Immunity & Nat Immunol：滤泡T细胞分泌IL-4促进B细胞产生特异性抗体

B细胞是身体的抗体生长工厂，能够大量地产生抗体分子来选择性地靶向外部危险物。然而，这种过程也需要T细胞分泌一种被称作白细胞介素-4(interleukin-4, IL-4)的蛋白，其中IL-4促进一种被称作“类型转换(class switching)”的机制发挥作用，从而产生功能性的特定抗体亚型。然而，科学家们仍然不清楚是哪些T细胞产生IL-4信号。

如今，日本理化研究所过敏症与免疫学研究中心研究员Masato Kubo和同事们提供强大的证据表明最近发现的一类滤泡T细胞(follicular T cell, Tfh)产生IL-4信号，从而促进B细胞高速运转起来。而在之前的一项研究中，他的研究团队鉴定出编码IL-4的基因中的几个DNA片段可能调节这它的活性。一种候选DNA序列CNS2对 Th2细胞产生IL-4没有影响，但是缺乏这种基因组区域的小鼠在类型转换上表现出严重性的缺陷。他说，“我们开始思考其他T细胞亚类可能负责IL-4介导的体液免疫反应。”

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通过将一个荧光基因放置在CNS2的控制之下，研究人员证实这种调节性区域在Tfh细胞中是特别有活性的。就像它们的名字所提示的那样，Tfh细胞位于非常靠近生发中心(germinal center)的滤泡之内，其中生发中心是B细胞成熟的地方。与Th2细胞产生IL-4机制明显不同，Tfh细胞也主动地分泌IL-4。Kubo研究团队发现缺乏CNS2的突变小鼠能够产生成熟的Tfh细胞，但是这些细胞表达水平显著下降的IL-4。作为比照，Th2细胞受到的影响最小化。然而，这些接受基因改造的小鼠在产生包括IgE和IgG1之类的几种抗体亚型上表现出显著性的缺陷。

Kubo说，“IL-4是控制IgG1和IgE抗体反应的一种关键性细胞因子，但是它在Th2细胞和Tfh细胞中的表达是独立地受到不同成分的调控。再者，Th2细胞和Tfh细胞是负责体液免疫反应的T细胞亚型。” 
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<a title="" href="http://dx.doi.org/10.1016/j.immuni.2012.02.002" target="_blank">doi: 10.1016/j.immuni.2012.02.002</a>
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<br/><strong>The 3′ Enhancer CNS2 Is a Critical Regulator of Interleukin-4-Mediated Humoral Immunity in Follicular Helper T Cells</strong><br/>


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.

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<a title="" href="http://dx.doi.org/10.1038/ni.1966" target="_blank">doi: 10.1038/ni.1966</a>
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<br/><strong>The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells</strong><br/>


Shinya Tanaka, Yasutaka Motomura, Yoshie Suzuki, Ryoji Yagi, Hiromasa Inoue, Shoichiro Miyatake &amp; 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.

<br/>来源：生物谷

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