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Nat Commun. 2018 Jul 6;9(1):2627. doi: 10.1038/s41467-018-05095-7.

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

Author information

1
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
2
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
3
Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA.
4
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000, Ghent, Belgium.
5
VIB Inflammation Research Center, Ghent University, B-9000, Ghent, Belgium.
6
Bioinformatics Core Facility, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
7
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
8
Department of Clinical Science, University of Bergen, Bergen, N-5021, Norway.
9
Department of Microbiology, Jagiellonian University, Krakow, 30-387, Poland.
10
NGS facility, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA.
11
Division of Cellular Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA. nbottini@ucsd.edu.
12
Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA. nbottini@ucsd.edu.
13
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA. mitch@lji.org.
14
Division of Biological Sciences, University of California San Diego, La Jolla, CA, 92037, USA. mitch@lji.org.

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.

PMID:
29980684
PMCID:
PMC6035278
DOI:
10.1038/s41467-018-05095-7
[Indexed for MEDLINE]
Free PMC Article

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