An obligate cell-intrinsic function for CD28 in Tregs
An obligate cell-intrinsic function for CD28 in Tregs
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DOI：
10.1172/jci65013
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发表时间：
2013-02-01
影响因子：
15.9
通讯作者：
Turka, Laurence A.
中科院分区：
文献类型：
--
作者：
Zhang, Ruan;Huynh, Alexandria;Turka, Laurence A.
表达转录因子FOXP 3的T细胞对免疫稳态至关重要。共刺激分子CD 28是幼稚T细胞的最佳活化和功能所必需的;然而，其在Treg功能中的作用一直难以剖析，因为CD 28是胸腺Treg发育和CD 28配体阻断所必需的。相互作用在非调节细胞上具有反式混杂效应。为了解决这个问题，我们创建了Treg特异性Cd 28条件性敲除小鼠。尽管存在正常数量的FOXP 3（+）细胞，但这些动物积累了大量活化的T细胞，产生了严重的自身免疫，主要影响皮肤和肺部，并且未能适当地解决诱导的实验性过敏性脑脊髓炎。这种体内功能损害伴随着CTLA-4、PD-1和CCR 6的表达减弱。疾病的发生是不是由于颠覆镉28-缺陷的TbR到致病细胞，与正常TbR的互补防止疾病的发生。有趣的是，在这些“竞争性”环境中，Cd 28缺陷型TcB表现出明显的增殖/存活劣势。这些数据证明了CD 28在FOXP 3（+）TcB中的明确的成熟后作用，并提供了我们认为是新的机制来解释CD 28-配体相互作用的中断如何增强免疫应答，而不依赖于对胸腺发育或其他细胞类型的影响。
Tregs expressing the transcription factor FOXP3 are critical for immune homeostasis. The costimulatory molecule CD28 is required for optimal activation and function of naive T cells; however, its role in Treg function has been difficult to dissect, as CD28 is required for thymic Treg development, and blockade of CD28-ligand. interactions has confounding effects in trans on nonregulatory cells. To address this question, we created Treg-specific Cd28 conditional knockout mice. Despite the presence of normal numbers of FOXP3(+) cells, these animals accumulated large numbers of activated T cells, developed severe autoimmunity that primarily affected the skin and lungs, and failed to appropriately resolve induced experimental allergic encephalomyelitis. This in vivo functional impairment was accompanied by dampened expression of CTLA-4, PD-1, and CCR6. Disease occurrence was not due to subversion of Cd28-deficient Tregs into pathogenic cells, as complementation with normal Tregs prevented disease occurrence. Interestingly, in these "competitive" environments, Cd28-deficient Tregs exhibited a pronounced proliferative/survival disadvantage. These data demonstrate clear postmaturational roles for CD28 in FOXP3(+) Tregs and provide mechanisms which we believe to be novel to explain how interruption of CD28-ligand interactions may enhance immune responses independent of effects on thymic development or on other cell types.