Transforming growth factor-β1 in regulatory T cell biology

Abstract

Transforming growth factor-β1 (TGF-β1) is inextricably linked to regulatory T cell (T_reg) biology. However, precisely untangling the role for TGF-β1 in T_reg differentiation and function is complicated by the pleiotropic and context-dependent activity of this cytokine and the multifaceted biology of T_regs. Among CD4⁺ T cells, T_regs are the major producers of latent TGF-β1 and are uniquely able to activate this cytokine via expression of cell surface docking receptor glycoprotein A repetitions predominant (GARP) and αv integrins. Although a preponderance of evidence indicates no essential roles for T_reg-derived TGF-β1 in T_reg immunosuppression, TGF-β1 signaling is crucial for T_reg development in the thymus and periphery. Furthermore, active TGF-β1 instructs the differentiation of other T cell subsets, including T_H17 cells. Here, we will review TGF-β1 signaling in T_reg development and function and discuss knowledge gaps, future research, and the TGF-β1/T_reg axis in the context of cancer immunotherapy and fibrosis.

Fig. 1.. Timeline of notable discoveries on the role of TGF-β1 and TGF-β1 signaling in the biology of T cells and T_regs.

Work on the roles of TGF-β in T_reg biology is highlighted in red.

Fig. 2.. TGF-β1 biogenesis, activation, and signaling.

TGF-β1 can be produced and secreted by a number of cell types, including T_regs. LTGF-β1 can be secreted in the SLC or LLC form. Upon secretion, the LLC can bind to fibronectin or fibrillin in the ECM. The SLC can bind to cell surface GARP (e.g., on T_regs, platelets, and endothelial cells) or LRRC33 (e.g., on macrophages and microglia). Activation of LTGF-β1 requires cleavage or conformational change of the SLC or LLC, which releases the mature TGF-β1 from the complex or exposes its active binding motif. Active TGF-β1 binds to TGF-βRII on target cells, which recruits and activates TGF-βRI intracellular domain. Phosphorylation of the TGF-β RI cytoplasmic tails leads to activation and signaling via the canonical (Smad-dependent) or noncanonical pathways. All signaling pathways regulate downstream gene expression. TF, transcription factor.

Fig. 3.. An integrated view of TGF-β1 in T_reg biology.

TGF-β1 is uniquely poised to be a focal point in T_reg biology because T_regs highly express the TGF-β receptor, are major producers of latent TGF-β1, and have their activating machinery. (A) Signaling through receptor dimers of TGF-βRI and TGF-βRII is a requirement for both thymic T_reg development and induced T_reg differentiation. (B) T_reg-derived TGF-β1 has long been hypothesized to have a major role in T_reg function as these cells are a source of latent TGF-β1 and express both GARP and αvβ8 integrin, which work in tandem to activate TGF-β1. Accumulating evidence suggests that T_reg-produced TGF-β1 contributes to immunoregulation but is one of several mechanisms in the T_reg arsenal. Although not critical to homeostatic function, T_reg generation of bioactive TGF-β1 is likely to have tissue- and context-specific immunomodulatory activity.

Fig. 4.. Contributions of TGF-β1 to immune evasion and immunity in cancer.

The pleiotropic roles of TGF-β1 within the TME include (A) dampening the antitumor immune responses, (B) enhancing protumorigenic responses, and (C) promoting other elements of protective immunity through interactions with various cell types. Key functional aspects of these interactions are depicted. DC, dendritic cell; NK, natural killer; IgA, immunoglobulin A; NFκB, nuclear factor κB.