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End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas.

ABSTRACT: Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-gamma-producing T cells. The BALB/c-Tgfb1(-/-) mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-gamma-producing CD4(+) and CD8(+) T cells. Liver damage depends on the presence of an intact Ifng gene. We determined the relevant cellular source(s) of IFN-gamma. In Tgfb1(-/-) liver, CD4(+) T cells were more numerous than CD8(+) T cells and NK cells, and produced more IFN-gamma. Depletion of CD4(+) T cells eliminated both the elevation in plasma IFN-gamma and aspartate aminotransferase, whereas depletion of CD8(+) T cells did not. Rag1(-/-)Tgfb1(-/-) mice exhibited neither IFN-gamma elevation nor tissue damage, indicating that NK cells are not sufficient. IFN-gamma was required for strong overexpression of class II genes but not for CD4(+) T cell activation, oligoclonal expansion, or accumulation in the liver. The T cell inhibitory molecule PD-L1 was strongly expressed in Tgfb1(-/-) livers, ruling out a lack of PD-L1 expression as an explanation for aberrant liver T cell activation. Finally, whereas Tgfb1(-/-) CD4(+) T cells overexpressed Fas ligand, hepatocellular damage was observed in Fas(lpr/lpr)Tgfb1(-/-) mice, indicating that liver pathology is Fas independent. We conclude that liver damage in this model of fulminant autoimmune hepatitis is driven by CD4(+) T cell production of IFN-gamma, is independent of both CD8(+) T cells and the Fas ligand/Fas pathway, and is not explained by a lack of PD-L1 expression.

SUBMITTER: Robinson RT

PROVIDER: S-EPMC2764282 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas.

Robinson Richard T RT Wang Jing J Cripps James G JG Milks Michael W MW English Kathryn A KA Pearson Todd A TA Gorham James D JD

Journal of immunology (Baltimore, Md. : 1950) 20090301 5

Fulminant inflammation in the liver is often accompanied by the accumulation of IFN-gamma-producing T cells. The BALB/c-Tgfb1(-/-) mouse exhibits extensive, spontaneously developing necroinflammation in the liver, accompanied by the accumulation of IFN-gamma-producing CD4(+) and CD8(+) T cells. Liver damage depends on the presence of an intact Ifng gene. We determined the relevant cellular source(s) of IFN-gamma. In Tgfb1(-/-) liver, CD4(+) T cells were more numerous than CD8(+) T cells and NK c ...[more]

PMID: 19234226

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Project description:Pneumonia elicits the production of cytotoxic beta amyloid (Aβ) that contributes to end-organ dysfunction, yet the mechanism(s) linking infection to activation of the amyloidogenic pathway that produces cytotoxic Aβ is unknown. Here, we tested the hypothesis that gamma-secretase activating protein (GSAP), which contributes to the amyloidogenic pathway in the brain, promotes end-organ dysfunction following bacterial pneumonia. First-in-kind Gsap knockout rats were generated. Wild-type and knockout rats possessed similar body weights, organ weights, circulating blood cell counts, arterial blood gases, and cardiac indices at baseline. Intratracheal Pseudomonas aeruginosa infection caused acute lung injury and a hyperdynamic circulatory state. Whereas infection led to arterial hypoxemia in wild-type rats, the alveolar-capillary barrier integrity was preserved in Gsap knockout rats. Infection potentiated myocardial infarction following ischemia-reperfusion injury, and this potentiation was abolished in knockout rats. In the hippocampus, GSAP contributed to both pre- and postsynaptic neurotransmission, increasing the presynaptic action potential recruitment, decreasing neurotransmitter release probability, decreasing the postsynaptic response, and preventing postsynaptic hyperexcitability, resulting in greater early long-term potentiation but reduced late long-term potentiation. Infection abolished early and late long-term potentiation in wild-type rats, whereas the late long-term potentiation was partially preserved in Gsap knockout rats. Furthermore, hippocampi from knockout rats, and both the wild-type and knockout rats following infection, exhibited a GSAP-dependent increase in neurotransmitter release probability and postsynaptic hyperexcitability. These results elucidate an unappreciated role for GSAP in innate immunity and highlight the contribution of GSAP to end-organ dysfunction during infection.NEW & NOTEWORTHY Pneumonia is a common cause of end-organ dysfunction, both during and in the aftermath of infection. In particular, pneumonia is a common cause of lung injury, increased risk of myocardial infarction, and neurocognitive dysfunction, although the mechanisms responsible for such increased risk are unknown. Here, we reveal that gamma-secretase activating protein, which contributes to the amyloidogenic pathway, is important for end-organ dysfunction following infection.

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End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas.

Publications

End-organ damage in a mouse model of fulminant liver inflammation requires CD4+ T cell production of IFN-gamma but is independent of Fas.

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