Bruton酪氨酸激酶不僅對(duì)B細(xì)胞的發(fā)育及分化至關(guān)重要，也參與調(diào)節(jié)了Toll樣受體(TLR）引起的巨噬細(xì)胞的先天性免疫反應(yīng),。然而，Btk是否參與調(diào)節(jié)了NK細(xì)胞的先天性免疫功能目前還不明確,。近日,，來自第二軍醫(yī)大的研究人員闡明了該機(jī)制。
他們發(fā)現(xiàn),，在老鼠NK細(xì)胞的成熟及激活期間,，Btk的表達(dá)表現(xiàn)上調(diào)。應(yīng)答TLR3配體時(shí),，老鼠Btk-/- NK細(xì)胞的免疫反應(yīng)下降,，同時(shí)IFN-γ、穿孔素及顆粒酶B的表達(dá)也降低,，表現(xiàn)出降低的細(xì)胞毒性,。此外,，Btk被發(fā)現(xiàn)能夠促進(jìn)TLR3引起的NK細(xì)胞的激活，這種激活作用主要是通過激活NF-κB通路,。
研究發(fā)現(xiàn),，在Btk-/-老鼠或體內(nèi)具有Btk抑制劑的老鼠,，由聚肌胞苷酸（Poly I:C）誘導(dǎo)的NK細(xì)胞介導(dǎo)的嚴(yán)重肝損傷被緩解,。相應(yīng)的，在Btk-/-老鼠體內(nèi)過繼轉(zhuǎn)移Btk+/+ NK細(xì)胞后,，肝損傷加重,。進(jìn)一步研究表明，Btk介導(dǎo)的NK細(xì)胞的激活促進(jìn)了TLR3引起的急性肝損傷,。
重要的是,，在Btk缺陷的X-連鎖無丙種球蛋白血癥(XLA)患者，他們發(fā)現(xiàn)TLR3引起的人NK細(xì)胞的激活作用被降低,，進(jìn)一步研究表明,，這是由于IFN-γ、CD69,、及CD107a的表達(dá)降低,，導(dǎo)致細(xì)胞毒性降低所致。
這些結(jié)果表明,，Btk被需要于NK細(xì)胞的激活,，這對(duì)研究Btk調(diào)節(jié)免疫細(xì)胞及先天性炎癥反應(yīng)具有重要意義。（生物谷Deepblue編譯）
doi: 10.1074/jbc.M112.372425
PMC:
PMID:
Tyrosine kinase Btk is required for NK cell activation
Yan Bao*, Jian Zheng, Chaofeng Han, Jing Jin, Huanxing Han, Yinping Liu, Yu-Lung Lau, Wenwei Tu and Xuetao Cao.
Brutons tyrosine kinase (Btk) is not only critical for B cell development and differentiation, but also involved in the regulation of Toll-like receptor (TLR)-triggered innate response of macrophages.However, whether Btk is involved in the regulation of NK cell innate function remains unknown. Here we show that Btk expression is upregulated during maturation and activation of mouse NK cells.Murine Btk-/- NK cells have decreased innate immune responses to TLR3 ligand, with reduced expressions of IFN-γ, perforin and Granzyme-B, and decreased cytotoxic activity.Furthermore, Btk is found to promote TLR3-triggered NK cell activation mainly through activating NF-κB pathway. Poly I:C-induced, NK cell-mediated acute hepatitis is observed to be attenuated in Btk-/- mice or the mice with in vivo administration of Btk inhibitor.Correspondingly, liver damage is aggravated in Btk-/- mice once adoptive transfer of Btk+/+ NK cells, further indicating that Btk-mediated NK cell activation contributes to TLR3-triggered acute liver injury.Importantly, reduced TLR3-triggered activation of human NK cells is observed in Btk-deficient patients with X-linked agammaglobulinemia (XLA), as evidenced by the reduced IFN-γ, CD69, CD107a expression and cytotoxic activity.These results indicate that Btk is required for activation of NK cells, thus providing insight into the physiological significance of Btk in the regulation of immune cell functions and innate inflammatory response.
