Antigen-induced Pten gene deletion in T cells exacerbates neuropathology in experimental autoimmune encephalomyelitis
Antigen-induced Pten gene deletion in T cells exacerbates neuropathology in experimental autoimmune encephalomyelitis
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DOI：
10.2353/ajpath.2008.070892
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发表时间：
2008-04-01
影响因子：
6
通讯作者：
Jirik, Frank R.
中科院分区：
文献类型：
--
作者：
Johnson, Trina A.;Tsutsui, Shigeki;Jirik, Frank R.
Pten肿瘤抑制基因对T细胞的正常胸腺内发育至关重要;然而，其在成熟抗原活化的T细胞中的作用尚不明确。一个基因杂交的小鼠系Pten（fl/fl）GBC，其中Pten基因缺失主要局限于抗原激活的CD 8（+）T细胞，使我们能够评估Pten缺失对实验性自身免疫性脑脊髓炎过程的影响。与Pten（fl/fl）对照相比，髓鞘少突胶质细胞糖蛋白（MOG）肽免疫Pten（fl/fl）GBC小鼠发展更严重和持久的疾病。这伴随着脊髓白色物质髓鞘碱性蛋白耗竭和轴突损伤的增加，以及在疾病的慢性期巨噬细胞和颗粒酶B表达细胞神经浸润的显著持续。这种持久性可以通过观察到抗CD 3活化的Pten（fl/fl）GBC T细胞对促凋亡刺激更有抗性来解释。与Pten损失的预测结果一致，来自Pten（fl/fl）GBC小鼠的纯化的CD 8（+）T细胞显示对抗T细胞受体刺激的增强的增殖应答，并且MOG引发的Pten（fl/fl）GBC T细胞显示对MOG肽的降低的活化阈值。Pten（fl/fl）GBC小鼠也发生了非典型中枢神经系统疾病，表现为突出的颈髓和前脑受累。总的来说，我们的研究结果表明，磷脂酰肌醇3-激酶信号通路是实验性自身免疫性脑脊髓炎中CD 8（+）T细胞效应器功能的重要调节因子。
The Pten tumor suppressor gene is critical for normal intrathymic development of T cells; however, its role in mature antigen-activated T cells is less well defined. A genetically crossed mouse line, Pten(fl/fl) GBC, in which Pten gene deletions could be primarily confined to antigen-activated CD8(+) T cells, enabled us to evaluate the consequences of Pten loss on the course of experimental autoimmune encephalomyelitis. Compared with Pten(fl/fl) controls, myelin oligodendrocyte glycoprotein (MOG) peptide-immunized Pten(fl/fl) GBC mice developed more severe and protracted disease. This was accompanied by increased spinal cord white matter myelin basic protein depletion and axonal damage, as well as a striking persistence of macrophage and granzyme B-expressing cellular neuroinfiltrates in the chronic phase of the disease. This persistence may be explained by the observation that anti-CD3 activated Pten(fl/fl) GBC T cells were more resistant to proapoptotic stimuli. Consistent with the predicted consequences of Pten loss, purified CD8(+) T cells from Pten(fl/fl) GBC mice displayed augmented proliferative responses to anti-T-cell receptor stimulation, and MOG-primed Pten(fl/fl) GBC T cells exhibited a reduced activation threshold to MOG peptide. Pten(fl/fl) GBC mice also developed atypical central nervous system disease, manifested by prominent cervical cord and forebrain involvement. Collectively, our findings indicate that the phosphatidylinositol 3-kinase signaling pathway is an essential regulator of CD8(+) T-cell effector function in experimental autoimmune encephalomyelitis.