Single-Cell Heterogeneity of the Liver-Infiltrating Lymphocytes in Individuals with Chronic Echinococcus multilocularis Infection

Jiang, Tiemin; Sun, Wujianan; Aji, Tuerganaili; Shao, Yingmei; Guo, Chuang; Zhang, Chuanshan; Ran, Bo; Hou, Jiao; Yasen, Aimaiti; Guo, Qiang; Wang, Hui; Qu, Kun; Wen, Hao

doi:10.1128/iai.00177-22

Cited by 11 publications

(11 citation statements)

References 62 publications

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“…To further characterize CD4 + T cells, we analyzed a 10× 5’ single-cell sequencing dataset of CD45 + immune cells from paired liver tissue and peripheral blood (PB) mononuclear cells from 4 patients with AE (accession no. HRA000553; https://figshare.com/s/f2a4578be27c2cb767f9 [ 20 ]). We identified an induced Treg (iTreg) cluster expressing high levels of CD38 , HAVCR2 , MIR4435-1HG , CTLA4 , CXCR6 , LAG3 and MT1E in CLT, DLT and PB ( Fig 1F ).…”

Section: Resultsmentioning

confidence: 99%

Upregulation of LAG3 modulates the immune imbalance of CD4+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model

Li,

Ainiwaer,

Zheng

et al. 2023

PLoS Pathog

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Infection with the cestode Echinococcus multilocularis (E. multilocularis) causes alveolar echinococcosis (AE), a tumor-like disease predominantly affecting the liver but able to spread to any organ. T cells develop functional defects during chronic E. multilocularis infection, mostly due to upregulation of inhibitory receptors such as T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and programmed death-1 (PD-1). However, the role of lymphocyte activation gene-3 (LAG3), an inhibitory receptor, in AE infection remains to be determined. Here, we discovered that high expression of LAG3 was mainly found in CD4+ T cells and induced regulatory T cells (iTregs) in close liver tissue (CLT) from AE patients. In a mouse model of E. multilocularis infection, LAG3 expression was predominantly found in T helper 2 (Th2) and Treg subsets, which secreted significantly more IL-4 and IL-10, resulting in host immune tolerance and disease progression at a late stage. Furthermore, LAG3 deficiency was found to drive the development of effector memory CD4+ T cells and enhance the type 1 CD4+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4+ T cells from LAG3-deficient mice produced more IFN-γ and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4+ T cells were more likely to develop into Th1 cells and less likely to develop into Tregs in recipient mice. Our work reveals that high expression of LAG3 accelerates AE disease progression by modulating the immune imbalance of CD4+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection.

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Section: Resultsmentioning

confidence: 99%

Upregulation of LAG3 modulates the immune imbalance of CD4+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model

Li,

Ainiwaer,

Zheng

et al. 2023

PLoS Pathog

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“…Immune suppressions are associated with AE deterioration, as demonstrated by the accelerated disease progression in patients with AIDS or other immunosuppressive conditions 43 . Experimental studies also reveal the upregulation of immune inhibitive signals in the late stage of E. multilocularis infection, with a focus on T cells and macrophages 18,20,[44][45][46] . Recent studies in cancer research have revealed the functional heterogeneity of neutrophils, which could negatively modulate both innate and adaptive immunity 47,48 .…”

Section: Discussionmentioning

confidence: 99%

“…However, the exact cell composition in the infection tissues and the cellular structural dynamics during sustained infection remain obscure. In the late infection stage, the upregulation of exhaustion-related genes such as NFKBIA, PD-1, CTLA4, TIGIT, and TIM-3 transforms the immune cells including CD4 + and CD8 + T cells into an immune inhibition phenotype, facilitating the persistent propagation of the metacestodes in the host [18][19][20] . Neutrophils are the first leukocytes recruited to eliminate invading pathogens through multiple mechanisms such as NETosis and phagocytosis 21 .…”

Section: Alveolar Echinococcosis (Ae) Is a Zoonotic Parasitic Disease...mentioning

confidence: 99%

“…However, a high-resolution spatial landscape of the infection foci and the cell-cell interaction mechanism driving disease progression remain to be elucidated. To solve this problem, single-cell RNA sequencing (scRNA-seq) can be applied to acquire the transcriptomes of single cells after tissue dissociation, which can reveal the changes in cell types and cell states during parasite infection 18,19 . Meanwhile, the spatial transcriptomics (ST) technology can reveal the cell-cell interactions in specific pathological niches by capturing tissue transcriptomes in situ .…”

Section: Introductionmentioning

confidence: 99%

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Spatiotemporal transcriptomic profiling reveals the dynamic immunological landscape of alveolar echinococcosis

