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Nat Commun. 2018 Jul 9;9(1):2650. doi: 10.1038/s41467-018-05026-6.

TCR signal strength controls thymic differentiation of iNKT cell subsets.

Author information

1
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, Aurora, CO, 80045, USA.
2
Department of Biomedical Research, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA.
3
Department of Oncology, University of Lausanne, Chemin des Boveresses 155, Epalinges, 1066, Switzerland.
4
Center for Genes, Environment, and Health, Department of Biomedical Research, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA.
5
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, 80206, CO, USA.
6
ARUP Laboratories, Institute of Clinical and Experimental Pathology, 500 Chipeta Way, Salt Lake City, 84108, UT, Switzerland.
7
Department of Pathology, University of Utah, 30N 1900E, Salt Lake City, 84132, UT, USA.
8
Merck Research Laboratories, San Francisco, CA, USA.
9
RNA Bioscience Initiative, University of Colorado School of Medicine, 12800 E. 19th Ave, Aurora, 80045, CO, USA.
10
Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine, 12800 E. 19th Ave, Aurora, CO, 80045, USA.
11
La Jolla Institute, 9420 Athena Cir, La Jolla, 92037, CA, USA.
12
Sanford Consortium for Regenerative Medicine, 2880 Torrey Pines Scenic Dr, La Jolla, CA, 92037, USA.
13
University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
14
Department of Medicine, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, Aurora, CO, 80045, USA.
15
Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, 12800 E. 19th Ave, Aurora, CO, 80045, USA. Laurent.Gapin@ucdenver.edu.
16
Department of Biomedical Research, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA. Laurent.Gapin@ucdenver.edu.

Abstract

During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells.

PMID:
29985393
PMCID:
PMC6037704
DOI:
10.1038/s41467-018-05026-6
[Indexed for MEDLINE]
Free PMC Article

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