Neuropilin-1 (Nrp-1) expression on CD8+ T cells has been identified in tumor-infiltrating lymphocytes and in persistent murine gamma-herpes virus infections, where it interferes with the development of long-lived memory T cell responses. In parasitic and acute viral infections, the role of Nrp-1 expression on CD8+ T cells remains unclear. Here, we demonstrate a strong induction of Nrp-1 expression on CD8+ T cells in Plasmodium berghei ANKA (PbA)-infected mice that correlated with neurological deficits of experimental cerebral malaria (ECM). Likewise, the frequency of Nrp-1+CD8+ T cells was significantly elevated and correlated with liver damage in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. Transcriptomic and flow cytometric analyses revealed a highly activated phenotype of Nrp-1+CD8+ T cells from infected mice. Correspondingly, in vitro experiments showed rapid induction of Nrp-1 expression on CD8+ T cells after stimulation in conjunction with increased expression of activation-associated molecules. Strikingly, T cell-specific Nrp-1 ablation resulted in reduced numbers of activated T cells in the brain of PbA-infected mice as well as in spleen and liver of LCMV-infected mice and alleviated the severity of ECM and LCMV-induced liver pathology. Mechanistically, we identified reduced blood-brain barrier leakage associated with reduced parasite sequestration in the brain of PbA-infected mice with T cell-specific Nrp-1 deficiency. In conclusion, Nrp-1 expression on CD8+ T cells represents a very early activation marker that exacerbates deleterious CD8+ T cell responses during both, parasitic PbA and acute LCMV infections.

中文翻译：

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Neuropilin-1 可识别寄生虫和病毒感染期间高度激活的 CD8+ T 细胞的子集。

在肿瘤浸润淋巴细胞和持续性鼠伽马疱疹病毒感染中，CD8+ T 细胞上的 Neuropilin-1 (Nrp-1) 表达已被鉴定，它会干扰长寿命记忆 T 细胞反应的发展。在寄生虫和急性病毒感染中，Nrp-1 表达在 CD8+ T 细胞上的作用仍不清楚。在这里，我们证明了伯氏疟原虫 ANKA (PbA) 感染小鼠 CD8+ T 细胞上 Nrp-1 表达的强烈诱导，这与实验性脑型疟疾 (ECM) 的神经缺陷相关。同样，在淋巴细胞性脉络膜脑膜炎病毒（LCMV）感染的急性期，Nrp-1+CD8+T细胞的频率显着升高，并与肝损伤相关。转录组学和流式细胞术分析显示，受感染小鼠的 Nrp-1+CD8+ T 细胞具有高度激活的表型。相应地，体外实验表明，刺激后 CD8+ T 细胞上 Nrp-1 表达快速诱导，同时激活相关分子表达增加。引人注目的是，T 细胞特异性 Nrp-1 消除导致 PbA 感染小鼠大脑以及 LCMV 感染小鼠脾脏和肝脏中活化 T 细胞数量减少，并减轻了 ECM 和 LCMV 诱导的肝脏病理的严重程度。从机制上讲，我们发现血脑屏障渗漏减少与 T 细胞特异性 Nrp-1 缺陷的 PbA 感染小鼠大脑中寄生虫隔离减少相关。总之，CD8+ T 细胞上的 Nrp-1 表达代表了一种非常早期的激活标记，在寄生 PbA 和急性 LCMV 感染期间会加剧有害的 CD8+ T 细胞反应。