JBC: NK细胞的激活需要络氨酸激酶Btk

Bruton酪氨酸激酶不仅对B细胞的发育及分化至关重要，也参与调节了Toll样受体(TLR）引起的巨噬细胞的先天性免疫反应。然而，Btk是否参与调节了NK细胞的先天性免疫功能目前还不明确。近日，来自第二军医大的研究人员阐明了该机制。

他们发现，在老鼠NK细胞的成熟及激活期间，Btk的表达表现上调。应答TLR3配体时，老鼠Btk-/- NK细胞的免疫反应下降，同时IFN-γ、穿孔素及颗粒酶B的表达也降低，表现出降低的细胞毒性。此外，Btk被发现能够促进TLR3引起的NK细胞的激活，这种激活作用主要是通过激活NF-κB通路。

研究发现，在Btk-/-老鼠或体内具有Btk抑制剂的老鼠，由聚肌胞苷酸（Poly I:C）诱导的NK细胞介导的严重肝损伤被缓解。相应的，在Btk-/-老鼠体内过继转移Btk+/+ NK细胞后，肝损伤加重。进一步研究表明，Btk介导的NK细胞的激活促进了TLR3引起的急性肝损伤。

重要的是，在Btk缺陷的X-连锁无丙种球蛋白血症(XLA)患者，他们发现TLR3引起的人NK细胞的激活作用被降低，进一步研究表明，这是由于IFN-γ、CD69、及CD107a的表达降低，导致细胞毒性降低所致。

这些结果表明，Btk被需要于NK细胞的激活，这对研究Btk调节免疫细胞及先天性炎症反应具有重要意义。（生物谷Deepblue编译）

doi: 10.1074/jbc.M112.372425
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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.