Enhanced T cell apoptosis within Drak2-deficient mice promotes resistance to autoimmunity.
Enhanced T cell apoptosis within Drak2-deficient mice promotes resistance to autoimmunity.
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DOI：
10.4049/jimmunol.181.11.7606
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发表时间：
2008-12-01
期刊：
影响因子：
--
通讯作者：
Walsh CM
中科院分区：
文献类型：
--
作者：
Ramos SJ;Hernandez JB;Gatzka M;Walsh CM
T细胞的克隆扩增对获得性免疫至关重要，但必须严格控制这一过程以预防自身免疫性疾病。丝氨酸/苏氨酸激酶DRAK 2是T细胞受体（TCR）信号传导的负调节剂，并设定初始和记忆T细胞以及选择的胸腺细胞的活化阈值。尽管T细胞活化增强，Drak 2 −/−小鼠对实验性自身免疫性脑脊髓炎（EAE）具有抵抗力，这是一种类似多发性硬化症的自身免疫性脱髓鞘疾病。然而，这种自身免疫抗性的基础目前尚不清楚。在这里，我们表明，在DRAK 2信号的情况下，T细胞需要更大的滋补信号在克隆扩增过程中的维护。在刺激后，Drak 2 −/− T细胞对内在形式的凋亡更敏感，这种凋亡可以通过CD 28连接、稳态细胞因子或强制Bcl-xL表达来阻止。T细胞特异性Bcl-xL表达也恢复了Drak 2 −/−小鼠对EAE的易感性，并增强了胸腺的阳性选择。这些发现表明，DRAK 2对T细胞存活具有选择性重要性，并强调了DRAK 2阻断可能通过内在凋亡途径导致永久性自身免疫性T细胞破坏的潜力。
Clonal expansion of T cells is vital to adaptive immunity, yet this process must be tightly controlled to prevent autoimmune disease. The serine/threonine kinase DRAK2 is a negative regulator of T cell receptor (TCR) signaling and sets the threshold for the activation of naïve and memory T cells, and selected thymocytes. Despite enhanced T cell activation, Drak2−/− mice are resistant to experimental autoimmune encephalomyelitis (EAE), an autoimmune demyelinating disease that resembles multiple sclerosis. However, the basis for this autoimmune resistance is currently unknown. Here we show that, in the absence of DRAK2 signaling, T cells require greater tonic signaling for maintenance during clonal expansion. Following stimulation, Drak2−/− T cells were more sensitive to an intrinsic form of apoptosis that was prevented by CD28 ligation, homeostatic cytokines, or enforced Bcl-xL expression. T cell-specific Bcl-xL expression also restored the susceptibility of Drak2−/− mice to EAE and enhanced thymic positive selection. These findings demonstrate that DRAK2 is selectively important for T cell survival and highlight the potential that DRAK2 blockade may lead to permanent autoimmune T cell destruction via intrinsic apoptosis pathways.
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影响因子：
5.3
作者：
Kawai, T;Matsumoto, M;Akira, S
通讯作者：
Akira, S
影响因子：
56.9
作者：
Bouillet, P;Metcalf, D;Strasser, A
通讯作者：
Strasser, A
DOI：
10.1084/jem.20050687
发表时间：
2005-09-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Feske S;Prakriya M;Rao A;Lewis RS
通讯作者：
Lewis RS
DOI：
10.1084/jem.182.3.821
发表时间：
1995-09-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Chao DT;Linette GP;Boise LH;White LS;Thompson CB;Korsmeyer SJ
通讯作者：
Korsmeyer SJ
影响因子：
32.4
作者：
Hildeman, DA;Mitchell, T;Marrack, PC
通讯作者：
Marrack, PC