Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice.
Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice.
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DOI：
10.1084/jem.20101484
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发表时间：
2011-08-01
期刊：
影响因子：
--
通讯作者：
Lane PJ
中科院分区：
文献类型：
--
作者：
Gaspal F;Withers D;Saini M;Bekiaris V;McConnell FM;White A;Khan M;Yagita H;Walker LS;Anderson G;Lane PJ
FoxP3缺陷型小鼠通过OX40和CD30信号的组合缺失而免于组织和器官破坏以及随后的致死性自身免疫疾病。我们以前的研究表明，通过肿瘤坏死家族受体OX40和CD30的信号传导对于维持CD4记忆应答至关重要。我们表明，通过这两种分子的信号也需要CD4效应介导的自身免疫性组织损伤。在正常情况下，缺乏叉头转录因子FoxP3的雄性小鼠，缺乏调节性CD4 T细胞，在生命的最初几周内发展致命的自身免疫性疾病。然而，在OX40和CD30共同缺失的情况下，FoxP3缺陷小鼠发育正常并成功繁殖。FoxP3疾病的广泛组织浸润和器官破坏特征在这些小鼠中没有出现，它们的死亡率与自身免疫无关。虽然OX40的缺乏起着主导作用，但CD30充足但OX40信号缺乏的FoxP3缺陷小鼠最终仍会发展成致命性疾病。这一结果得到了以下观察结果的支持：针对OX40和CD30配体的阻断抗体也消除了由FoxP3缺陷型T细胞介导的疾病。这些观察结果将OX40和CD30信号鉴定为临床相关的CD4依赖性自身免疫的发展所必需的，并表明消除这些信号的联合疗法可用于治疗已建立的人类自身免疫性疾病。
FoxP3-deficient mice are rescued from tissue and organ destruction and subsequent lethal autoimmune disease by the combined absence of OX40 and CD30 signals. Our previous studies have implicated signaling through the tumor necrosis family receptors OX40 and CD30 as critical for maintaining CD4 memory responses. We show that signals through both molecules are also required for CD4 effector-mediated autoimmune tissue damage. Under normal circumstances, male mice deficient in the forkhead transcription factor FoxP3, which lack regulatory CD4 T cells, develop lethal autoimmune disease in the first few weeks of life. However, in the combined absence of OX40 and CD30, FoxP3-deficient mice develop normally and breed successfully. The extensive tissue infiltration and organ destruction characteristic of FoxP3 disease does not appear in these mice, and their mortality is not associated with autoimmunity. Although the absence of OX40 plays the dominant role, FoxP3-deficient mice sufficient in CD30 but deficient in OX40 signals still eventually develop lethal disease. This result was supported by the observation that blocking antibodies to OX40 and CD30 ligands also abrogated disease mediated by FoxP3-deficient T cells. These observations identify OX40 and CD30 signals as essential for the development of clinically relevant CD4-dependent autoimmunity and suggest that combination therapies that abrogate these signals might be used to treat established human autoimmune diseases.
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