HIV-1感染通过激活pDCs引起ILC2s损耗及机制研究

II型天然淋巴细胞（ILC2s）是新定义的淋巴细胞亚群，HIV感染可导致其细胞损耗，但机制未明。我们前期发现HIV感染可导致浆细胞样树突状细胞（pDCs）激活，一般认为这是引起三类ILCs（ILC1s,ILC2s,ILC3s）细胞凋亡的重要原因，但pDCs介导ILC2s细胞凋亡及机制未见报道。本项目从感染人群出发，明确HIV感染对ILC2s细胞频率和细胞凋亡的影响与pDCs状态及疾病进程的相关性，进一步将分离的健康人pDCs和ILC2s混合培养，采用pDCs体外感染HIV和TLR7/9激活等确证激活的pDCs介导了ILC2s的细胞凋亡，并采用transwell培养、抗体中和等确定pDCs影响ILC2s的关键因子，最后采用凋亡抗体阵列等筛查并确认pDCs调控ILC2s细胞凋亡的通路及关键因子。本项目旨在阐明HIV感染导致ILC2s损耗的分子机制，为HIV感染和天然免疫相互作用提供新认识。

Group II innate lymphoid cells (ILC2s) represent a novel subset of lymphoid cells. HIV infection could induce depletion of ILC2s in the blood. However, the mechanism(s) remains unknown. Our previous studies have shown that HIV infection leads to activation of plasmacytoid dendritic cells (pDCs), which is believed to play an important role in inducing apoptosis of three subsets of innate lymphoid cells (ILCs), namely, ILC1s, ILC2s, and ILC3s. Nevertheless, whether activated pDCs mediate apoptosis of ILC2s and the mechanism(s) involved have not been reported yet. This project will start from a population-based study. HIV-1 infected patients with or without combination antiretroviral therapy (cART) and healthy control subjects will be recruited for the investigation of the impact of HIV-1 infection on the frequency and apoptpsis of ILC2s cells as well as the relationship of these impacts with the status of pDCs or disease progression. Next, isolated pDCs and isolated ILC2s from healthy subjects will be co-cultured to clarify the role of activated pDCs in inducing apoptosis of ILC2s, under the conditions using HIV-1 to infect pDCs or TLR 7/9 agonists to activate pDCs. Transwell culture and antibody neutralization will be used to determine the key factors accounting for the effect of pDCs on ILC2s. Furthermore, apoptosis antibody array as well as other molecular biological techniques will be employed to screen and identify the key apoptosis pathway and factors that involve in the pDCs-regulated apoptosis of ILC2s. In summary, our proposed study aims to reveal the mechanism(s) of HIV-1-induced ILC2s depletion. We expect that this study will provide novel understanding of interaction between HIV-1 infection and host innate immunity.