B細胞是身體的抗體生長工廠，能夠大量地產生抗體分子來選擇性地靶向外部危險物。然而，這種過程也需要T細胞分泌一種被稱作白細胞介素-4(interleukin-4, IL-4)的蛋白，其中IL-4促進一種被稱作「類型轉換(class switching)」的機制發揮作用，從而產生功能性的特定抗體亞型。然而，科學家們仍然不清楚是哪些T細胞產生IL-4信號。
如今，日本理化研究所過敏症與免疫學研究中心研究員Masato Kubo和同事們提供強大的證據表明最近發現的一類濾泡T細胞(follicular T cell, Tfh)產生IL-4信號，從而促進B細胞高速運轉起來。而在之前的一項研究中，他的研究團隊鑑定出編碼IL-4的基因中的幾個DNA片段可能調節這它的活性。一種候選DNA序列CNS2對 Th2細胞產生IL-4沒有影響，但是缺乏這種基因組區域的小鼠在類型轉換上表現出嚴重性的缺陷。他說，「我們開始思考其他T細胞亞類可能負責IL-4介導的體液免疫反應。」
通過將一個螢光基因放置在CNS2的控制之下，研究人員證實這種調節性區域在Tfh細胞中是特別有活性的。就像它們的名字所提示的那樣，Tfh細胞位於非常靠近生發中心(germinal center)的濾泡之內，其中生發中心是B細胞成熟的地方。與Th2細胞產生IL-4機制明顯不同，Tfh細胞也主動地分泌IL-4。Kubo研究團隊發現缺乏CNS2的突變小鼠能夠產生成熟的Tfh細胞，但是這些細胞表達水平顯著下降的IL-4。作為比照，Th2細胞受到的影響最小化。然而，這些接受基因改造的小鼠在產生包括IgE和IgG1之類的幾種抗體亞型上表現出顯著性的缺陷。
Kubo說，「IL-4是控制IgG1和IgE抗體反應的一種關鍵性細胞因子，但是它在Th2細胞和Tfh細胞中的表達是獨立地受到不同成分的調控。再者，Th2細胞和Tfh細胞是負責體液免疫反應的T細胞亞型。」(生物谷：Bioon.com)
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.
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.