Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening

IF 17.6 1区 医学 Q1 IMMUNOLOGY
Leon U. B. Enk, Malte Hellmig, Kristoffer Riecken, Christoph Kilian, Paul Datlinger, Saskia L. Jauch-Speer, Tobias Neben, Zeba Sultana, Varshi Sivayoganathan, Alina Borchers, Hans-Joachim Paust, Yu Zhao, Nariaki Asada, Shuya Liu, Theodora Agalioti, Penelope Pelczar, Thorsten Wiech, Christoph Bock, Tobias B. Huber, Samuel Huber, Stefan Bonn, Nicola Gagliani, Boris Fehse, Ulf Panzer, Christian F. Krebs
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Abstract

Pro-inflammatory CD4+ T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (TH17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody–associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in TH17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (TH1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover TH17 to TH1 cell plasticity in the human kidney in the context of renal autoimmunity.
通过集合单细胞 CRISPR 筛选,瞄准肾脏和肠道炎症中的 T 细胞可塑性。
促炎性 CD4+ T 细胞是自身免疫性疾病的主要驱动因素,但目前还缺乏调节 T 细胞表型以促进抗炎状态的疗法。在这里,我们根据单细胞(sc)T细胞受体分析和scRNA速度,确定了抗中性粒细胞胞浆抗体相关性肾小球肾炎患者肾脏中T辅助细胞17(TH17)的可塑性。为了发现驱动 T 细胞极化和可塑性的分子,我们建立了体内集合 scCRISPR 液滴测序(iCROP-seq)筛选,并将其应用于肾小球肾炎和结肠炎小鼠模型。基于CRISPR的TH17细胞基因打靶可根据所产生的转录扰动进行排序,并可量化T辅助细胞1(TH1)和调节性T细胞的极化偏向。此外,我们还发现,iCROP-seq 能以疾病和组织特异性的方式对基因和通路进行有效的功能分层,从而促进治疗靶点的确定。这些发现揭示了肾脏自身免疫背景下人类肾脏中 TH17 到 TH1 细胞的可塑性。
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来源期刊
Science Immunology
Science Immunology Immunology and Microbiology-Immunology
CiteScore
32.90
自引率
2.00%
发文量
183
期刊介绍: Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.
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