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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.
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1 Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Biomedical Research, National Jewish Health, Denver, CO, USA
2 Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Biomedical Research, National Jewish Health, Denver, CO, USA; Department of Oncology, University of Lausanne, Epalinges, Switzerland
3 Center for Genes, Environment, and Health, Department of Biomedical Research, National Jewish Health, Denver, CO, USA; Department of Pediatrics, National Jewish Health, Denver, CO, USA
4 Department of Pediatrics, National Jewish Health, Denver, CO, USA; ARUP Laboratories, Institute of Clinical and Experimental Pathology, Salt Lake City, UT, Switzerland; Department of Pathology, University of Utah, Salt Lake City, UT, USA
5 Department of Pediatrics, National Jewish Health, Denver, CO, USA; Merck Research Laboratories, San Francisco, CA, USA
6 RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA
7 RNA Bioscience Initiative, University of Colorado School of Medicine, Aurora, CO, USA; Department of Biochemistry & Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
8 La Jolla Institute, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA; University of California San Diego, La Jolla, CA, USA
9 Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Biomedical Research, National Jewish Health, Denver, CO, USA; Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
10 La Jolla Institute, La Jolla, CA, USA; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA