{
  "abstract": "Introduction Chronic hepatitis B (CHB) remains a major cause of inflammatory liver disease worldwide. Increasingly, CHB co-exists with metabolic dysfunction-associated steatotic liver disease (MASLD), a combination associated with heightened hepatic inflammation, immune dysregulation, and delayed virological responses to antiviral therapy (AVT). Metabolic stress may therefore reshape intrahepatic immune responses and drive bystander innate-like T-cell activation, sustaining liver injury despite viral suppression.Methods Peripheral and intrahepatic CD8 + T cells from healthy controls and patients with CHB (treatment-naïve and AVT-treated) were analysed using multi-parameter flow cytometry. Cellular activation, natural killer receptor (NKR) expression, effector function, and sensitivity to free fatty acids (FFAs; palmitic acid, oleic acid, docosahexaenoic acid [DHA], and arachidonic acid [AA]) were assessed. CD8+ T cells were also isolated for transcriptomic profiling. In parallel, HepG2-NTCP models of HBV infection were used to assess the impact of lipid overload on HBV transcription and antiviral efficacy.Results Activated (CD38 +HLA-DR+) CD56+ CD8+ T cells were significantly expanded in CHB, particularly in immune-active disease, with increased expression of NKRs including NKG2A and NKp30. Although AVT reduced their overall frequency, elevated NKR expression and innate-associated transcriptional signatures (including KLRK1 and NCR3) persisted. Functionally, CD56+ CD8+ T cells showed comparable IFN-gamma production following TCR-dependent and TCR-independent stimulation, but enhanced TNF-alpha production following IL-15 stimulation (TCR-independent), indicating a differential functional profile consistent with a bystander activation. These cells were also more susceptible to functional suppression following FFA exposure. Complementary in vitro studies demonstrated that FFA exposure increased HBV transcriptional activity in infected HepG2-NTCP cells and this effect was not fully abrogated by AVT.Conclusions CHB is characterised by persistent expansion of metabolically sensitive, innate-like CD56 + CD8+ T cells with bystander inflammatory potential in the context of metabolic dysfunction. In parallel, lipid overload sustains HBV transcription despite AVT. Together, these findings identify a convergent immunometabolic axis linking MASLD, immune-mediated liver injury, and incomplete viral suppression in CHB.",
  "authors": [
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom",
        "School of Clinical Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong",
        "Joint first authors"
      ],
      "name": "Loey Lung-Yi Mak"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom",
        "Joint first authors"
      ],
      "name": "Corinna Pade"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom"
      ],
      "name": "Shue Xiong"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom"
      ],
      "name": "Chanelle Fernandes"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom"
      ],
      "name": "Yu Lei"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom"
      ],
      "name": "Gerard Hernandez-Mir"
    },
    {
      "affiliations": [
        "Department of Virology, Barts Health NHS Trust, London, United Kingdom"
      ],
      "name": "Anna Riddell"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom",
        "Department of Hepatology, Barts Health NHS Trust, London, United Kingdom"
      ],
      "name": "Apostolos Koffas"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Sebastian Deschler"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany"
      ],
      "name": "Katrin Böttcher"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom",
        "Department of Hepatology, Barts Health NHS Trust, London, United Kingdom",
        "Joint senior authors"
      ],
      "name": "Patrick Kennedy"
    },
    {
      "affiliations": [
        "Centre for Immunobiology & Infection, The Blizard Institute, Barts and The London Faculty of Medicine & Dentistry, QMUL, London, United Kingdom",
        "Department of Hepatology, Barts Health NHS Trust, London, United Kingdom",
        "Joint senior authors"
      ],
      "name": "Upkar Gill"
    }
  ],
  "title": "P83 Immunometabolic stress drives persistent bystander activation of innate-like CD8+ T cells and hepatocyte HBV transcription despite antiviral therapy",
  "uid": "82948697-5cd0-522d-bda5-20d5c7a8ec1f"
}