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

AK Singh, A Eken, M Fry, E Bettelli, M Oukka - Nature communications, 2014 - nature.com
AK Singh, A Eken, M Fry, E Bettelli, M Oukka
Nature communications, 2014nature.com
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 …
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.
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