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TCR signal strength controls thymic differentiation of iNKT cell subsets

Author

Listed:
  • Kathryn D. Tuttle

    (University of Colorado Anschutz Medical Campus
    National Jewish Health)

  • S. Harsha Krovi

    (University of Colorado Anschutz Medical Campus
    National Jewish Health)

  • Jingjing Zhang

    (University of Colorado Anschutz Medical Campus
    National Jewish Health)

  • Romain Bedel

    (University of Colorado Anschutz Medical Campus
    National Jewish Health
    University of Lausanne)

  • Laura Harmacek

    (National Jewish Health
    National Jewish Health)

  • Lisa K. Peterson

    (National Jewish Health
    Institute of Clinical and Experimental Pathology
    University of Utah)

  • Leonard L. Dragone

    (National Jewish Health
    Merck Research Laboratories)

  • Adam Lefferts

    (University of Colorado Anschutz Medical Campus
    National Jewish Health)

  • Catherine Halluszczak

    (University of Colorado Anschutz Medical Campus
    National Jewish Health)

  • Kent Riemondy

    (University of Colorado School of Medicine)

  • Jay R. Hesselberth

    (University of Colorado School of Medicine
    University of Colorado School of Medicine)

  • Anjana Rao

    (La Jolla Institute
    Sanford Consortium for Regenerative Medicine
    University of California San Diego)

  • Brian P. O’Connor

    (National Jewish Health
    National Jewish Health)

  • Philippa Marrack

    (University of Colorado Anschutz Medical Campus
    National Jewish Health
    University of Colorado Anschutz Medical Campus)

  • James Scott-Browne

    (La Jolla Institute
    Sanford Consortium for Regenerative Medicine)

  • Laurent Gapin

    (University of Colorado Anschutz Medical Campus
    National Jewish Health)

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.

Suggested Citation

  • 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. Hesselbert, 2018. "TCR signal strength controls thymic differentiation of iNKT cell subsets," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05026-6
    DOI: 10.1038/s41467-018-05026-6
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    Cited by:

    1. Ludivine Amable & Luis Antonio Ferreira Martins & Remi Pierre & Marcio Cruseiro & Ghita Chabab & Arnauld Sergé & Camille Kergaravat & Marc Delord & Christophe Viret & Jean Jaubert & Chaohong Liu & Sao, 2023. "Intrinsic factors and CD1d1 but not CD1d2 expression levels control invariant natural killer T cell subset differentiation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Ivy K Brown & Nathan Dyjack & Mindy M Miller & Harsha Krovi & Cydney Rios & Rachel Woolaver & Laura Harmacek & Ting-Hui Tu & Brian P O’Connor & Thomas Danhorn & Brian Vestal & Laurent Gapin & Clemenci, 2021. "Single cell analysis of host response to helminth infection reveals the clonal breadth, heterogeneity, and tissue-specific programming of the responding CD4+ T cell repertoire," PLOS Pathogens, Public Library of Science, vol. 17(6), pages 1-34, June.

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