Tissue Determinants of Antiviral Immunity in the Liver

Abstract

The liver is an organ bearing important metabolic and immune functions. Hepatocytes are the main metabolically active cells of the liver and are the target of infection by hepatotropic viruses. Virus-specific CD8 T cells are essential for the control of hepatocyte infection with hepatotropic viruses but may be subject to local regulation of their effector function. Here, we review our current knowledge of the tissue determinants of antiviral immunity in the liver. Liver Sinusoidal Endothelial Cells (LSECs) not only allow through their fenestrations the access of circulating virus-specific CD8 T cells to engage in direct contact with infected hepatocytes without the need for extravasation but also cross-present viral antigens released from infected hepatocytes to these CD8 T cells. Two important features of LSECs and hepatocytes contribute to antiviral immune surveillance and liver failure. First, CD8 T cell immunity targeting LSECs leads to widespread endothelial cell death and results in sinusoidal microcirculation failure, causing fulminant viral hepatitis, whereas immune-mediated loss of hepatocytes is rapidly compensated by the regenerative capacity of the liver. Second, virus-infected hepatocytes support clearance of infection by responding to TNF, which is released from virus-specific CD8 T cells, with the selective induction of apoptosis. This increased sensitivity for TNF-induced death is caused by reduced mitochondrial resilience in virus-infected hepatocytes and may assist antiviral immunity in preferential targeting of virus-infected hepatocytes. Thus, hepatocytes and LSECs actively contribute to the outcome of antiviral CD8 T cell immunity in the liver. The knowledge of the mechanisms determining CD8 T cell control of hepatotropic viral infection will help to improve strategies to increase antiviral immune surveillance.

Zusammenfassung

Die Leber ist ein Organ mit wichtigen Stoffwechsel- und Immunfunktionen. Hepatozyten, die Parenchymzellen der Leber, sind die stoffwechselaktiven Zellen und das Ziel der Infektion von hepatotropen Viren. Virus-spezifische CD8-T-Zellen sind für die Kontrolle dieser Virus-Infektionen unerlässlich, ihre Effektorfunktion ist jedoch einer lokalen Regulation unterlegen. In diesem Review fassen wir den aktuellen Wissenstand über die Mechanismen der Regulation der Immunantworten zusammen. Sinusoidale Endothelzellen der Leber (LSEC = Liver Sinusoidal Endothelial Cells) ermöglichen durch ihre Fenestrae nicht nur den Zugang zirkulierender virus-spezifischer CD8-T-Zellen zu Hepatozyten, ohne dass eine Extravasation erforderlich ist. Sie kreuz-präsentieren auch virale Antigene, welche von infizierten Hepatozyten sezerniert wurden, an CD8-T-Zellen. Zwei wichtige Eigenschaften von LSEC und Hepatozyten tragen zur Immunüberwachung und zum Leberversagen bei. Erstens führt eine gegen LSEC gerichtete CD8-T-Zell-Immunantwort zu einem Absterben der Endothelzellen und in dessen Verlauf zu einem Versagen der hepatischen Mikrozirkulation, was zu einer fulminanten Virushepatitis führt, während der immunvermittelte Verlust von Hepatozyten durch die Regenerationsfähigkeit der Leber kompensiert wird. Zweitens unterstützen Virus-infizierte Hepatozyten die Beseitigung der Infektion, indem sie auf TNF, welches von Virus-spezifischen CD8-T-Zellen sezerniert wird, mit der spezifischen Induktion von Apoptose reagieren. Diese erhöhte Sensitivität gegenüber TNF-induziertem Zelltod virusinfizierter Hepatozyten wird durch eine verringerte mitochondriale Resilienz verursacht und kann die Effizienz der antiviralen Immunität fördern. Hepatozyten und LSEC spielen somit eine aktive Rolle während der antiviralen Immunität in der Leber. Eine genaue Kenntnis über die Mechanismen, welche die CD8-T-Zell-Effektorfunktion gegen eine Virusinfektion der Leber regulieren, kann dazu beitragen, Strategien zur Verbesserung der antiviralen Immunität zu verbessern.

Keywords

Liver - Hepatitis - CD8 T cells - HBV

Schlüsselwörter

Leber - Hepatitis - CD8 T Zellen - HBV

Publication History

Received: 04 September 2024

Accepted after revision: 13 November 2024

Article published online:
10 January 2025

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