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TPL2 Kinase Is a Crucial Signaling Factor and Mediator of NKT Effector Cytokine Expression in Immune-Mediated Liver Injury

Lookup NU author(s): Professor Fiona OakleyORCiD, Dr Maria Perugorria, Professor Derek Mann


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Invariant NKT (iNKT) cells represent a subset of innate-like T lymphocytes that function as orchestrators of hepatic inflammation underpinning liver damage. In this study, we demonstrate that TPL2, an MAP3 kinase that has mostly been appreciated for its physiological role in macrophage responses, is a signaling factor in CD3(+)NK1.1(+)iNKT cells and mediator of hepatic inflammation. Genetic ablation of TPL2 in the mouse ameliorates liver injury induced by Con A and impinges on hallmarks of NKT cell activation in the liver without affecting NKT cell development in the thymus. The pivotal role of TPL2 in iNKT cell functions is further endorsed by studies using the iNKT-specific ligand a-galactosylceramide, which causes mild hepatitis in the mouse in a TPL2-dependent manner, including production of the effector cytokines IL-4 and IFN-gamma, accumulation of neutrophils and licensing and activation of other immune cell types in the liver. A TPL2 kinase inhibitor mirrors the effects of genetic ablation of TPL2 in vivo and uncovers ERK and Akt as the TPL2-regulated signaling pathways responsible for IL-4 and IFN-gamma expression through the activation of the transcription factors JunB and NFAT. Collectively, these findings expand our understanding of the mechanisms of iNKT cell activation and suggest that modulation of TPL2 has the potential to minimize the severity of immune-driven liver diseases.

Publication metadata

Author(s): Vyrla D, Nikolaidis G, Oakley F, Perugorria MJ, Tsichlis PN, Mann DA, Eliopoulos AG

Publication type: Article

Publication status: Published

Journal: Journal of Immunology

Year: 2016

Volume: 196

Issue: 10

Pages: 4298-4310

Print publication date: 15/05/2016

Online publication date: 06/04/2015

Acceptance date: 26/02/2016

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists


DOI: 10.4049/jimmunol.1501609


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Funder referenceFunder name
Greek national funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework
research funding program Heracleitus II
University of Crete Maria Manassaki Bequest Scholarship
European Union (European Social Fund)
223151European Commission research program Inflammation and Cancer Research in Europe
285948European Commission