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DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs

Author

Listed:
  • Akhilesh K. Singh

    (Center for Immunity and Immunotherapies, Seattle Children’s Research Institute)

  • Ahmet Eken

    (Center for Immunity and Immunotherapies, Seattle Children’s Research Institute)

  • Mallory Fry

    (Center for Immunity and Immunotherapies, Seattle Children’s Research Institute)

  • Estelle Bettelli

    (Benaroya Research Institute, Immunology Program)

  • Mohamed Oukka

    (Center for Immunity and Immunotherapies, Seattle Children’s Research Institute
    University of Washington)

Abstract

Retinoic acid receptor-related orphan receptor-γt-positive (RORγt+) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt+ ILCs is not thoroughly understood. Here, we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt+ ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt+ ILCs are less responsive to IL-7 mediated signalling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt+ ILCs.

Suggested Citation

  • Akhilesh K. Singh & Ahmet Eken & Mallory Fry & Estelle Bettelli & Mohamed Oukka, 2014. "DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5603
    DOI: 10.1038/ncomms5603
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