Natural killer cell receptor-expressing B cells as regulators of mucosal immunity in SIV infection

项目摘要 最近，一种似乎是新的天然免疫细胞亚群，具有自然杀伤（NK）细胞和B细胞的特征， 在老鼠身上发现。所谓的NKB细胞似乎是粘膜表面病毒感染的第一反应者，但NKB细胞的免疫反应是最重要的。 完整的功能生态位仍然未知，在我们最近的研究之前，还不清楚这些细胞是否存在于 高等灵长类在我们最近发表的研究结果中（Manickam等人，艾滋病2018）和新的初步 我们发现，表型相似的NKB细胞群体可以在人体内全身发现， 非人灵长类动物，但在脾脏中富集，与小鼠相似。此外，NKB细胞具有稳定的表面 非分泌性IgM和伊加的表达，并在慢性SIV期间在结肠组织中大量扩增 感染在这个新的建议中，我们将严格测试我们将测试的首要假设，NKB细胞是 粘膜感染部位的早期应答者和这种细胞类型的激活对于启动抗- HIV/SIV先天免疫应答通过两个集中的具体目标：（1）鉴定转录组和 在稳态条件下NKB细胞的功能特征;和（2）鉴定作用和 粘膜NKB细胞在SIV感染中的功能意义。该提案的结果将提供 慢病毒感染期间NKB细胞的第一个详细分析以及靶向这些独特的细胞的潜在方法， 用于免疫治疗或疫苗策略的细胞。

PROJECT SUMMARY Recently, a seemingly novel innate immune cell subset bearing features of natural killer (NK) and B cells was identified in mice. So-called NKB cells appear as first responders to viral infections at mucosal surfaces, but the full functional niche remains unknown and prior to our recent studies it has been unclear if these cells existed in higher order primates. In our recently published findings (Manickam et al., AIDS 2018) and new preliminary data we found that phenotypically analogous populations of NKB cells can be found systemically in humans and non-human primates, but are enriched in spleen, similar to mice. Furthermore, NKB cells had stable surface expression of non-secreted IgM and IgA, and are massively expanded in colonic tissues during chronic SIV infection. In this new proposal we will rigorously test we will test the overarching hypothesis that NKB cells are early responders at mucosal sites of infection and activation of this cell type is critical to initiate anti- HIV/SIV innate immune responses through two focused specific aims: (1) Identify transcriptomic and functional signatures of NKB cells under homeostatic conditions; and (2) Identify the role(s) and functional significance of mucosal NKB cells in SIV infection. The outcomes of this proposal will provide the first detailed analyses of NKB cells during lentivirus infection and potentially means to target these unique cells for immunotherapeutics or vaccine strategies.