Neuropilin-1 Expression on CD4 T Cells Is Atherogenic and Facilitates T Cell Migration to the Aorta in Atherosclerosis.
Neuropilin-1 Expression on CD4 T Cells Is Atherogenic and Facilitates T Cell Migration to the Aorta in Atherosclerosis.
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DOI：
10.4049/jimmunol.1900245
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发表时间：
2019-12-15
期刊：
影响因子：
--
通讯作者：
Hedrick CC
中科院分区：
文献类型：
--
作者：
Gaddis DE;Padgett LE;Wu R;Hedrick CC
Neuropilin 1 （Nrp1）是一种I型跨膜蛋白，在轴突引导、神经元发育和血管生成中起重要作用。Nrp1帮助胸腺来源的调节性T细胞迁移到产生血管内皮生长因子（VEGF）的肿瘤。在动脉粥样硬化过程中，Nrp1对CD4 T细胞的作用知之甚少。western diet （WD）喂养15周的ApoE - / -小鼠，我们发现这些小鼠的脾脏、主动脉周围淋巴结（PaLN）和主动脉的Nrp1+Foxp3 - CD4 T细胞比正常小鼠增加了两倍。与Nrp1 - CD4 T细胞相比，Nrp1+Foxp3−CD4 T细胞具有更高的增殖潜力，表达更高水平的记忆标志物CD44，并产生更多的IFNγ。用oxLDL处理CD4 T细胞增加Nrp1的表达。我们使用在T细胞上选择性缺乏Nrp1表达的动脉粥样硬化易感小鼠，发现缺乏Nrp1的小鼠比Nrp1充足的小鼠更少发生动脉粥样硬化。在机制上，我们发现表达Nrp1的CD4 T细胞比Nrp1−T细胞有更高的迁移到主动脉和PaLN的能力，这表明Nrp1的表达促进了CD4 T细胞募集到主动脉，在主动脉中它们可能是致病的。因此，我们已经确定了Nrp1在动脉粥样硬化中对CD4 T细胞的新作用。这些结果表明，操纵T细胞上Nrp1的表达可以影响动脉粥样硬化的结局和降低疾病发病率。
Neuropilin 1 (Nrp1) is a type I transmembrane protein that plays important roles in axonal guidance, neuronal development, and angiogenesis. Nrp1 helps migrate thymus-derived regulatory T cells to vascular endothelial growth factor (VEGF)-producing tumors. Little is known about the role of Nrp1 on CD4 T cells during atherosclerosis. In ApoE−/− mice fed a western diet (WD) for 15 weeks, we found a two-fold increase in Nrp1+Foxp3− CD4 T cells in the spleens, peri-aortic lymph nodes (PaLN) and aortas of those mice compared to chow-fed mice. Nrp1+Foxp3− CD4 T cells had higher proliferation potential, expressed higher levels of the memory marker CD44, and produced more IFNγ when compared to Nrp1− CD4 T cells. Treatment of CD4 T cells with oxLDL increased Nrp1 expression. Using atherosclerosis-susceptible mice that were selectively deficient for Nrp1 expression on T cells, we found that mice lacking Nrp1 developed less atherosclerosis than their Nrp1-sufficient counterparts. Mechanistically, we found that CD4 T cells that express Nrp1 have higher capacity to migrate to the aorta and PaLN than Nrp1− T cells, suggesting that the expression of Nrp1 facilitates the recruitment of CD4 T cells into the aorta where they can be pathogenic. Thus, we have identified a novel role of Nrp1 on CD4 T cells in atherosclerosis. These results suggest that manipulation of Nrp1 expression on T cells can affect the outcome of atherosclerosis and lower disease incidence.
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