Altered thymic differentiation and modulation of arthritis by invariant NKT cells expressing mutant ZAP70

Meng Zhao, Mattias N. D. Svensson, Koen Venken, Ashu Chawla, Shu Liang, Isaac Engel, Piotr Mydel, Jeremy Day, Dirk Elewaut, Nunzio Bottini () and Mitchell Kronenberg ()
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Meng Zhao: La Jolla Institute for Allergy and Immunology
Mattias N. D. Svensson: La Jolla Institute for Allergy and Immunology
Koen Venken: Ghent University
Ashu Chawla: La Jolla Institute for Allergy and Immunology
Shu Liang: La Jolla Institute for Allergy and Immunology
Isaac Engel: La Jolla Institute for Allergy and Immunology
Piotr Mydel: University of Bergen
Jeremy Day: La Jolla Institute for Allergy & Immunology
Dirk Elewaut: Ghent University
Nunzio Bottini: La Jolla Institute for Allergy and Immunology
Mitchell Kronenberg: La Jolla Institute for Allergy and Immunology

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Various subsets of invariant natural killer T (iNKT) cells with different cytokine productions develop in the mouse thymus, but the factors driving their differentiation remain unclear. Here we show that hypomorphic alleles of Zap70 or chemical inhibition of Zap70 catalysis leads to an increase of IFN-γ-producing iNKT cells (NKT1 cells), suggesting that NKT1 cells may require a lower TCR signal threshold. Zap70 mutant mice develop IL-17-dependent arthritis. In a mouse experimental arthritis model, NKT17 cells are increased as the disease progresses, while NKT1 numbers negatively correlates with disease severity, with this protective effect of NKT1 linked to their IFN-γ expression. NKT1 cells are also present in the synovial fluid of arthritis patients. Our data therefore suggest that TCR signal strength during thymic differentiation may influence not only IFN-γ production, but also the protective function of iNKT cells in arthritis.

Date: 2018
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DOI: 10.1038/s41467-018-05095-7

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