Abstract
Suppression of IL-2 βproduction from T cells is an important process for the immune regulation by TGF-β. However, the mechanism by which this suppression occurs remains to be established. Here, we demonstrate that Smad2 and Smad3, two major TGF-β-downstream transcription factors, are redundantly essential for TGF-β-mediated suppression of IL-2 production in CD4(+) T cells using Smad2- and Smad3-deficient T cells. Both Smad2 and Smad3 were recruited into the proximal region of the IL-2 promoter in response to TGF-β. We then investigated the histone methylation status of the IL-2 promoter. Although both histone H3 lysine 9 (H3K9) and H3K27 trimethylation have been implicated in gene silencing, only H3K9 trimethylation was increased in the proximal region of the IL-2 promoter in a Smad2/3-dependent manner, whereas H3K27 trimethylation was not. The H3K9 methyltransferases Setdb1 and Suv39h1 bound to Smad3 and suppressed IL-2 promoter activity in collaboration with Smad3. Overexpression of Suv39h1 in 68-41 T cells strongly inhibited IL-2 production in response to T cell receptor stimulation irrespective of the presence or absence of TGF-β, whereas Setdb1 overexpression only slightly suppressed IL-2 production. Silencing of Suv39h1 by shRNA reverted the suppressive effect of TGF-β on IL-2 production. Furthermore, TGF-β induced Suv39h1 recruitment to the proximal region of the IL-2 promoter in wild type primary T cells; however, this was not observed in Smad2(-/-)Smad3(+/-) T cells. Thus, we propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription.
Highlights
Suppression of IL-2 production from T cells is an important process for the immune regulation by transforming growth factor-beta (TGF-)
We have shown that both Smad2 and Smad3 are redundantly essential for the suppression of IL-2 transcription induced by T cell receptor (TCR) signals
The importance of either Smad2 or Smad3 has already been proposed [16, 33, 34]: McKarns et al [34] have reported that TGF--mediated suppression of IL-2 production from activated T cells is severely impaired by Smad3 deficiency; another report, suggests only a partial impairment of TGF--mediated suppression of IL-2 production in Smad3Ϫ/Ϫ T cells [33]
Summary
Suppression of IL-2 production from T cells is an important process for the immune regulation by transforming growth factor-beta (TGF-). Results: Smad and Smad were redundantly essential for IL-2 suppression and recruited histone H3K9 methyltransferase, Suv39h1 to the proximal region of the IL-2 promoter, thereby suppressing IL-2 transcription. We demonstrate that Smad and Smad, two major TGF--downstream transcription factors, are redundantly essential for TGF--mediated suppression of IL-2 production in CD4؉ T cells using Smad2- and Smad3-deficient T cells. Both Smad and Smad were recruited into the proximal region of the IL-2 promoter in response to TGF-. We propose that Smads recruit H3K9 methyltransferases Suv39h1 to the IL-2 promoter, thereby inducing suppressive histone methylation and inhibiting T cell receptor-mediated IL-2 transcription. TGF- first binds to a TGF- receptor, which primarily activates Smad transcription factors, including three structurally similar proteins: two receptor-associated Smads known as Smad and Smad and one common
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