Ou,

Li,

Ren

et al. 2024

Preprint

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Alveolar echinococcosis (AE) is caused by the invasive growth of the metacestodes ofEchinococcus multilocularis(E. multilocularis). The early diagnosis, management, and treatment of AE remains challenging. Herein, we integrated bulk RNA-seq, scRNA-seq, and ST technologies to reveal the immune characteristics both spatially and chronologically inE. multilocularisinfected mouse liver. An unprecedented high-resolution spatial atlas of theE. multilocularisinfection foci was obtained, revealing the pivotal role of neutrophils,Spp1+monocyte-derived macrophages (MoMFs), and fibroblasts in AE progression. We observed continuous recruitment of neutrophils and macrophages into the infected tissues, indicating prolonged immune stimulation by the growing metacestodes. However, their spatial distribution patterns and functions changed during the infection cause. At the early infection stage,Il1bhineutrophils aggregated in the lesion displayed the highest pattern-recognition receptor activity and may kill the metacestodes through NETosis, but their death in the infection foci might also trigger immune suppression. Meanwhile,Spp1+MoMFs attached to the protoscoleces to clear the infection. At the late infection stage, the neutrophils failed to infiltrate into the lesion although their continuous recruitment into the infected liver. Even though theSpp1+MoMFs enclosing the microcysts ofE. multilocularismay retain their pathogen-killing ability, they may also promote fibrosis and angiogenesis through interaction with fibroblasts. The pro- and anti-inflammatory phenotype balance of these immune cells may be associated with the transition of parasite control strategy from “active killing” to “negative segregation” by the host. Our findings identify key molecular traits involved in AE development, which may benefit the treatment of echinococcosis.

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“…Moreover, in malaria-infected parasitic diseases, the frequency of activated MAIT cells increased significantly in a plasmodium falciparum sporozoites pathogens infection dose-dependent manner ( 29 ). Our previous study revealed that MAIT cells with the T-cell receptor (TCR) clone TRAV1-2_TRAJ33_TRAC were expanded in AE patients’ peripheral blood and liver tissues and enriched in the liver tissues by single-cell RNA and TCR sequencing ( 30 ). However, the phenotype and function of MAIT cells and the correlation with clinicopathologic features are unknown.…”

Section: Introductionmentioning

confidence: 99%

Phenotype and function of MAIT cells in patients with alveolar echinococcosis

Li,

Zhao,

et al. 2024

Front. Immunol.

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Mucosal-associated invariant T (MAIT) cells are a subpopulation of unconventional T cells widely involved in chronic liver diseases. However, the potential role and regulating factors of MAIT cells in alveolar echinococcosis (AE), a zoonotic parasitic disease by Echinococcus multilocularis (E. multilocularis) larvae chronically parasitizing liver organs, has not yet been studied. Blood samples (n=29) and liver specimens (n=10) from AE patients were enrolled. The frequency, phenotype, and function of MAIT cells in peripheral blood and liver tissues of AE patients were detected by flow cytometry. The morphology and fibrosis of liver tissue were examined by histopathology and immunohistochemistry. The correlation between peripheral MAIT cell frequency and serologic markers was assessed by collecting clinicopathologic characteristics of AE patients. And the effect of in vitro stimulation with E. multilocularis antigen (Emp) on MAIT cells. In this study, MAIT cells are decreased in peripheral blood and increased in the close-to-lesion liver tissues, especially in areas of fibrosis. Circulating MAIT exhibited activation and exhaustion phenotypes, and intrahepatic MAIT cells showed increased activation phenotypes with increased IFN-γ and IL-17A, and high expression of CXCR5 chemokine receptor. Furthermore, the frequency of circulating MAIT cells was correlated with the size of the lesions and liver function in patients with AE. After excision of the lesion site, circulating MAIT cells returned to normal levels, and the serum cytokines IL-8, IL-12, and IL-18, associated with MAIT cell activation and apoptosis, were altered. Our results demonstrate the status of MAIT cell distribution, functional phenotype, and migration in peripheral blood and tissues of AE patients, highlighting their potential as biomarkers and therapeutic targets.

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Single-Cell Heterogeneity of the Liver-Infiltrating Lymphocytes in Individuals with Chronic Echinococcus multilocularis Infection

Abstract: Human alveolar echinococcosis (AE) is a tumor-like disease predominantly located in the liver. The cellular composition and heterogeneity of the lesion-infiltrating lymphocytes which produce an “immunosuppressive” microenvironment are poorly understood.

Cited by 11 publications

References 62 publications

Upregulation of LAG3 modulates the immune imbalance of CD4+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model

Upregulation of LAG3 modulates the immune imbalance of CD4+ T-cell subsets and exacerbates disease progression in patients with alveolar echinococcosis and a mouse model

Spatiotemporal transcriptomic profiling reveals the dynamic immunological landscape of alveolar echinococcosis

Phenotype and function of MAIT cells in patients with alveolar echinococcosis

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