TGF-beta1 Uses Distinct Mechanisms to Inhibit IFN-gamma Expression in CD4~+T Cells at Priming and at Recall:Differential Involvement of Stat4 and T-bet

摘要

TGF-beta1 plays a critical role in restraining pathogenic Thl autoimmune responses in vivo,but the mechanisms that mediate TGF-beta1's suppressive effects on CD4~+T cell expression of IFN-gamma expression remain incompletely understood.To evaluate mechanisms by which TGF-beta1 inhibits IFN-gamma expression in CD4~+T cells,we primed naive wild-type murine BALB/c CD4~+T cells in vitro under Thl development conditions in the presence or the absence of added TGF-beta1.We found that the presence of TGF-beta1 during priming of CD4~+T cells suppressed both IFN-gamma expression during priming as well as the development of Thl effector cells expressing IFN-gamma at a recall stimulation.TGF-beta1 inhibited the development of IFN-gamma-expressing cells in a dose-dependent fashion and in the absence of APC,indicating that TGF-beta1 can inhibit Thl development by acting directly on the CD4~+T cell.During priming,TGF-beta1 strongly inhibited the expression of both T-bet(T box expressed in T cells)and Stat4.We evaluated the importance of these two molecules in the suppression of IFN-gamma expression at the two phases of Thl responses.Enforced expression of T-bet by retrovirus prevented TGF-beta1's inhibition of Thl development,but did not prevent TGF-beta1's inhibition of IFN-gamma expression at priming.Conversely,enforced expression of Stat4 partly prevented TGF-beta1's inhibition of IFN-gamma expression during priming,but did not prevent TGF-beta1's inhibition of Thl development.These data show that TGF-beta1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4~+T cells at priming and at recall.