| Autor: |
Enk, Leon U. B., Hellmig, Malte, Riecken, Kristoffer, Kilian, Christoph, Datlinger, Paul, Jauch-Speer, Saskia L., Neben, Tobias, Sultana, Zeba, Sivayoganathan, Varshi, Borchers, Alina, Paust, Hans-Joachim, Zhao, Yu, Asada, Nariaki, Liu, Shuya, Agalioti, Theodora, Pelczar, Penelope, Wiech, Thorsten, Bock, Christoph, Huber, Tobias B., Huber, Samuel |
| Předmět: |
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| Zdroj: |
Science Immunology; 2024, Vol. 9 Issue 96, p1-15, 15p |
| Abstrakt: |
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. Editor's summary: Modulating plasticity in pathogenic T cells to promote a tolerogenic phenotype is a promising therapeutic approach in autoimmunity and cancer. To explore how pathogenic TH17 cell plasticity is regulated in mouse models of kidney and gut inflammation, Enk et al. optimized an in vivo pooled single-cell CRISPR droplet sequencing (iCROP-seq) screen. iCROP-seq enabled the assessment and quantification of CRISPR-modified TH17 cell polarization states in vivo. Furthermore, T cells from patients with antineutrophil cytoplasmic antibody (ANCA)–associated glomerulonephritis exhibited plasticity. These findings indicate that iCROP-seq can be applied to preclinical mouse models of inflammation and suggest that targeting TH17 plasticity in patients with ANCA-glomerulonephritis is a promising therapeutic approach. —Hannah Isles [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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