Cardiolipin activates antigen-presenting cells via TLR2-PI3K-PKN1-AKT/p38-NF-kB signaling to prime antigen-specific naive T cells in mice
Cardiolipin activates antigen-presenting cells via TLR2-PI3K-PKN1-AKT/p38-NF-kB signaling to prime antigen-specific naive T cells in mice
复制标题
DOI：
10.1002/eji.201747222
复制
发表时间：
2018-05-01
影响因子：
5.4
通讯作者：
Seong, Seung-Yong
中科院分区：
文献类型：
--
作者：
Cho, Jung-Ah;Kim, Tae-Joo;Seong, Seung-Yong
线粒体缺陷和抗线粒体心磷脂（CL）抗体在自身免疫性疾病患者中经常检测到。来自线粒体失调的CL激活各种模式识别受体，如NLRP3。然而，线粒体CL激活APCs作为原始抗原特异性幼稚T细胞的损伤相关分子模式的机制尚不清楚，这对于自身免疫性疾病中T细胞依赖性抗心磷脂IgG抗体的产生至关重要。在这里，我们发现CL在体外和体内都增加了CD11c(+) APCs中共刺激分子的表达。CL通过TLR2-PI3K-PKN1-AKT/p38MAPK-NF-kappa B信号激活CD11c(+) apc。被CL激活的CD11c(+) apc足以启动H-Y肽特异性初始CD4(+) T细胞和ova特异性初始CD8(+) T细胞。TLR2是体内抗cl IgG抗体应答所必需的。腹腔注射CL对CD14 KO小鼠的CD11c(+) apc的激活程度与野生型小鼠不同。CL与CD14结合（Kd = 7 × 10(-7) M）。CD14而非MD2在CL激活NF-kB中起作用，提示CD14（+）巨噬细胞有助于识别CL。综上所述，CL激活CD11c(+) APCs的信号通路，其机制类似于革兰氏（+）细菌，并在启动抗原特异性幼稚T细胞中起关键作用。
Mitochondrial defects and antimitochondrial cardiolipin (CL) antibodies are frequently detected in autoimmune disease patients. CL from dysregulated mitochondria activates various pattern recognition receptors, such as NLRP3. However, the mechanism by which mitochondrial CL activates APCs as a damage-associated molecular pattern to prime antigen-specific naive T cells, which is crucial for T-cell-dependent anticardiolipin IgG antibody production in autoimmune diseases is unelucidated. Here, we show that CL increases the expression of costimulatory molecules in CD11c(+) APCs both in vitro and in vivo. CL activates CD11c(+) APCs via TLR2-PI3K-PKN1-AKT/p38MAPK-NF-kappa B signaling. CD11c(+) APCs that have been activated by CL are sufficient to prime H-Y peptide-specific naive CD4(+) T cells and OVA-specific naive CD8(+) T cells. TLR2 is necessary for anti-CL IgG antibody responses in vivo. Intraperitoneal injection of CL does not activate CD11c(+) APCs in CD14 KO mice to the same extent as in wild-type mice. CL binds to CD14 (Kd = 7 x 10(-7) M). CD14, but not MD2, plays a role in NF-kB activation by CL, suggesting that CD14(+) macrophages contribute to recognizing CL. In summary, CL activates signaling pathways in CD11c(+) APCs through a mechanism similar to gram (+) bacteria and plays a crucial role in priming antigen-specific naive T cells.