Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis.
Unexpected role for granzyme K in CD56bright NK cell-mediated immunoregulation of multiple sclerosis.
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DOI：
10.4049/jimmunol.1100789
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发表时间：
2011-07-15
期刊：
影响因子：
--
通讯作者：
Bielekova B
中科院分区：
文献类型：
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作者：
Jiang W;Chai NR;Maric D;Bielekova B
功能性 NK 细胞缺陷与自身免疫性疾病有关，包括多发性硬化症 (MS)。 NK 细胞可以通过细胞因子的产生或对未成熟树突状细胞和活化 T 细胞的细胞毒性来促进或抑制适应性免疫。在人类中，这种免疫调节作用存在于 CD56bright NK 细胞亚群中，该亚群可被 daclizumab（一种抑制 MS 相关炎症的 CD25 阻断抗体）选择性扩增。本研究的目的是研究 NK 细胞对活化 T 细胞的细胞毒性的分子机制。我们证明 NK 细胞会诱导不依赖半胱天冬酶的细胞凋亡，这需要 NK 细胞脱颗粒并导致激活的 T 细胞线粒体功能障碍。虽然颗粒酶 A (GrA) 和 K (GrK) 都可以介导这种形式的细胞凋亡，但我们定量地观察到 GrK 优先转移到靶细胞。因此，保留 CD56bright NK 细胞功能特征的 NK-92 细胞系中 GrK 的基因沉默极大地抑制了 NK-92 杀死激活的同系 T 细胞的能力。最后，我们证明达珠单抗治疗显着增强了 CD56bright NK 细胞的这种新定义的细胞毒性机制。我们的研究代表了 GrK 在人类适应性免疫的免疫调节中发挥重要生理作用的第一个例子，并表明该途径的治疗利用有利于控制自身免疫。
Functional NK cell deficiencies are associated with autoimmune diseases, including multiple sclerosis (MS). NK cells can promote or inhibit adaptive immunity via either cytokine production or cytotoxicity towards immature dendritic cells and activated T cells. In humans, this immunoregulatory role resides in the CD56bright NK cell subset, which is selectively expanded by daclizumab, a CD25-blocking antibody that suppresses MS-associated inflammation. The objective of this study was to investigate the molecular mechanisms underlying the cytotoxicity of NK cells toward activated T cells. We demonstrated that NK cells induce caspase-independent apoptosis that requires NK cell degranulation and causes mitochondrial dysfunction in activated T cells. While both granzymes A (GrA) and K (GrK) can mediate this form of apoptosis, quantitatively we observed preferential transfer of GrK to target cells. Consequently, gene silencing of GrK in the NK-92 cell line, which retains functional characteristics of CD56bright NK cells, profoundly inhibited the ability of NK-92 to kill activated syngeneic T cells. Finally we demonstrated that daclizumab treatment significantly enhanced this newly defined mechanism of cytotoxicity by CD56bright NK cells. Our study represents the first example of the important physiological role GrK plays in immunoregulation of adaptive immunity in humans and indicates that therapeutic exploitation of this pathway is beneficial in controlling autoimmunity.
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影响因子：
--
作者：
Bielekova, Bibiana;Howard, Thomas;Packer, Amy N.;Richert, Nancy;Blevins, Gregg;Ohayon, Joan;Waldmann, Thomas A.;McFarland, Henry F.;Martin, Roland
通讯作者：
Martin, Roland
影响因子：
3.3
作者：
Kastrukoff, LF;Lau, A;Paty, DW
通讯作者：
Paty, DW
DOI：
10.1073/pnas.0601335103
发表时间：
2006-04-11
影响因子：
11.1
作者：
Bielekova, B;Catalfamo, M;Martin, R
通讯作者：
Martin, R
DOI：
10.1073/pnas.0402653101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Bielekova, B;Richert, N;Martin, R
通讯作者：
Martin, R
影响因子：
3.3
作者：
KASTRUKOFF, LF;MORGAN, NG;PATY, DW
通讯作者：
PATY, DW