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Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4⁺ T cells.

ABSTRACT: In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4⁺ T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFN? were expressed in liver tissue. IL-33 induced strong activation and expression of type 2 cytokines as well as IL-6 by hepatic ILC2 while IFN? suppressed cytokine production. Interestingly, this inhibitory effect was overcome by IL-33. The phenotype of activated hepatic ILC2 were stable since they did not show functional plasticity in response to liver inflammation-induced cytokines. Moreover, hepatic ILC2 induced a Th2 phenotype in activated CD4⁺ T cells, which increased ILC2-derived cytokine expression via IL-2. In contrast, Th1 cells inhibited survival of ILC2 by production of IFN?. Thus, hepatic ILC2 function is regulated by IL-33, IL-2, and IFN?. While IL-33 and IL-2 support hepatic ILC2 activation, their inflammatory activity in immune-mediated hepatitis might be limited by infiltrating IFN?-expressing Th1 cells.

SUBMITTER: Steinmann S

PROVIDER: S-EPMC6978388 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4<sup>+</sup> T cells.

Steinmann Silja S Schoedsack Marek M Heinrich Fabian F Breda Philippe C PC Ochel Aaron A Tiegs Gisa G Neumann Katrin K

Scientific reports 20200123 1

In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4<sup>+</sup> T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFNγ were expressed in liver tissue. IL-33 induced strong activ ...[more]

PMID: 31974518

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Project description:Background & aimsLittle 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.MethodsDifferent 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.ResultsWe 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 (TH17) polarization state. Functional and chromatin accessibility experiments revealed that circulating naive T cells in patients with PSC were predisposed to polarize towards TH17 cells.ConclusionWe 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 TH17 cells.Lay summaryThe 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.

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Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4⁺ T cells.

Publications

Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4<sup>+</sup> T cells.

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Dataset Information

Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4+ T cells.

Publications

Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4⁺ T cells.