Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4+ T cells in primary sclerosing cholangitis

JOURNAL OF HEPATOLOGY

卷:75

Article

Poch, Tobias¹  Krause, Jenny¹  Casar, Christian^1,2  Liwinski, Timur^1,3  Glau, Laura⁴  Kaufmann, Max⁵  Ahrenstorf, Annika E.⁶  Hess, Leonard U.⁶  Ziegler, Annerose E.⁶  Martrus, Gloria⁶  Lunemann, Sebastian⁶  Sebode, Marcial¹  Li, Jun⁷  Schwinge, Dorothee¹  Krebs, Christian F.^8,9  Franke, Andre¹⁰  Friese, Manuel A.⁵  Oldhafer, Karl J.¹¹  Fischer, Lutz¹²  Altfeld, Marcus^4,6  Lohse, Ansgar W.^1,9  Huber, Samuel^1,9  Tolosa, Eva⁴  Gagliani, Nicola^1,7,13  Schramm, Christoph^1,9,14 

[1] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Martinistr 52, D-20246 Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Bioinformat Core, D-20246 Hamburg, Germany

[3] Weizmann Inst Sci, Lmmunol Dept, IL-7610001 Rehovot, Israel

[4] Univ Med Ctr Hamburg Eppendorf, Inst Immunol, D-20246 Hamburg, Germany

[5] Univ Med Ctr Hamburg Eppendorf, Inst Neuroimmunol & Multiple Sclerosis, D-20246 Hamburg, Germany

[6] Leibniz Inst Expt Virol, Heinrich Pette Inst, Virus Immunol Dept, D-20246 Hamburg, Germany

[7] Univ Med Ctr Hamburg Eppendorf, Dept Gen Visceral & Thorac Surg, D-20246 Hamburg, Germany

[8] Univ Med Ctr Hamburg Eppendorf, Dept Med Translat Immunol 3, D-20246 Hamburg, Germany

[9] Univ Med Ctr Hamburg Eppendorf, Hamburg Ctr Translat Immunol, D-20246 Hamburg, Germany

[10] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, D-24105 Kiel, Germany

[11] Semmelweis Univ Med, Asklepios Hosp Barmbek, Dept Gen & Abdominal Surg, Hamburg, Germany

[12] Univ Med Ctr Hamburg Eppendorf, Dept Visceral Transplant Surg, D-20246 Hamburg, Germany

[13] Karolinska Inst, Dept Med Solna, Immunol & Allergy Unit, S-17177 Stockholm, Sweden

[14] Univ Med Ctr Hamburg Eppendorf, Martin Zeitz Ctr Rare Dis, D-20246 Hamburg, Germany

关键词: Primary Sclerosing Cholangitis;    Immune-mediated liver disease;    Single-cell sequencing;    Atlas;    T cells;    Naive T cells;    T(H)17 cells;    Tissue residency;   

DOI  :  10.1016/j.jhep.2021.03.016

来源: Elsevier

【 摘 要 】

Background & Aims: Little is known about the composition of intrahepatic immune cells and their contribution to the pathogenesis of primary sclerosing cholangitis (PSC). Herein, we aimed to create an atlas of intrahepatic T cells and thereby perform an in-depth characterization of T cells in inflamed human liver. Methods: Different single-cell RNA sequencing methods were combined with in silico analyses on intrahepatic and peripheral T cells from patients with PSC (n = 11) and healthy donors (HDs, n = 4). Multi-parameter flow cytometry and functional in vitro experiments were conducted on samples from patients with PSC (n = 24), controls with other liver diseases and HDs. Results: We identified a population of intrahepatic naive-like CD4(+) T cells, which was present in all liver diseases tested, but particularly expanded in PSC. This population had a transcriptome and T cell receptor repertoire similar to circulating naive T cells but expressed a set of genes associated with tissue residency. Their periductal location supported the concept of tissue-resident naive-like T cells in livers of patients with PSC. Trajectory inference suggested that these cells had the developmental propensity to acquire a T helper 17 (T(H)17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards T(H)17 cells. Conclusion: We report the first atlas of intrahepatic T cells in PSC, which led to the identification of a previously unrecognized population of tissue-resident naive-like T cells in the inflamed human liver and to the finding that naive CD4(+) T cells in PSC harbour the propensity to develop into T(H)17 cells. Lay summary: The composition of intrahepatic immune cells in primary sclerosing cholangitis (PSC) and their contribution to disease pathogenesis is widely unknown. We analysed intrahepatic T cells and identified a previously uncharacterized population of liver-resident CD4(+) T cells which are expanded in the livers of patients with PSC compared to healthy liver tissue and other liver diseases. These cells are likely to contribute to the pathogenesis of PSC and could be targeted in novel therapeutic approaches. (C) 2021 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.

【 授权许可】

Free