Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen
Differential Roles for Bim and Nur77 in Thymocyte Clonal Deletion Induced by Ubiquitous Self-Antigen
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DOI：
10.4049/jimmunol.1400030
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发表时间：
2015-03-15
影响因子：
4.4
通讯作者：
Baldwin, Troy A.
中科院分区：
文献类型：
--
作者：
Hu, Qian Nancy;Baldwin, Troy A.
负选择主要通过自身反应性胸腺细胞的克隆删除介导，对于建立自我耐受和预防自身免疫至关重要。最近的研究表明，负选择的分子机制因胸腺区室和胸腺细胞被删除的发育阶段而异。使用针对普遍存在的自身抗原的负选择的生理学 HYcd4 TCR 转基因模型，我们之前发现涉及克隆缺失的主要介质之一 Bim 是 caspase-3 激活所必需的，但最终对于负选择来说是可有可无的。根据这些数据，我们假设 Nur77（另一种被认为是克隆删除的关键介质的分子）可能负责 Bim 独立删除。尽管在阴性选择过程中胸腺细胞中的 Nur77 诱导相当，但 Bim 缺陷导致高亲和力信号胸腺细胞的积累以及 caspase 介导的和不依赖 caspase 的细胞死亡受损。尽管这些数据表明 Bim 可能是 Nur77 介导的细胞死亡所必需的，但我们发现转基因 Nur77 表达足以独立于 Bim 诱导细胞凋亡。然而，转基因 Nur77 诱导的细胞凋亡在 TCR 信号传导的背景下受到显着抑制，这表明内源 Nur77 在负选择过程中也可以受到类似的调节。虽然单独的 Nur77 缺陷不会改变正选择或负选择，但 Bim 和 Nur77 的联合缺陷会损害克隆删除效率并显着提高正选择效率。总的来说，这些数据揭示了 Bim 和 Nur77 在普遍存在的 Ag 介导的克隆缺失中的不同作用，并强调了它们在组织限制性 Ag 介导的克隆缺失中所报道的作用的潜在差异。
Negative selection, primarily mediated through clonal deletion of self-reactive thymocytes, is critical for establishing self-tolerance and preventing autoimmunity. Recent studies suggest that the molecular mechanisms of negative selection differ depending on the thymic compartment and developmental stage at which thymocytes are deleted. Using the physiological HYcd4 TCR transgenic model of negative selection against ubiquitous self-antigen, we previously found that one of the principal mediators implicated in clonal deletion, Bim, is required for caspase-3 activation but is ultimately dispensable for negative selection. On the basis of these data, we hypothesized that Nur77, another molecule thought to be a key mediator of clonal deletion, could be responsible for Bim-independent deletion. Despite comparable Nur77 induction in thymocytes during negative selection, Bim deficiency resulted in an accumulation of high-affinity-signaled thymocytes as well as impairment in caspase-mediated and caspase-independent cell death. Although these data suggested that Bim may be required for Nur77-mediated cell death, we found that transgenic Nur77 expression was sufficient to induce apoptosis independently of Bim. However, transgenic Nur77-induced apoptosis was significantly inhibited in the context of TCR signaling, suggesting that endogenous Nur77 could be similarly regulated during negative selection. Although Nur77 deficiency alone did not alter positive or negative selection, combined deficiency in Bim and Nur77 impaired clonal deletion efficiency and significantly increased positive selection efficiency. Collectively, these data shed light on the different roles for Bim and Nur77 during ubiquitous Ag-mediated clonal deletion and highlight potential differences from their reported roles in tissue-restricted Ag-mediated clonal deletion.