Kupffer Cell-Dependent Hepatitis Occurs during Influenza Infection

Polakos, Noelle K.; Cornejo, Judith; Murray, Debbie; Wright, Kate O.; Treanor, John J.; Crispe, Ian Nicholas; Topham, David J.; Pierce, Robert H.

doi:10.2353/ajpath.2006.050875

Cited by 139 publications

(132 citation statements)

References 48 publications

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“…Furthermore, in several experiments, the percentage of IFN-␥ ϩ BAL cells exceeded the percentage of CD8 ϩ D b NP 366 tetramer ϩ cells, which may reflect pronounced TCR down-regulation, which in turn is indicative of a higher avidity interaction (74,75). The liver populations' reduced functional avidity or dampened sensitivity to peptide is consistent with the proposed tolerogenic role of the liver (23,25,26) and may help to protect against hepatic damage by activated CTL following influenza infection (20). Differences in the APC populations may have contributed to the reduced sensitivity to peptide recorded for the liver population.…”

Section: Discussionsupporting

confidence: 58%

“…Early studies pointed to the liver as a site for T cell contraction (10 -13) that is essential for the immune system to maintain homeostasis (14). Despite this protective capacity, antiviral CD8 ϩ T cells can also promote tissue destruction and exacerbate disease (15)(16)(17)(18), including the induction of hepatitis during influenza infection though there is no detectable viral Ag in the liver (19,20). Accordingly, programmed contraction and exhaustion of Ag-specific CD8 ϩ T cells during chronic infection may circumvent possible immunopathology.…”

Section: Irus Infections Induce the Expansion And Differentiationmentioning

confidence: 99%

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Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Keating

Yue

Rutigliano

et al. 2007

The Journal of Immunology

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Influenza A virus infection of C57BL/6 mice is a well-characterized model for studying CD8+ T cell-mediated immunity. Analysis of primary and secondary responses showed that the liver is highly enriched for CD8+ T cells specific for the immunodominant H2DbNP366–374 (DbNP366) epitope. Functional analysis established that these liver-derived virus-specific CD8+ T cells are fully competent cytotoxic effectors and IFN-γ secretors. In addition, flow cytometric analysis of early apoptotic cells showed that these influenza-specific CD8+ T cells from liver are as viable as those in the spleen, bronchoalveolar lavage, mediastinal lymph nodes, or lung. Moreover, cytokine profiles of the influenza-specific CD8+ T cells recovered from different sites were consistent with the bronchoalveolar lavage, rather than liver population, being the most susceptible to activation-induced cell death. Importantly, adoptively transferred influenza virus-specific CD8+ T cells from the liver survived and were readily recalled after virus challenge. Together, these results show clearly that the liver is not a “graveyard” for influenza virus-specific CD8+ T cells.

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Section: Discussionsupporting

confidence: 58%

Section: Irus Infections Induce the Expansion And Differentiationmentioning

confidence: 99%

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Keating

Yue

Rutigliano

et al. 2007

The Journal of Immunology

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“…In a primary influenza infection, virus-specific T-and B-cell responses are difficult to detect until 5 days after viral inoculation (39,46). Assuming that the contributions of the adaptive antibody and cellular responses of the immune system are negligible during this period, we used model 2 to fit the viral titer data during the first 5 days of infection.…”

Section: Resultsmentioning

confidence: 99%

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

Miao

Hollenbaugh

Zand

et al. 2010

J Virol

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350

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Seasonal and pandemic influenza A virus (IAV) continues to be a public health threat. However, we lack a detailed and quantitative understanding of the immune response kinetics to IAV infection and which biological parameters most strongly influence infection outcomes. To address these issues, we use modeling approaches combined with experimental data to quantitatively investigate the innate and adaptive immune responses to primary IAV infection. Mathematical models were developed to describe the dynamic interactions between target (epithelial) cells, influenza virus, cytotoxic T lymphocytes (CTLs), and virus-specific IgG and IgM. IAV and immune kinetic parameters were estimated by fitting models to a large data set obtained from primary H3N2 IAV infection of 340 mice. Prior to a detectable virus-specific immune response (before day 5), the estimated half-life of infected epithelial cells is ϳ1.2 days, and the half-life of free infectious IAV is ϳ4 h. During the adaptive immune response (after day 5), the average half-life of infected epithelial cells is ϳ0.5 days, and the average half-life of free infectious virus is ϳ1.8 min. During the adaptive phase, model fitting confirms that CD8 ؉ CTLs are crucial for limiting infected cells, while virus-specific IgM regulates free IAV levels. This may imply that CD4 T cells and class-switched IgG antibodies are more relevant for generating IAV-specific memory and preventing future infection via a more rapid secondary immune response. Also, simulation studies were performed to understand the relative contributions of biological parameters to IAV clearance. This study provides a basis to better understand and predict influenza virus immunity.

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“…In the influenza model, we found a focal transient hepatitis that was the consequence of intrahepatic accumulation of influenza-specific CD8 ϩ T cells (13). CD8…”

mentioning

confidence: 99%

Early Intrahepatic Accumulation of CD8+ T Cells Provides a Source of Effectors for Nonhepatic Immune Responses

Polakos

Klein

Richter

et al. 2007

The Journal of Immunology

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Interactions between the liver and CD8+ T cells can lead to tolerance, due in part to CD8+ T cell death. To test whether this was the case in an extrahepatic infection, we investigated the fate and effector capacity of intrahepatic CD8+ T cells during lung-restricted influenza infection in mice. Virus-specific T cells accumulated in livers without detectable intrahepatic presentation of viral Ags, and this accumulation was not restricted to the contraction phase, but was apparent as early as day 5. Intrahepatic influenza-specific cells were functionally similar to those recovered from the bronchioalveolar lavage, based on ex vivo cytokine production and specific target lysis. Both adoptive transfer of liver lymphocytes and orthotopic liver transplant of organs containing accumulated effector T cells revealed that activated CD8s from the liver were viable, expanded during reinfection, and generated a memory population that trafficked to lymphoid organs. Thus, intrahepatic CD8+ T cells re-enter circulation and generate functional memory, indicating that the liver does not uniformly incapacitate activated CD8+ T cells. Instead, it constitutes a substantial reservoir of usable Ag-specific effector CD8+ T cells involved in both acute and recall immune responses.

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Kupffer Cell-Dependent Hepatitis Occurs during Influenza Infection

Cited by 139 publications

References 48 publications

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

Quantifying the Early Immune Response and Adaptive Immune Response Kinetics in Mice Infected with Influenza A Virus

Early Intrahepatic Accumulation of CD8+ T Cells Provides a Source of Effectors for Nonhepatic Immune Responses

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