Neuropilin-1 Expression Is Induced on Tolerant Self-Reactive CD8+ T Cells but Is Dispensable for the Tolerant Phenotype
Neuropilin-1 Expression Is Induced on Tolerant Self-Reactive CD8+ T Cells but Is Dispensable for the Tolerant Phenotype
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DOI：
10.1371/journal.pone.0110707
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发表时间：
2014-10-24
期刊：
影响因子：
3.7
通讯作者：
Teague, Ryan M.
中科院分区：
文献类型：
--
作者：
Jackson, Stephanie R.;Berrien-Elliott, Melissa;Teague, Ryan M.
建立外周CD 8（+）T细胞耐受对于避免免疫介导的健康自身组织的破坏至关重要。然而，它也对肿瘤免疫构成了主要障碍，因为肿瘤来源于自身组织，并且经常诱导T细胞耐受和功能障碍。因此，了解调节T细胞耐受性与免疫力的机制对人类健康具有重要意义。从组织环境接收的信号在很大程度上决定了响应T细胞是否被激活或耐受。例如，在自身反应性CD 8（+）T细胞表面上的负调节受体的诱导表达和随后的连接在耐受性的诱导中是不可或缺的。我们利用T细胞耐受性的小鼠模型来更完整地定义参与该过程的分子。我们发现，除了其他已知的调节受体外，耐受性自身反应性CD 8（+）T细胞还明显表达表面受体神经毛蛋白-1（Nrp 1）。Nrp 1在自身抗原反应中被高度诱导，但在免疫条件下遇到相同抗原时仅适度诱导，这表明与T细胞耐受性可能存在机械联系。我们还观察到在人类肿瘤浸润性CD 4（+）和CD 8（+）T细胞上类似的Nrp 1表达谱。尽管Nrp 1在耐受性CD 8（+）T细胞上高表达，但我们的研究表明，Nrp 1在耐受性表型中没有可检测的作用。具体而言，Nrp 1缺陷型T细胞显示出与野生型自身反应性T细胞相同的功能缺陷，缺乏体内细胞溶解潜力、IFN γ产生和抗肿瘤反应。虽然报告的数据大多是负面的，但我们的研究结果具有治疗意义，因为Nrp 1现在正在临床试验中被靶向用于人类癌症治疗，但治疗期间参与的精确分子途径和免疫细胞仍然不完全确定。
Establishing peripheral CD8(+) T cell tolerance is vital to avoid immune mediated destruction of healthy self-tissues. However, it also poses a major impediment to tumor immunity since tumors are derived from self-tissue and often induce T cell tolerance and dysfunction. Thus, understanding the mechanisms that regulate T cell tolerance versus immunity has important implications for human health. Signals received from the tissue environment largely dictate whether responding T cells become activated or tolerant. For example, induced expression and subsequent ligation of negative regulatory receptors on the surface of self-reactive CD8(+) T cells are integral in the induction of tolerance. We utilized a murine model of T cell tolerance to more completely define the molecules involved in this process. We discovered that, in addition to other known regulatory receptors, tolerant self-reactive CD8(+) T cells distinctly expressed the surface receptor neuropilin-1 (Nrp1). Nrp1 was highly induced in response to self-antigen, but only modestly when the same antigen was encountered under immune conditions, suggesting a possible mechanistic link to T cell tolerance. We also observed a similar Nrp1 expression profile on human tumor infiltrating CD4(+) and CD8(+) T cells. Despite high expression on tolerant CD8(+) T cells, our studies revealed that Nrp1 had no detectable role in the tolerant phenotype. Specifically, Nrp1-deficient T cells displayed the same functional defects as wild-type self-reactive T cells, lacking in vivo cytolytic potential, IFN gamma production, and antitumor responses. While reporting mostly negative data, our findings have therapeutic implications, as Nrp1 is now being targeted for human cancer therapy in clinical trials, but the precise molecular pathways and immune cells being engaged during treatment remain incompletely defined.