Production of TGF-β 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-β 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-β 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-β propeptide in T cells. STAT6 is also necessary for several helminth-triggered events in mice, such as TGF-β-dependent suppression of alloreactive inflammation in graft-versus-host disease. Besides STAT6, helminth-induced secretion of active TGF-β requires cleavage of propeptide by the endopeptidase furin. Thus, for the immune regulatory pathway necessary for TGF-β production by T cells, our results support a two-step model, composed of STAT6 and furin.
Bibliographical noteFunding Information:
This work was supported by research funds from the National Institutes of Health R56 AI 116715 (to M.N.I.), R01 HL56067, AI34495, HL11879 (to B.R.B.), and R01 AI095282 (to M.H.K.), the Department of Veterans Affairs BX002906 (to M.N.I.) and BX002715 (to D.E.E.), Research Foundation - Flanders G.0738.15N, Belgium (to J.W.C.), the Sigrid Juselius Foundation, and the Academy of Finland (to M.P.).