Intranodal Interaction with Dendritic Cells Dynamically Regulates Surface Expression of the Co-stimulatory Receptor CD226 Protein on Murine T Cells
Intranodal Interaction with Dendritic Cells Dynamically Regulates Surface Expression of the Co-stimulatory Receptor CD226 Protein on Murine T Cells
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DOI：
10.1074/jbc.m111.264697
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发表时间：
2011-11-11
影响因子：
4.8
通讯作者：
Bernhardt, Guenter
中科院分区：
文献类型：
--
作者：
Seth, Sebastian;Qiu, Quan;Bernhardt, Guenter
树突状细胞（DC）是免疫系统中最有效的抗原呈递细胞。根据其成熟状态，它们启动 T 细胞以诱导适应性免疫或耐受性。 DC 表达 CD155，这是一种与 T 细胞和自然杀伤 (NK) 细胞上存在的 CD226 结合的免疫球蛋白样受体。 CD226 是 T 细胞启动过程中重要的共刺激因子，同时也是细胞毒性 T 细胞和 NK 细胞的激活受体。在这里，我们报告与野生型（WT）相比，CD155（-/-）小鼠的T和NK细胞谱系的细胞表达显着升高的CD226蛋白水平。在杂合 CD155(+/-) T 细胞上，CD226 上调是最大的一半，这意味着反向基因剂量效应。此外，CD226 上调与抗原驱动的激活无关，因为它已经发生在胸腺细胞和天然外周 T 细胞中。在体内，中和性抗 CD155 抗体会引起 T 细胞上 CD226 的上调，这表明观察到的调节可以通过中断 CD155-CD226 接触来触发。将WT或CD155(-/-) T细胞分别过继转移至CD155(-/-)或WT受体中，表明CD226调节是反式完成的。骨髓嵌合体的分析表明反式调节因子是造血起源的。我们证明 DC 能够在体内操纵 T 细胞上的 CD226 水平，但不能在体外操纵 T 细胞上的 CD226 水平，这表明 T 细胞主动扫描次级淋巴器官内抗原呈递 DC 的过程是 CD226 调节所必需的。因此，与 WT 不同的 CD226 水平可用作传感器来检测异常 DC/T 细胞串扰，如缺乏 CCR7 的小鼠中的 T 细胞所示。
Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. Depending on their maturation status, they prime T cells to induce adaptive immunity or tolerance. DCs express CD155, an immunoglobulin-like receptor binding CD226 present on T and natural killer (NK) cells. CD226 represents an important co-stimulator during T cell priming but also serves as an activating receptor on cytotoxic T and NK cells. Here, we report that cells of the T and NK cell lineage of CD155(-/-) mice express markedly elevated protein levels of CD226 compared with wild type (WT). On heterozygous CD155(+/-) T cells, CD226 up-regulation is half-maximal, implying an inverse gene-dosis effect. Moreover, CD226 up-regulation is independent of antigen-driven activation because it occurs already in thymocytes and native peripheral T cells. In vivo, neutralizing anti-CD155 antibody elicits up-regulation of CD226 on T cells demonstrating, that the observed modulation can be triggered by interrupting CD155-CD226 contacts. Adoptive transfers of WT or CD155(-/-) T cells into CD155(-/-) or WT recipients, respectively, revealed that CD226 modulation is accomplished in trans. Analysis of bone marrow chimeras showed that regulators in trans are of hematopoietic origin. We demonstrate that DCs are capable of manipulating CD226 levels on T cells in vivo but not in vitro, suggesting that the process of T cells actively scanning antigen-presenting DCs inside secondary lymphoid organs is required for CD226 modulation. Hence, a CD226 level divergent from WT may be exploited as a sensor to detect abnormal DC/T-cell cross-talk as illustrated for T cells in mice lacking CCR7.