Deep Immune Phenotyping and Single-Cell Transcriptomics Allow Identification of Circulating TRM-Like Cells Which Correlate With Liver-Stage Immunity and Vaccine-Induced Protection From Malaria.
Deep Immune Phenotyping and Single-Cell Transcriptomics Allow Identification of Circulating TRM-Like Cells Which Correlate With Liver-Stage Immunity and Vaccine-Induced Protection From Malaria.
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DOI：
10.3389/fimmu.2022.795463
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发表时间：
2022
影响因子：
7.3
通讯作者：
Spencer AJ
中科院分区：
文献类型：
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作者：
Noé A;Datoo MS;Flaxman A;Husainy MA;Jenkin D;Bellamy D;Makinson RA;Morter R;Ramos Lopez F;Sheridan J;Voukantsis D;Prasad N;Hill AVS;Ewer KJ;Spencer AJ
预防肝期疟疾需要大量 CD8+ T 细胞来发现并杀死疟原虫感染的细胞。一种新的疟疾疫苗策略，即主要目标疫苗接种，涉及通过肌内和静脉内途径进行连续病毒载体疫苗接种，以针对肝脏的细胞免疫。肝组织驻留记忆 (TRM) CD8+ T 细胞已被证明对于通过这种疫苗方案预防啮齿动物疟疾是必要且充分的。最终，为了最忠实地评估这些局部、专门的肝 T 细胞的免疫治疗反应，定期进行肝脏采样是必要的，但这在大规模人体试验中是不可行的。在这里，作为主要目标疫苗接种的 I/II 期恶性疟原虫挑战研究的一部分，我们对肝细针抽吸物和外周血样本进行了深度免疫表型分析、单细胞 RNA 测序和动力学，以研究肝脏 CD8+ TRM 细胞和循环对应细胞。我们发现，虽然这些外周“TRM 样”细胞在先前描述的特征方面与 TRM 细胞不同，但它们在表型上相似，并且在关键 T 细胞驻留转录特征方面无法区分。通过以单细胞分辨率探索肝脏 CD8+ TRM 细胞的异质性，我们发现了两个主要亚群，每个亚群都与血液 T 细胞共享表达谱。最后，我们的工作指出了使用 TRM 样细胞作为肝期疟疾疫苗保护的相关性的潜力，特别是那些采用主要目标方法的疫苗。随着肝期疟疾疫苗进入第三阶段，在非洲婴儿中进行大规模测试，简单且可重复的保护相关性在肝期疟疾疫苗试验中特别有价值。我们提供了一个蓝图，用于了解和监测由主要目标疟疾疫苗方法诱导的肝脏 TRM 细胞。
Protection from liver-stage malaria requires high numbers of CD8+ T cells to find and kill Plasmodium-infected cells. A new malaria vaccine strategy, prime-target vaccination, involves sequential viral-vectored vaccination by intramuscular and intravenous routes to target cellular immunity to the liver. Liver tissue-resident memory (TRM) CD8+ T cells have been shown to be necessary and sufficient for protection against rodent malaria by this vaccine regimen. Ultimately, to most faithfully assess immunotherapeutic responses by these local, specialised, hepatic T cells, periodic liver sampling is necessary, however this is not feasible at large scales in human trials. Here, as part of a phase I/II P. falciparum challenge study of prime-target vaccination, we performed deep immune phenotyping, single-cell RNA-sequencing and kinetics of hepatic fine needle aspirates and peripheral blood samples to study liver CD8+ TRM cells and circulating counterparts. We found that while these peripheral ‘TRM-like’ cells differed to TRM cells in terms of previously described characteristics, they are similar phenotypically and indistinguishable in terms of key T cell residency transcriptional signatures. By exploring the heterogeneity among liver CD8+ TRM cells at single cell resolution we found two main subpopulations that each share expression profiles with blood T cells. Lastly, our work points towards the potential for using TRM−like cells as a correlate of protection by liver-stage malaria vaccines and, in particular, those adopting a prime-target approach. A simple and reproducible correlate of protection would be particularly valuable in trials of liver-stage malaria vaccines as they progress to phase III, large-scale testing in African infants. We provide a blueprint for understanding and monitoring liver TRM cells induced by a prime-target malaria vaccine approach.