Distinct effects of TGF-β1 on CD4+ and CD8+ T cell survival, division, and IL-2 production:: A role for T cell intrinsic Smad3
Distinct effects of TGF-β1 on CD4+ and CD8+ T cell survival, division, and IL-2 production:: A role for T cell intrinsic Smad3
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DOI：
10.4049/jimmunol.174.4.2071
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发表时间：
2005-02-15
影响因子：
4.4
通讯作者：
Schwartz, RH
中科院分区：
文献类型：
--
作者：
McKarns, SC;Schwartz, RH
TGF-β 1对维持T细胞稳态至关重要。Smad 3参与了这一调控过程，但其细胞靶点和分子细节仍知之甚少。在这项研究中，我们报告说，TGF-β 1损害进入CD 4（+）和CD 8（+）T细胞的细胞周期，以及他们的进展，通过随后的几轮分裂，并表明Smad 3是必不可少的TGF-β 1抑制TCR诱导的分裂只有CD 4（+），而不是CD 8（+）T细胞。来自Smad 3（-/-）小鼠的CD 8（+）和CD 4（+）T细胞对TGF-β 1诱导的IL-2产生抑制均不敏感，因此证明并非所有CD 8 + T细胞对TGF-β 1的反应都不依赖于Smad 3。这些TGF-β 1效应都是T细胞内在的，因为它们在纯化的CD 4（+）和CD 8（+）T细胞中重现。最后，我们发现Smad 3对体外活化后的CD 8（+）T细胞的存活至关重要，但对CD 4（+）T细胞的存活则不重要。TCR诱导的Smad 3（-/-）CD 8（+）T细胞死亡不依赖于TNF-α的产生。外源性TGF-β 1通过Smad 3非依赖性信号通路部分拯救了CD 8（+）T细胞。TGF-β 1还以Smad 3非依赖性方式增强TCR刺激的CD 4（+）CD 44（high）T细胞的存活。总的来说，这些发现第一次坚定地确立了TGF-β 1通过不同的细胞内途径信号传导有区别地调节CD 4（+）和CD 8（+）T细胞扩增。
TGF-beta1 is critical for maintaining T cell homeostasis. Smad3 has been implicated in this regulatory process, yet the cellular targets and molecular details remain poorly understood. In this study, we report that TGF-beta1 impairs the entry of CD4(+) and CD8(+) T cells into the cell cycle as well as their progression through subsequent rounds of division, and show that Smad3 is essential for TGF-beta1 to inhibit TCR-induced division of only CD4(+) and not CD8(+) T cells. Both CD8(+) and CD4(+) T cells from Smad3(-/-) mice were refractory to TGF-beta1-induced inhibition of IL-2 production, thus demonstrating that not all CD8+ T cell responses to TGF-beta1 are Smad3 independent. These TGF-beta1 effects were all T cell intrinsic, as they were reproduced in purified CD4(+) and CD8(+) T cells. Finally, we found that Smad3 was critical for the survival of CD8(+), but not CD4(+) T cells following activation ex vivo. The TCR-induced death of Smad3(-/-) CD8(+) T cells was not dependent upon TNF-alpha production. Exogenous TGF-beta1 partially rescued the CD8(+) T cells by signaling through a Smad3-independent pathway. TGF-beta1 also enhanced survival of TCR-stimulated CD4(+) CD44(high) T cells in a Smad3-independent manner. Collectively, these findings firmly establish for the first time that TGF-beta1 discriminately regulates CD4(+) and CD8(+) T cell expansion by signaling through distinct intracellular pathways.