STAT6 and Furin Are Successive Triggers for the Production of TGF-beta by T Cells

Production of TGF-beta by T cells is key to various aspects of immune homeostasis, with defects in this process causing or aggravating immune-mediated disorders. The molecular mechanisms that lead to TGF-beta generation by T cells remain largely unknown. To address this issue, we take advantage of the fact that intestinal helminths stimulate Th2 cells besides triggering TGF-beta generation by T lymphocytes and regulate immune-mediated disorders. We show that the Th2 cell-inducing transcription factor STAT6 is necessary and sufficient for the expression of TGF-beta propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-beta-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-beta requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-beta production by T cells, our results support a two-step model, composed of STAT6 and furin.