Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

Marotel, Marie; Villard, Marine; Drouillard, Annabelle; Tout, Issam; Besson, Laurie; Allatif, Omran; Pujol, Marine; Rocca, Yamila; Ainouze, Michelle; Roblot, Guillaume; Viel, Sébastien; Gomez, Melissa; Loustaud, V.; Alain, Sophie; Durantel, David; Walzer, Thierry; Hasan, Uzma; Marçais, Antoine

doi:10.7554/elife.60095

Cited by 28 publications

(25 citation statements)

References 76 publications

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“…Hepatitis B infection alters the surface receptor expression and activation status of innate and adaptive immune cells. During CHB, NK cells display higher expression of inhibitory receptor NKG2A, while activation receptors CD16 and NKp30 were downregulated [ 58 , 59 ]. These changes are associated with serum HBV DNA load.…”

Section: Innate and Adaptive Immune Response Against Hbv Infectionmentioning

confidence: 99%

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

Khanam

Chua

Kottilil

2021

IJMS

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More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation and subsequently cause liver pathologies. During the initial phase of HBV infection, innate immunity is triggered leading to antiviral cytokines production, followed by activation and intrahepatic recruitment of the adaptive immune system resulting in successful virus elimination. In chronic HBV infection, significant alterations in both innate and adaptive immunity including expansion of regulatory cells, overexpression of co-inhibitory receptors, presence of abundant inflammatory mediators, and modifications in immune cell derived exosome release and function occurs, which overpower antiviral response leading to persistent viral infection and subsequent immune pathologies associated with disease progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, we discuss the current knowledge of innate and adaptive immune cells transformations that are associated with immunopathogenesis and disease outcome in CHB patients.

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Section: Innate and Adaptive Immune Response Against Hbv Infectionmentioning

confidence: 99%

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

Khanam

Chua

Kottilil

2021

IJMS

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“…[7,82] Similar observations were made in NK cells, both in mouse and human, during cancer or chronic infections. [83][84][85][86] How this unbalance contributes to the exhausted phenotype is not entirely clear. As reviewed here, T-bet is important to promote terminal maturation and blood circulation, to preserve viability, and to sustain responsiveness to IL-12 and other cytokines.…”

Section: Loss Of T-bet and Maintenance Of Eomes In Exhausted T And Nk...mentioning

confidence: 99%

Eomes and T‐bet, a dynamic duo regulating NK cell differentiation

2022

Self Cite

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T-bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells.Recent genome-wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion.We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T-bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking. K E Y W O R D S cytotoxicity, development, IFN-γ, natural Killer cells, T-box transcription factors NK CELL DIFFERENTIATION, PARALLELS WITH T CELLSNK cells develop mainly in the bone marrow (BM). At early developmental stages, they actively proliferate in this anatomical site before maturation. We previously reported that immature NK cells could be dissected into two different subsets expressing or not CD27. [10] However, mathematical modeling led us to refine this model and propose that most immature NK cells were in fact CD11b − CD27 + . [11]

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“…In patients with chronic HBV and HCV infection, low frequencies of circulating NK cells combined with diminished production of proinflammatory cytokines, TNF-α, and IFN-γ have been reported as compared to healthy controls [11,12]. Nevertheless, controversy exists regarding the impact of chronic viral infection on NK cell cytolytic function; while several researchers reported impaired NK cytotoxicity, other reports showed that effector function was not changed [17,18]. The differences in outcomes between these studies were probably due to the lack of standardized protocol and reagents, as well as the heterogeneity of patients.…”

Section: Nk Cells In Chronic Viral Hepatitismentioning

confidence: 99%

“…Therefore, targeting TGF-β appears to represent an intervention strategy to boost NK cell mediated tumor immunity and should be considered in future cancer treatment modalities. The importance of NK cells and their activating receptor/ligand axis in HCC immune surveillance has been extensively of 18 studied and patients with decreased expression of major histocompatibility complex class I chain-related protein A (MICA) in HCC tissue showed reduced disease-free and overall survival compared with patients with preserved MICA expression [78]. Innate lymphoid cell (ILC-1) or liver-resident NK cells play versatile roles in liver diseases.…”

Section: Nk Cells and Immune Surveillancementioning

confidence: 99%

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

Kalathil

Thanavala

2021

Cells

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Natural killer (NK) cells account for 25–50% of the total number of hepatic lymphocytes, which implicates that NK cells play an important role in liver immunity. The frequencies of both circulating and tumor infiltrating NK cells are positively correlated with survival benefit in hepatocellular cancer (HCC) and have prognostic implications, which suggests that functional impairment in NK cells and HCC progression are strongly associated. In HCC, T cell exhaustion is accompanied by the interaction between immune checkpoint ligands and their receptors on tumor cells and antigen presenting cells (APC). Immune checkpoint inhibitors (ICIs) have been shown to interfere with this interaction and have altered the therapeutic landscape of multiple cancer types including HCC. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as first-line therapy for HCC. NK cells are the first line effectors in viral hepatitis and play an important role by directly eliminating virus infected cells or by activating antigen specific T cells through IFN-γ production. Furthermore, chimeric antigen receptor (CAR)-engineered NK cells and T cells offer unique opportunities to create CAR-NK with multiple specificities learning from the experience gained with CAR-T cells with potentially less adverse effects. This review focus on the abnormalities of NK cells, T cells, and their functional impairment in patients with chronic viral hepatitis, which contributes to progression to hepatic malignancy. Furthermore, we discuss and summarize recent advances in the NK cell and T cell based immunotherapeutic approaches in HCC.

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Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion

Cited by 28 publications

References 76 publications

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

Eomes and T‐bet, a dynamic duo regulating NK cell differentiation

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

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