Figure 3. TGF-β and immune regulation.

Scheme of the main classes of immune cells and their regulation by TGF-β in the adult. TGF-β is a critical modulator of both adaptive and innate immunity arms, acting as a general enforcer of immune tolerance and a suppressor of inflammation. In the adaptive arm, TGF-β inhibits the maturation of naïve CD4⁺ T cells into T_H1 and T_H2 T helper cells and of naïve CD8⁺ T cell into cytotoxic T lymphocytes (CTL). TGF-β exerts these effects through direct inhibition of CD4⁺ and CD8⁺ maturation and through inhibition of dendritic cell subsets (DC1, DC2) that drive naïve these maturation steps. TGF-β additionally inhibits the helper functions of T_H1 and T_H2, and the effector functions of CTL cells, and it can do so by acting directly on these cells as well as by promoting the differentiation of CD4⁺ T cells into peripheral regulatory T cells (pT_reg), which inhibit T_H1 and T_H2 cells partly through TGF-β. A specialized RORγt⁺ antigen-presenting cell (TC ) activates pT_reg cells in the intestinal lymph nodes. TGF-β inhibits B cell proliferation but stimulates IgA class switching in B cells. In the innate immunity arm, TGF-β blunts the effector functions of natural killer (NK) cells, and the inflammatory functions of neutrophils and macrophages while favoring, in the context of tumors, the adoption of tumor-associated neutrophil (TAN) and macrophage (TAM) states which support tumor progression. In chronic infection, inflammation, and cancer, the persistent myelopoiesis includes production of myeloid-derived suppressor cells (MDSC) with TGF-β dependent immunosuppressive functions. These regulatory effects of TGF-β on the immune system occur to different extents in different tissue contexts and depending on whether the circumstance is homeostasis, acute injury or infection, or chronic inflammation, fibrosis, or cancer.