furin but remain noncovalently associated. The LAP region folds around the mature cytokine, blocking access of TGF-β to its receptor, and is termed the small latent complex. In the LAP of TGF-β1 and 3 (but not TGF-β2) there is an arginine-glycine-aspartic acid (RGD) site that facilitates binding to integrins. In some cells, the small latent complex can associate with latent TGF-β binding protein (LTBP) via interactions with LAP, forming the large latent complex. LTBP can facilitate binding of the large latent complex to proteins of the extracellular matrix.

Figure 2

Signaling pathways triggered by TGF-β. Active TGF-β binds to a dimer of TGF-βRII, which associates with a dimer of TGF-βRI to form a tetrameric receptor complex. TGF-βRII then phosphorylates the cytoplasmic domain of TGF-βRI, which activates the kinase activity of TGF-βRI. TGF-βRI can then associate with and phosphorylate receptor Smads (Smad2 or 3), which subsequently form a complex with either Smad4 or TIF1γ. The activated Smad complexes then act to modulate gene expression by binding to Smad-responsive elements in genes. TGF-β receptor activation can also trigger non-Smad-mediated signaling events (e.g., via MAPK, Rho GTPases, or PI3 kinase) to regulate gene expression.

Figure 3

Regulation of multiple CD4⁺ T cell phenotypes by TGF-β. The latent complex of TGF-β must be activated to function, and recent data highlight a key role for integrin αvβ6 expressed by epithelial cells and integrin αvβ8 expressed by dendritic cells in activating TGF-β. Once activated, TGF-β performs important functions in controlling both anti-inflammatory and proinflammatory T cell responses, with the presence of other cytokines dictating the functional outcome of TGF-β signaling in T cells.

Figure 4

Latent TGF-β can be activated by integrins via generation of physical force. Physical force generated by contraction of the actin cytoskeleton of cells expressing certain TGF-β-activating integrins (e.g., αvβ6) unfolds the unstructured region (straitjacket) of the latency-associated peptide that forms the major contact points with the active TGF-β dimer, thereby releasing active TGF-β and freeing it to interact with TGF-β receptors. Integrins αvβ3 and αvβ5 are proposed to activate latent TGF-β via a similar mechanism (not shown). Adapted from Reference and reprinted with permission from Nature Publishing Group and Prof. Timothy Springer (Harvard University).

Figure 5

Th17 cell induction via dendritic cell (DC)–expressed, integrin αvβ8–mediated TGF-β activation requires MHC-II–antigen–TCR interaction. (a) Activation of TGF-β by integrin αvβ8 expressed by DCs, in the presence of proinflammatory cytokines, can induce Th17 cell differentiation when the DC presents antigen via MHC-II to naive T cells. (b) In the absence of integrin αvβ8 expression, DCs are unable to induce Th17 cell differentiation. Additionally, DCs that express integrin αvβ8 but express a mismatched haplotype of MHC-II that cannot present antigen to T cells cannot induce Th17 cells.