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Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH
Anna Woestemeier, … , Samuel Huber, Nicola Gagliani
Anna Woestemeier, … , Samuel Huber, Nicola Gagliani
Published January 10, 2023
Citation Information: JCI Insight. 2023;8(1):e153831. https://doi.org/10.1172/jci.insight.153831.
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Technical Advance Hepatology Immunology

Multicytokine-producing CD4+ T cells characterize the livers of patients with NASH

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Abstract

A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.

Authors

Anna Woestemeier, Pasquale Scognamiglio, Yu Zhao, Jonas Wagner, Franziska Muscate, Christian Casar, Francesco Siracusa, Filippo Cortesi, Theodora Agalioti, Simone Müller, Adrian Sagebiel, Leonie Konczalla, Ramez Wahib, Karl-Frederick Karstens, Anastasios D. Giannou, Anna Duprée, Stefan Wolter, Milagros N. Wong, Anne K. Mühlig, Agata A. Bielecka, Vikas Bansal, Tianran Zhang, Oliver Mann, Victor G. Puelles, Tobias B. Huber, Ansgar W. Lohse, Jakob R. Izbicki, Noah W. Palm, Stefan Bonn, Samuel Huber, Nicola Gagliani

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Figure 1

scRNA-seq of CD4+ T cells found in the liver of NAFLD patients.

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scRNA-seq of CD4+ T cells found in the liver of NAFLD patients.
(A) Sche...
(A) Schematic of experimental setup: FACS-isolated CD45RA–CD4+ T cells (CD4+ T cells) from liver tissue of NAFLD patients were processed for scRNA-seq. (B) t-SNE plot of the unsupervised clustering of CD4+ T cells. (C) Heatmap of CD4+ T cell clusters displaying key signature genes to annotate the different clusters. CM1 and CM2, central memory populations 1 and 2. (D) Violin plots comparing the most differentially expressed genes between the central memory clusters. (E) Expression of the tissue-resident memory T cell (Trm) gene signature score of the indicated clusters of human CD4+ T cells. (F) t-SNE plot of the subclustering of Tr1, Th1, and Th17 clusters. (G) PCA plot of slingshot pseudotime developmental trajectory analysis.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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