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Platelets mediate cytotoxic T lymphocyte–induced liver damage

Abstract

We found that platelet depletion reduces intrahepatic accumulation of virus-specific cytotoxic T lymphocytes (CTLs) and organ damage in mouse models of acute viral hepatitis. Transfusion of normal but not activation-blocked platelets in platelet-depleted mice restored accumulation of CTLs and severity of disease. In contrast, anticoagulant treatment that prevented intrahepatic fibrin deposition without reducing platelet counts did not avert liver injury. Thus, activated platelets contribute to CTL-mediated liver immunopathology independently of procoagulant function.

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Figure 1: Activated platelets enhance intrahepatic accumulation of CTLs and severity of liver disease in HBV transgenic mice independently of fibrin deposition.
Figure 2: Platelet depletion ameliorates liver disease in adenovirus-infected mice and reduces the intrahepatic accumulation of virus-specific CTLs.

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Acknowledgements

We are grateful to S. Wieland for providing the pCMV-lacZ plasmid and for discussions. We also thank S. Medrano and M. Chadwell for technical assistance. This work was supported by US National Institutes of Health grants HL31950, HL42846, HL78784 (to Z.M.R.), CA40489 (to F.V.C.) and AI40696 (to L.G.G.). Work in the Board of Governors Gene Therapy Research Institute is funded by the Board of Governors at Cedars-Sinai Medical Center, the US National Institutes of Health and the Bram and Elaine Goldsmith Chair in Gene Therapeutics. This is manuscript number 16807-MEM from the Scripps Research Institute.

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Correspondence to Luca G Guidotti.

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Supplementary information

Supplementary Fig. 1

Platelets accumulate within necroinflammatory foci of the liver. (PDF 2379 kb)

Supplementary Fig. 2

Reduced levels of IFN-γ expression and inhibition of viral replication reflect the homing of fewer but functional CTLs in the liver of thrombocytopenic HBV transgenic mice. (PDF 412 kb)

Supplementary Fig. 3

TKK-PLTs are recognized by α-PLT both in vitro and in vivo. (PDF 845 kb)

Supplementary Fig. 4

Restoration of liver disease severity, CTL accumulation and intrahepatic IFN-γ expression in platelet-depleted mice upon TKK-PLT transfusion. (PDF 727 kb)

Supplementary Fig. 5

Platelet-dependent fibrin deposition within the inflamed liver. (PDF 2428 kb)

Supplementary Table 1

α-PLT treatment selectively depletes platelets in vivo. (PDF 20 kb)

Supplementary Video 1

CTLs interact with activated platelets in vitro. (MOV 41155 kb)

Supplementary Methods (PDF 65 kb)

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Iannacone, M., Sitia, G., Isogawa, M. et al. Platelets mediate cytotoxic T lymphocyte–induced liver damage. Nat Med 11, 1167–1169 (2005). https://doi.org/10.1038/nm1317

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