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Identification of pathogenic TRAIL-expressing innate immune cells during HIV-1 infection in humanized mice by scRNA-Seq
Liang Cheng, … , Xiao-Ning Xu, Lishan Su
Liang Cheng, … , Xiao-Ning Xu, Lishan Su
Published May 14, 2020
Citation Information: JCI Insight. 2020;5(11):e135344. https://doi.org/10.1172/jci.insight.135344.
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Resource and Technical Advance AIDS/HIV

Identification of pathogenic TRAIL-expressing innate immune cells during HIV-1 infection in humanized mice by scRNA-Seq

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Abstract

Depletion of CD4+ T cells during HIV-1 infection is mostly mediated by inflammatory cells via indirect but not clearly defined mechanisms. In this report, we used single-cell RNA-Seq (scRNA-Seq) technology to study HIV-induced transcriptomic change in innate immune cells in lymphoid organs. We performed scRNA-Seq on hCD45+hCD3–hCD19– human leukocytes isolated from spleens of humanized NOD/Rag2–/–γc–/– (NRG) mice transplanted with human CD34+ hematopoietic stem progenitor cells (NRG-hu HSC mice). We identified major populations of innate immune cells, including plasmacytoid dendritic cells (pDCs), myeloid dendritic cells (mDCs), macrophages, NK cells, and innate lymphoid cells (ILCs). HIV-1 infection significantly upregulated genes involved in type I IFN inflammatory pathways in each of the innate immune subsets. Interestingly, we found that TRAIL was upregulated in the innate immune populations, including pDCs, mDCs, macrophages, NK cells, and ILCs. We further demonstrated that blockade of the TRAIL signaling pathway in NRG-hu HSC mice prevented HIV-1–induced CD4+ T cell depletion in vivo. In summary, we characterized HIV-induced transcriptomic changes of innate immune cells in the spleen at single-cell levels, identified the TRAIL+ innate immune cells, and defined an important role of the TRAIL signaling pathway in HIV-1–induced CD4+ T cell depletion in vivo.

Authors

Liang Cheng, Haisheng Yu, John A. Wrobel, Guangming Li, Peng Liu, Zhiyuan Hu, Xiao-Ning Xu, Lishan Su

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Figure 2

HIV-1–induced alterations of human innate immune cells by scRNA-Seq analysis of human cells in spleens of NRG-hu HSC mice.

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HIV-1–induced alterations of human innate immune cells by scRNA-Seq anal...
NRG-hu HSC mice were infected with HIV-1 and terminated at 3 weeks after infection. Splenocytes were enriched for hCD45+hCD3–hCD19– cells for single-cell transcriptomics assay. (A) t-SNE analysis of hCD45+hCD3–hCD19– innate immune clusters from spleens of 2 mock and 2 HIV-1–infected NRG-hu HSC mice reconstituted with CD34+ cells from the same donor. Different colors indicate distinct cell types on the left. Blue dots indicate cells from mock mice, while red dots indicate cells from HIV-1–infected mice on the right. (B) Distribution of upregulated and downregulated genes in HIV-1–infected NRG-hu HSC mice compared with mock control mice for each cell type. (C) GO term analysis of pathways upregulated by HIV-1 in pDCs, mDCs, macrophages, NK cells, and ILCs. The red points connected by a red line indicate the –log10 Benjamini-Hochberg adjusted P values for enrichment of the upregulated genes for the specified biological process with the scale on the top axis. The blue bars indicate the number of upregulated genes found in the specified biological process, with the scale on the bottom axis. (D) Venn diagram showing overlap of genes upregulated by HIV-1 for each of the 5 innate immune subsets. The differentially modulated genes common to all 5 innate immune subsets are listed in the center region of each Venn diagram.

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