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1 Uses Distinct Mechanisms to Inhibit IFN-
Expression in CD4+ T Cells at Priming and at Recall: Differential Involvement of Stat4 and T-bet1
,
Departments of*
Microbiology and Immunology and Pathology and The Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756
TGF-
1 plays a critical role in restraining pathogenic Th1 autoimmune responses in vivo, but the mechanisms that mediate TGF-1’s suppressive effects on CD4+ T cell expression of IFN-
expression remain incompletely understood. To evaluate mechanisms by which TGF-1 inhibits IFN- expression in CD4+ T cells, we primed naive wild-type murine BALB/c CD4+ T cells in vitro under Th1 development conditions in the presence or the absence of added TGF-1. We found that the presence of TGF-1 during priming of CD4+ T cells suppressed both IFN- expression during priming as well as the development of Th1 effector cells expressing IFN- at a recall stimulation. TGF-1 inhibited the development of IFN--expressing cells in a dose-dependent fashion and in the absence of APC, indicating that TGF-1 can inhibit Th1 development by acting directly on the CD4+ T cell. During priming, TGF-1 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- expression at the two phases of Th1 responses. Enforced expression of T-bet by retrovirus prevented TGF-1’s inhibition of Th1 development, but did not prevent TGF-1’s inhibition of IFN- expression at priming. Conversely, enforced expression of Stat4 partly prevented TGF-1’s inhibition of IFN- expression during priming, but did not prevent TGF-1’s inhibition of Th1 development. These data show that TGF-1 uses distinct mechanisms to inhibit IFN- expression in CD4+ T cells at priming and at recall.
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