最近,，美國科學(xué)家發(fā)現(xiàn)了Th1分化的早期機(jī)制,。目前，已發(fā)現(xiàn)三種類型的CD4 T輔助性細(xì)胞,，它們分別是Th1,、Th2和Th17。對于Th1而言,，其最主要的特征是分泌大量的IFN-γ,，并且受轉(zhuǎn)錄因子T-bet調(diào)控。此次研究發(fā)現(xiàn),，Jak3信號通路依賴性的染色體重建為T-bet調(diào)控Ifng基因的表達(dá)開啟綠燈,。Berg等人發(fā)現(xiàn)，在促進(jìn)Th1分化的條件下,，不表達(dá)Jak3（或者藥物抑制Jak3的表達(dá)）的T細(xì)胞中IFN-γ的表達(dá)量急劇減少,。然而，IFN-γ表達(dá)量的大幅度下降,，既不是由于缺少TCR信號,，也不是由于STAT1、STAT4或者T-bet的下調(diào)所引起,。應(yīng)用染色體免疫共沉淀發(fā)現(xiàn),，由于T-bet不能結(jié)合到Ifng基因近端的啟動(dòng)子上，從而使得這種細(xì)胞無法表達(dá)IFN-γ,。此外，Ifng基因啟動(dòng)子區(qū)域組氨酸H3的乙?；潭让黠@降低,。為了進(jìn)一步證實(shí)是何種細(xì)胞因子以及轉(zhuǎn)錄因子在Jak3信號通路中起作用，研究人員還發(fā)現(xiàn)STAT5能夠與Ifng基因近端的啟動(dòng)子及其增強(qiáng)子CNS1結(jié)合,。相反,，使STAT5不表達(dá)或者阻斷IL-2信號通路都能明顯下調(diào)Th1分化過程中IFN-γ的表達(dá)。
那么,，為什么T-bet對Ifng基因的“開與關(guān)”需要依賴于Jak3信號通路呢,？其免疫學(xué)意義又是什么呢？還有待進(jìn)一步研究,。相關(guān)論文發(fā)表在《免疫》（Immunity）雜志上,。（生物谷bioon.com）
生物谷推薦原始出處：
Immunity,，Vol 28, 763-773，Min Shi,，Leslie J. Berg
Janus-Kinase-3-Dependent Signals Induce Chromatin Remodeling at the Ifng Locus during T Helper 1 Cell Differentiation
Min Shi,1 Tsung H. Lin,2 Kenneth C. Appell,2 and Leslie J. Berg1,
1 Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA
2 Pharmacopeia, PO Box 5350, Princeton, NJ 08540, USA
Corresponding author
Leslie J. Berg
[email protected]
Summary
Differentiation of naive CD4+ T cells into T helper type 1 (Th1) effector cells requires both T cell receptor (TCR) signaling and cytokines such as interleukin-12 and interferon γ (IFN-γ). Here, we report that a third cytokine signal, mediated by the Janus family tyrosine kinase 3 (Jak3) and signal transducer and activator of transcription 5 (STAT5) pathway, is also required for Th1 cell differentiation. In the absence of Jak3-dependent signals, naive CD4+ T cells proliferate robustly but produce little IFN-γ after Th1 cell polarization in vitro. This defect is not due to reduced activation of STAT1 or STAT4 or to impaired upregulation of the transcription factor T-bet. Instead, we find that T-bet binding to the Ifng promoter is greatly diminished in the absence of Jak3-dependent signals, correlating with a decrease in Ifng promoter accessibility and histone acetylation. These data indicate that Jak3 regulates epigenetic modification and chromatin remodeling of the Ifng locus during Th1 cell differentiation.
