| Transforming growth factor-beta 1 (TGF- β1) is a multifaceted and tightly regulated cytokine that plays a crucial role in regulating innate and adaptive immune responses. It is a member of the TGF-β superfamily and belongs to the TGF-β subfamily of cytokines, which consists of three isoforms in humans: TGF- β1, TGF- β2 and TGF- β3. Immune cells predominantly express TGF-β1, which is highly conserved across species. Noteworthy, TGF-β1 is synthesized as an inactive precursor containing a large N-terminal domain, referred as the latency-associated protein (LAP), and TGF-β1 at the C-terminus. Proteolytic cleavage results in release of active TGF-β1 from LAP, but LAP remains non-covalently associated with the mature TGF-β1 moiety, representing the small latent complex (SLC). Within the SLC, TGF-β1 is still kept in an inactive form, unable to bind to its receptor. In order to exert biological responses, it is inevitable to degenerate the LAP, for instance by extremes of pH, heat, reactive oxygen species, several serine proteases as well as by interaction with thrombospondin or integrins. Mature TGF-β1 forms a disulfide-linked homodimer that mediates signaling through a cell surface receptor complex composed of TGF-β type I and type II receptors. Upon ligand binding, the receptor complex activates downstream signaling pathways, including canonical Smad-dependent pathways and non-Smad pathways, leading to diverse cellular responses. TGF-β1 promotes the differentiation of naïve CD4+ T cells into regulatory T cells (Tregs), which play a key role in suppressing autoreactive T cells and preventing autoimmune reactions. Thus, TGF-β1 essentially contributes to peripheral tolerance. Moreover, TGF-β1 is able to inhibit the proliferation of both CD4+ and CD8+ T cells in order to prevent uncontrolled immune responses and to maintain immune homeostasis. Similarly, TGF-β1 can also inhibit the proliferation of B cells, thereby regulating the overall magnitude of immune responses and preventing excessive B cell activation. While TGF-β1 can inhibit the proliferation of B cells, it can also contribute to the induction of antibody production by promoting class switching to certain antibody isotypes, especially IgA. IgA is important for mucosal immunity, providing defense against pathogens at mucosal surfaces such as the gut and respiratory tract. Additionally, TGF-β1 has a significant impact on macrophages, influencing their activation and polarization. It can promote an anti-inflammatory or immunosuppressive phenotype in macrophages, contributing to tissue repair and resolution of inflammation. During embryonic development, TGF-β1 orchestrates organogenesis, whereas in adults, it maintains tissue homeostasis. Furthermore, TGF-β1 is a key mediator of wound healing, stimulating processes such as fibroblast activation, extracellular matrix (ECM) synthesis, and epithelial-mesenchymal transition (EMT). Perturbation of TGF-β1 signaling causes fibrotic disorders and autoimmune diseases. TGF-β1 is also involved in cancer, where it has a dual role acting as both a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Therefore, precise modulation of TGF-β1 signaling holds therapeutic promise in various diseases. To advance therapeutic strategies, it is of great interest to elucidate the multifaceted roles of TGF-β1 in health and disease. |
