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

项目总结 最近，一种看似新颖的具有自然杀伤(NK)和B细胞特征的天然免疫细胞亚群被认为是 在老鼠身上被鉴定出来。所谓的NKB细胞似乎是粘膜表面病毒感染的第一反应者，但 完整的功能定位尚不清楚，在我们最近的研究之前，还不清楚这些细胞是否存在于 高级灵长类动物。在我们最近发表的发现(Manickam等人，艾滋病2018)和新的初步研究中 我们发现，表型相似的NKB细胞群体可以在人类和 非人灵长类动物，但脾丰富，类似于小鼠。此外，NKB细胞表面稳定。 慢性SIV时结肠组织中非分泌型IgM和IgA的表达及大量扩增 感染。在这个新的提案中，我们将严格测试NKB细胞是 粘膜感染部位的早期反应者和这种细胞类型的激活对于启动抗- HIV/SIV先天免疫反应通过两个有针对性的特定目标：(1)识别转录和 NKB细胞在动态平衡条件下的功能特征；以及(2)确定角色(S)和 粘膜NKB细胞在SIV感染中的功能意义这项提案的结果将提供 首次对慢病毒感染期间的NKB细胞进行详细分析，并可能针对这些独特的 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.