B細(xì)胞是身體的抗體生長工廠，能夠大量地產(chǎn)生抗體分子來選擇性地靶向外部危險(xiǎn)物,。然而,，這種過程也需要T細(xì)胞分泌一種被稱作白細(xì)胞介素-4(interleukin-4, IL-4)的蛋白，其中IL-4促進(jìn)一種被稱作“類型轉(zhuǎn)換(class switching)”的機(jī)制發(fā)揮作用,，從而產(chǎn)生功能性的特定抗體亞型,。然而，科學(xué)家們?nèi)匀徊磺宄悄男㏕細(xì)胞產(chǎn)生IL-4信號,。
如今,，日本理化研究所過敏癥與免疫學(xué)研究中心研究員Masato Kubo和同事們提供強(qiáng)大的證據(jù)表明最近發(fā)現(xiàn)的一類濾泡T細(xì)胞(follicular T cell, Tfh)產(chǎn)生IL-4信號，從而促進(jìn)B細(xì)胞高速運(yùn)轉(zhuǎn)起來,。而在之前的一項(xiàng)研究中,，他的研究團(tuán)隊(duì)鑒定出編碼IL-4的基因中的幾個(gè)DNA片段可能調(diào)節(jié)這它的活性。一種候選DNA序列CNS2對 Th2細(xì)胞產(chǎn)生IL-4沒有影響,，但是缺乏這種基因組區(qū)域的小鼠在類型轉(zhuǎn)換上表現(xiàn)出嚴(yán)重性的缺陷,。他說，“我們開始思考其他T細(xì)胞亞類可能負(fù)責(zé)IL-4介導(dǎo)的體液免疫反應(yīng),。”
通過將一個(gè)熒光基因放置在CNS2的控制之下,，研究人員證實(shí)這種調(diào)節(jié)性區(qū)域在Tfh細(xì)胞中是特別有活性的。就像它們的名字所提示的那樣,，Tfh細(xì)胞位于非?？拷l(fā)中心(germinal center)的濾泡之內(nèi)，其中生發(fā)中心是B細(xì)胞成熟的地方。與Th2細(xì)胞產(chǎn)生IL-4機(jī)制明顯不同,，Tfh細(xì)胞也主動(dòng)地分泌IL-4,。Kubo研究團(tuán)隊(duì)發(fā)現(xiàn)缺乏CNS2的突變小鼠能夠產(chǎn)生成熟的Tfh細(xì)胞，但是這些細(xì)胞表達(dá)水平顯著下降的IL-4,。作為比照,，Th2細(xì)胞受到的影響最小化。然而,，這些接受基因改造的小鼠在產(chǎn)生包括IgE和IgG1之類的幾種抗體亞型上表現(xiàn)出顯著性的缺陷,。
Kubo說，“IL-4是控制IgG1和IgE抗體反應(yīng)的一種關(guān)鍵性細(xì)胞因子,，但是它在Th2細(xì)胞和Tfh細(xì)胞中的表達(dá)是獨(dú)立地受到不同成分的調(diào)控,。再者，Th2細(xì)胞和Tfh細(xì)胞是負(fù)責(zé)體液免疫反應(yīng)的T細(xì)胞亞型,。”(生物谷：Bioon.com)
doi: 10.1016/j.immuni.2012.02.002
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The 3′ Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells
Yohsuke Harada1, Shinya Tanaka2, Yasutaka Motomura1, 3, Yasuyo Harada1, Shin-ichiro Ohno3, Shinji Ohno4, Yusuke Yanagi4, Hiromasa Inoue5 and Masato Kubo
A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4+ T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP+ Tfh cells were derived from GFP− naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.
doi: 10.1038/ni.1966
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The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells
Shinya Tanaka, Yasutaka Motomura, Yoshie Suzuki, Ryoji Yagi, Hiromasa Inoue, Shoichiro Miyatake & Masato Kubo
GATA-3 is a master regulator of T helper type 2 (TH2) differentiation. However, the molecular basis of GATA-3-mediated TH2 lineage commitment is poorly understood. Here we identify the DNase I–hypersensitive site 2 (HS2) element located in the second intron of the interleukin 4 locus (Il4) as a critical enhancer strictly controlled by GATA-3 binding. Mice lacking HS2 showed substantial impairment in their asthmatic responses and their production of IL-4 but not of other TH2 cytokines. Overexpression of Gata3 in HS2-deficient T cells failed to restore Il4 expression. HS2 deletion impaired the trimethylation of histone H3 at Lys4 and acetylation of histone H3 at Lys9 and Lys14 in the Il4 locus. Our results indicate that HS2 is the target of GATA-3 in regulating chromosomal modification of the Il4 locus and is independent of the Il5 and Il13 loci.
