Drak2 Regulates the Survival of Activated T Cells and Is Required for Organ-Specific Autoimmune Disease
Drak2 Regulates the Survival of Activated T Cells and Is Required for Organ-Specific Autoimmune Disease
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DOI：
10.4049/jimmunol.181.11.7593
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发表时间：
2008-12-01
影响因子：
4.4
通讯作者：
Hedrick, Stephen M.
中科院分区：
文献类型：
--
作者：
McGargill, Maureen A.;Choy, Carmen;Hedrick, Stephen M.
Drak2是一种在T细胞和B细胞中表达的丝氨酸/苏氨酸激酶。缺乏Drak2使T细胞对次优刺激过敏，然而Drak2（-/-）小鼠对实验性自身免疫性脑脊髓炎（多发性硬化症的动物模型）具有不可思议的抵抗力。在这项研究中，我们发现Drak2（-/-）小鼠与自发发生自身免疫性糖尿病的NOD小鼠杂交后，对I型糖尿病也有完全的抵抗力。然而，没有普遍的免疫系统抑制，因为Drak2（-/-）小鼠仍然容易受到其他自身免疫模型的影响。过继性转移实验显示，对疾病的抵抗是T细胞固有的，是由于慢性自身免疫刺激条件下T细胞存活的丧失。重要的是，缺乏Drak2并不会改变幼稚T细胞、记忆T细胞或对急性病毒感染作出反应的T细胞的存活。这些实验揭示了免疫反应对持久的自我编码分子和暂时存在的感染因子之间的区别。我们提出了一个模型，其中T细胞存活依赖于平衡或TCR和共刺激信号，以解释缺乏Drak2如何影响自身免疫性疾病而不普遍抑制免疫系统。中华免疫学杂志，2008,18(1):793 -7605。
Drak2 is a serine/threonine kinase expressed in T and B cells. The absence of Drak2 renders T cells hypersensitive to suboptimal stimulation, yet Drak2(-/-) mice are enigmatically resistant to experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. We show in this study that Drak2(-/-) mice were also completely resistant to type I diabetes when bred to the NOD strain of mice that spontaneously develop autoimmune diabetes. However, there was not a generalized suppression of the immune system, because Drak2(-/-) mice remained susceptible to other models of autoimmunity. Adoptive transfer experiments revealed that resistance to disease was intrinsic to the T cells and was due to a loss of T cell survival under conditions of chronic autoimmune stimulation. Importantly, the absence of Drak2 did not alter the survival of naive T cells, memory T cells, or T cells responding to an acute viral infection. These experiments reveal a distinction between the immune response to persistent self-encoded molecules and transiently present infectious agents. We present a model whereby T cell survival depends on a balance or TCR and costimulatory signals to explain how the absence of Drak2 affects autoimmune disease without generalized suppression of the immune system. The Journal of Immunology, 2008, 181: 7593-7605.