TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet.
TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet.
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发表时间：
2005
影响因子：
4.4
通讯作者：
Jack T. Lin;Stacey L. Martin;L. Xia;J. Gorham
中科院分区：
文献类型：
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作者：
Jack T. Lin;Stacey L. Martin;L. Xia;J. Gorham
TGF-β 1在体内抑制致病性Th 1自身免疫反应中起着关键作用，但介导TGF-β 1对IFN-γ表达的CD 4（+）T细胞表达的抑制作用的机制仍不完全清楚。为了评估TGF-β 1抑制IFN-γ在CD 4（+）T细胞中表达的机制，我们在Th 1发育条件下，在存在或不存在添加的TGF-β 1的情况下，在体外致敏幼稚野生型小鼠BALB/c CD 4（+）T细胞。我们发现，在CD 4（+）T细胞的启动过程中，TGF-β 1的存在抑制了启动过程中IFN-γ的表达，以及在回忆刺激下表达IFN-γ的Th 1效应细胞的发育。TGF-β 1以剂量依赖性方式抑制IFN-γ表达细胞的发育，并且在没有APC的情况下，表明TGF-β 1可以通过直接作用于CD 4（+）T细胞来抑制Th 1发育。在引发过程中，TGF-β 1强烈抑制T-bet（T细胞中表达的T盒）和Stat 4的表达。我们评估了这两种分子在Th 1应答的两个阶段抑制IFN-γ表达的重要性。通过逆转录病毒增强T-bet的表达阻止了TGF-β 1对Th 1发育的抑制，但并没有阻止TGF-β 1在引发时对IFN-γ表达的抑制。相反，Stat 4的强制表达部分阻止了TGF-β 1在引发过程中对IFN-γ表达的抑制，但没有阻止TGF-β 1对Th 1发育的抑制。这些数据表明，TGF-β 1使用不同的机制来抑制IFN-γ在CD 4（+）T细胞中的表达在启动和回忆。
TGF-beta1 plays a critical role in restraining pathogenic Th1 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 Th1 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 Th1 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 Th1 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 Th1 responses. Enforced expression of T-bet by retrovirus prevented TGF-beta1's inhibition of Th1 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 Th1 development. These data show that TGF-beta1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4(+) T cells at priming and at recall.