TCR signal strength controls thymic differentiation of iNKT cell subsets

Kathryn D. Tuttle, S. Harsha Krovi, Jingjing Zhang, Romain Bedel, Laura Harmacek, Lisa K. Peterson, Leonard L. Dragone, Adam Lefferts, Catherine Halluszczak, Kent Riemondy, Jay R. Hesselberth, Anjana Rao, Brian P. O’Connor, Philippa Marrack, James Scott-Browne and Laurent Gapin ()
Additional contact information
Kathryn D. Tuttle: University of Colorado Anschutz Medical Campus
S. Harsha Krovi: University of Colorado Anschutz Medical Campus
Jingjing Zhang: University of Colorado Anschutz Medical Campus
Romain Bedel: University of Colorado Anschutz Medical Campus
Laura Harmacek: National Jewish Health
Lisa K. Peterson: National Jewish Health
Leonard L. Dragone: National Jewish Health
Adam Lefferts: University of Colorado Anschutz Medical Campus
Catherine Halluszczak: University of Colorado Anschutz Medical Campus
Kent Riemondy: University of Colorado School of Medicine
Jay R. Hesselberth: University of Colorado School of Medicine
Anjana Rao: La Jolla Institute
Brian P. O’Connor: National Jewish Health
Philippa Marrack: University of Colorado Anschutz Medical Campus
James Scott-Browne: La Jolla Institute
Laurent Gapin: University of Colorado Anschutz Medical Campus

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05026-6

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