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

Akhilesh K. Singh, Ahmet Eken, Mallory Fry, Estelle Bettelli and Mohamed Oukka ()
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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

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5603

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