Transforming growth factor-β in T-cell biology

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Abstract
Transforming growth factor-β (TGF-β) inhibits the differentiation of both CD4+ and CD8+ naive T cells into effectors. This effect is not dependent on inhibition of proliferation. TGF-β blocks T helper (TH)2 development by inhibiting expression of Gata-3 (a master TH2 transcriptional activator). Similarly, TGF-β might block TH1 development through inhibition of a master TH1 transcriptional activator; a candidate is T-bet (T-box expressed in T cells). Early interferon-γ (IFN-γ) production by differentiating TH1 cells can protect from the inhibitory effects of TGF-β. Fully differentiated TH1 cells do not express the IFN-γ receptor are so are resistant to the protective effects of IFN-γ. Fully differentiated TH2 cells are resistant to the inhibitory effects of TGF-β, but the mechanism has not been elucidated. T cells activated in vitro in the presence of TGF-β resemble central memory T cells in that they retain the capacity to produce interleukin-2 (IL-2) and can differentiate to TH1 or TH2 effector cells when restimulated. Blocking TGF-β signalling in T cells by using transgenic approaches leads to spontaneous T-cell activation and inflammation, indicating that TGF-β signalling in T cells is essential for T-cell homeostasis. The role for TGF-β in controlling T-cell homeostasis seems to be in preventing inappropriate responses to certain self- or environmental antigens, rather than control of normal T-cell responses to low-avidity self-ligands that constitute survival signals. When TGF-β signalling is blocked in T cells, inflammation is most severe at mucosal sites where exposure to environmental antigens is highest (gut and lung). Dysregulated responses to the normal gut flora have been implicated in the pathogenesis of inflammatory bowel disease. Mucosal T cells from patients with inflammatory bowel disease (IBD) express high levels of Smad7, an inhibitor of TGF-β signalling, implying dysregulated TGF-β signalling might have a role in the pathogenesis of IBD. A cell-surface form of TGF-β might be important for CD4+CD25+ regulatory T-cell function. TGF-β released directly by apoptotic cells, or by antigen-presenting cells that have ingested apoptotic cells, might prevent T-cell responses to self-antigens. TGF-β might also inhibit T cells indirectly through its inhibitory effects on antigen-presenting cells. TGF-β production is associated with many tumours and might normally suppress tumour-specific T-cell responses, as blocking TGF-β signals in T cells in mice leads to the generation of potent CD8+ T-cell responses and tumour rejection.