Oscillating CD8+ T Cell Effector Functions after Antigen Recognition in the Liver
Open accessAbstract
When hepatitis B virus (HBV)-specific CD8(+) cytotoxic T lymphocytes (CTLs) are adoptively transferred into HBV transgenic mice, they enter the liver, recognize antigen, secrete interferon gamma (IFNgamma), inhibit viral replication, and kill their target cells, causing hepatitis. In the current study, we examined the impact of antigen recognition on the evolution of the activation phenotype, antiviral effector functions, expansion and contraction kinetics, and compartmentalization of the transferred CTLs. The results reveal that noncytolytic and cytolytic effector functions and expansion-contraction kinetics of the CTLs are regulated asynchronously and in an oscillatory manner as a consequence of antigen recognition in the liver and in association with PD-1 upregulation. We suggest that such oscillations maximize viral clearance and minimize tissue injury during HBV infection and that poor coordination of these events could lead to viral persistence and chronic liver disease.
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Following presentation of viral antigens coupled to MHC class I molecules by infected hepatocytes, virus-specific CTLs clear hepatitis viruses by both cytolytic and non-cytolytic effector functions.
“Following presentation of viral antigens coupled to MHC class I molecules by infected hepatocytes, virus-specific CTLs are able to clear hepatitis viruses by means of both cytolytic and non-cytolytic effector functions (182-184).”
From The liver as a central "hub" of the immune system: pathophysiological implications (2025) · cites this paper as [183]
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Rejuvenating exhausted T cells during chronic viral infection.
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“Because PD-1 expression is observed at the same time as the emergence of granzyme B-positive T cells and persists after the disappearance of viral gene expression at day 7, PD-1 is thought to regulate the oscillatory response of HBV-specific CD8 T cells (Isogawa et al., 2005).”
BackgroundMartin, C. M., Welge, J. A., Shire, N. J., Shata, M. T. M., Sherman, K. E., & Blackard, J. T. (2009) · Cytokine · doi:10.1016/j.cyto.2009.06.005 · Cited by 40 · see citing works
“Several factors could be involved in the development of chronic HBV infection [1], including: (1) CD8+ T-cell exhaustion or partial tolerance [10]; (2) decreased CD4+ T-cell responsiveness through dendritic cell (DC) impairment [11,12] or increased PD-1 expression [2,13]; (3) impairment of innate immune responses thro…”
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“Chronic HBV– infected children may enter their inflammatory phase and develop spontaneous HBeAg seroconversion shortly after the onset of puberty (10,11,21,22).”
BackgroundCTLA‑4 interferes with the HBV‑specific T�cell immune response (Review)
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“Upon detachment from platelets, the effector CD8+ T cells crawl intrasinusoidally, irrespective of the direction of the blood flow, and probe the underlying hepatocytes for the presence of antigen by extending filopodia‐like protrusions through the sinusoidal fenestrae (15).”
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“Sustained recognition of HBsAg derived from cccDNA or integration of the viral genome into the host genome is the mechanism that mediates chronic liver injury induced by CD8+ T cells [76].”
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“have shown in an in vivo model of HBV infection that effector T cells can change their cytolytic or non-cytolytic function after recognition of antigen presented by hepatocytes [70].”
BackgroundHBsAg-specific CD8+ T cells as an indispensable trigger to induce murine hepatocellular carcinoma
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Mouse Models of Hepatitis B Virus Pathogenesis.Preprint
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“, killing of hepatocytes) potential of intrahepatic virus-specific effector CD8þ T cells is likely impaired in chronically infected patients (Isogawa et al. 2005).”
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Success and Failure of Virus-Specific T Cell Responses in Hepatitis C Virus Infection
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“Based on these observations, a role of PD-1 in T cell dysfunction has been established in many viral infections, including human immunodeficiency virus and hepatitis B virus [ ,”
BackgroundThe new nano-complex, Hep-c, improves the immunogenicity of the hepatitis B vaccine.
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Hepatitis B virus: from immunobiology to immunotherapy
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Determinants of hepatic effector CD8+ T cell dynamics.
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“A variable antigen burden can induce an oscillation cycle on which antiviral effector activities may be activated and suppressed alternatively (12).”
BackgroundLin, C.-Y., Tsai, M.-C., Huang, C.-H., Hsu, C.-W., Tseng, S., Tsai, I.-F., Chen, Y.-C., Yeh, C.-T., Sheen, I.-S., & Chien, R.-N. (2007) · Journal of Viral Hepatitis · doi:10.1111/j.1365-2893.2006.00835.x · Cited by 30
Progress of research on PD-1/PD-L1 in leukemia
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Human Adenovirus Associated Hepatic Injury
Zheng, N.-X., Wang, Y., Rong, H.-C., Wang, K., & Huang, X.-P. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.878161 · Cited by 28
“This is in accordance with other liver infection models, where the emergence of hepatocyte injury is related to the obtainment of the effector function via CD8+ T-cells (45).”
ResultChen, Y., Wang, Y., Luo, H., Meng, X., Zhu, W., Wang, D., Zeng, H., & Zhang, H. (2020) · Experimental Hematology and Oncology · doi:10.1186/s40164-020-00173-3 · Cited by 58 · see citing works
- Authors
- Isogawa, M., Furuichi, Y., & Chisari, F. V.
- Affiliations
- Scripps Research Institute (US)
- Corresponding author
- Chisari, Francis V.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2005-07
- Volume
- 23
- Issue
- 1
- Pages
- 53-63
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2047908014
- Cited by
- 186
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 7 · 2015: 9 · 2014: 11 · 2013: 11 · 2012: 11
- FWCI
- 10.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2974 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA40489)
- Topics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- hepatitis B virus, CD8+ cytotoxic T lymphocytes, antigen recognition, PD-1, interferon-gamma, viral clearance, liver, chronic hepatitis B, viral persistence, chronic liver disease, HBV transgenic mice
- MeSH terms
- Animals, Hepatitis B, Hepatitis B Surface Antigens, Immunologic Memory, Interferon-gamma, Liver, Mice, Transgenic, Receptors, Antigen, T-Cell, Serine Endopeptidases, Spleen, T-Lymphocytes, Cytotoxic, Viral Envelope Proteins, Adoptive Transfer, Mice, Granzymes
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