Adaptive immune dysfunction in acute decompensated cirrhosis
File(s)
Author(s)
Liu, Tong
Type
Thesis
Abstract
Background: Acute decompensation of cirrhosis (AD) is characterised by a sudden deterioration in liver function, frequently leading to severe complications, including an increased susceptibility to infections. These infections are a leading cause of morbidity and mortality in AD, largely due to adaptive immune dysfunction, which manifests as a diminished immune response capability, termed immunoparesis. Understanding the components and mechanisms underlying immunoparesis is essential for enhancing patient survival. Suppressive CD4+ T cells, encompassing both conventional regulatory T cells and non-conventional peripherally derived regulatory T cells, play a pivotal role in dampening systemic immune activation. This study aims to investigate the presence, regulation, and mechanisms of non-conventional suppressive CD4+ T cells in the peripheral blood of patients with AD.
Methods: Detailed phenotyping of immune cells from patients with AD was conducted using flow cytometry and transcriptomics. The functions of individual cell populations were assessed with in vitro functional assays. CD52 ligands were identified through proximity labelling and proteomics. The function of CD52 was evaluated using CD52 knockout in CD4+ T cells.
Results: Liver macrophages stimulated by bacterial products secreted high levels of IL-35 in AD, leading to the expansion of a CD4+HLA-G+ suppressive T cells. This population exerted its suppressive capacity through CTLA-4 and HLA-G. The CTLA-4-mediated suppression was linked to a shift in tryptophan metabolism towards the kynurenine pathway. Additionally, upregulated CD52 in effector T cells acted as a cis-ligand to the T cell receptor complex, inhibiting
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antigen-specific activation and further contributing to the suppressed immune responses.
Conclusion: Adaptive immune dysfunction in AD involves multiple mechanisms, including the expansion of suppressor cells and the impairment of effector cells. Understanding these mechanisms is critical for developing therapeutic strategies aimed at improving anti-microbial immune responses. Targeting the pathways associated with immune suppression holds potential for improving clinical outcomes of this patient population.
Methods: Detailed phenotyping of immune cells from patients with AD was conducted using flow cytometry and transcriptomics. The functions of individual cell populations were assessed with in vitro functional assays. CD52 ligands were identified through proximity labelling and proteomics. The function of CD52 was evaluated using CD52 knockout in CD4+ T cells.
Results: Liver macrophages stimulated by bacterial products secreted high levels of IL-35 in AD, leading to the expansion of a CD4+HLA-G+ suppressive T cells. This population exerted its suppressive capacity through CTLA-4 and HLA-G. The CTLA-4-mediated suppression was linked to a shift in tryptophan metabolism towards the kynurenine pathway. Additionally, upregulated CD52 in effector T cells acted as a cis-ligand to the T cell receptor complex, inhibiting
10
antigen-specific activation and further contributing to the suppressed immune responses.
Conclusion: Adaptive immune dysfunction in AD involves multiple mechanisms, including the expansion of suppressor cells and the impairment of effector cells. Understanding these mechanisms is critical for developing therapeutic strategies aimed at improving anti-microbial immune responses. Targeting the pathways associated with immune suppression holds potential for improving clinical outcomes of this patient population.
Version
Open Access
Date Issued
2024-04-16
Date Awarded
2024-10-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Khamri, Wafa
Thursz, Mark
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)